Association of JAK2V617F allele burden and clinical correlates in polycythemia vera: a systematic review and meta-analysis.

Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan.

OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

[Analysis of the factors influencing the severity of coronavirus disease 2019 in patients with myeloproliferative neoplasms based on an online questionnaire].

Objective: To explore the variables associated with the severity of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 omicron variant during the epidemic in patients with myeloproliferative neoplasms (MPN). Methods: A cross-sectional study. During the SARS-CoV-2 omicron variant pandemic from December 15, 2022, to March 15, 2023, COVID-19 related data for patients with MPN who were treated at Peking University People's Hospital were collected through an online questionnaire-based survey. All questionnaires and clinical data were checked by medical assistants. Logistic multivariate analysis was used to explore the prevalence and variables associated with the severity of COVID-19 in patients with MPN. Results: A total of 239 patients with MPN, including 90 (37.7%) presenting with essential thrombocythemia (ET), 50 (20.9%) with polycythemia vera (PV), and 99 (41.4%) with myelofibrosis (MF), were enrolled in the study. The 99 patients with MF included 87 (87.9%) with primary MF, 5 (5.1%) with post-PV MF, and 7 (7.1%) with post-ET MF. Overall, 239 (100%) patients reported that they experienced COVID-19 during the pandemic. Of these, 226 (94.6%) had mild disease, 4 (1.7%) had moderate disease, 7 (2.9%) had severe disease, and 2 (0.8%) had critical disease. Two (0.8%) patients with severe COVID-19 died, one of which suffered from MT and the other from PV. Multivariate analysis showed that older age (OR=2.36, 95%CI 1.24-4.49), MF (OR=10.22, 95%CI 1.13-92.80), or comorbidity (OR=5.25, 95%CI 1.25-22.03) were associated with a significantly higher risk of developing moderate, severe, or critical COVID-19. Among patients with MF, higher risk stratification reflected an increased risk of developing moderate, severe, or critical COVID-19 (P=0.034). Conclusion: During the omicron pandemic, older age, MF (especially higher-risk categories), and comorbidity were associated with a higher risk of developing moderate, severe, or critical COVID-19.

Exploring hematological alterations and genetics linked to SNV rs10974944 in myeloproliferative neoplasms among Amazon patients.

BCR::ABL1-negative myeloproliferative neoplasms are hematopoietic disorders characterized by panmyelosis. JAK2 V617F is a frequent variant in these diseases and often occurs in the 46/1 haplotype. The G allele of rs10974944 has been shown to be associated with this variant, specifically its acquisition, correlations with familial cases, and laboratory alterations. This study evaluated the association between the 46/1 haplotype and JAK2 V617F in patients with myeloproliferative neoplasms in a population from the Brazilian Amazon. Clinical, laboratory and molecular sequencing analyses were considered. Carriers of the G allele of rs10974944 with polycythemia vera showed an increase in mean corpuscular volume and mean corpuscular hemoglobin, while in those with essential thrombocythemia, there was an elevation in red blood cells, hematocrit, and hemoglobin. Associations were observed between rs10974944 and the JAK2 V617F, in which the G allele (OR 3.4; p < 0.0001) and GG genotype (OR 4.9; p = 0.0016) were associated with JAK2 V617F + and an increase in variant allele frequency (GG: OR 15.8; p = < 0.0001; G: OR 6.0; p = 0.0002). These results suggest an association between rs10974944 (G) and a status for JAK2 V617F, JAK2 V617F + _VAF ≥ 50%, and laboratory alterations in the erythroid lineage.

Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: the "RAMP" Italian multicenter prospective study.

Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.

Updated threshold, renewed problems: should the diagnostic criteria of polycythemia vera be reconsidered? A retrospective cross-sectional cohort study.

OBJECTIVE: This aim of this study was to evaluate hemoglobin and hematocrit values of polycythemia vera and secondary polycythemia patients with updated World Health Organization thresholds. In addition, by determining our own threshold values, we aimed to demonstrate the necessity of bone marrow biopsy and genetic analysis to be used for further diagnosis in patients with high-normal hematocrit and hemoglobin values. METHODS: A cross-sectional and retrospective study was performed with the medical records of patients from Eskisehir City Hospital hematology clinics and outpatient clinics between July 1, 2019 and July 1, 2020. The study included patients with polycythemia, divided into two groups according to polycythemia vera and secondary polycythemia. A bone marrow biopsy was performed on patients with either Janus kinase mutation positivity and/or subnormal erythropoietin levels. Receiver operating characteristics analysis was used to find threshold values, and the diagnostic efficiency of these values in differentiating World Health Organization thresholds in 2008 and 2016 was evaluated. RESULTS: A total of 73 patients were included. The median age was 43.5 years (min: 18; max: 84). The hematocrit value of 54.1 was predicted to diagnose polycythemia vera with a sensitivity of 45% and a specificity of 80%. Subsequent analysis revealed that an hemoglobin value of 17.7 was indicative of diagnosing polycythemia vera with a sensitivity of 60% and a specificity of 63%. The mean follow-up length was 6.4 months (2-12). CONCLUSION: Our study demonstrated that modified World Health Organization criteria might lead to unnecessary additional tests for polycythemia vera patients with high-normal hemoglobin and hematocrit values.

Extensive Hepatic Infarction due to Polycythemia Vera.

Polycythemia vera (PV) is one of the three BCR-ABL1-negative myeloproliferative neoplasms characterized by activating mutations in JAK2, which clinically presents as erythrocytosis and has an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia. Splanchnic vein thrombosis is a rare manifestation of venous thromboembolism involving one or more abdominal vessels and is strongly associated with PV. We herein report a case in which hepatic infarction due to PV was saved by conservative treatment.

Risk of thrombosis, hemorrhage and leukemic transformation in patients with myeloproliferative neoplasms: A nationwide longitudinal cohort study.

INTRODUCTION: There are few large-scale, population-based studies detailing the risks of thrombosis, hemorrhage, leukemic transformation in patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). METHODS: We performed a nationwide longitudinal cohort study using the Korean National Health Insurance System (NHIS) database. MPN patients (n = 11,991) and their 1:4 age- and sex-matched controls (n = 47,964) were enrolled. The risk of thrombosis, hemorrhage, leukemic transformation was estimated using a Cox proportional hazards regression, and stratified analyses were performed for related factors. RESULTS: During a median of 7.8 years of follow-up, 30.1 % of MPN patients (3614/11,991) and 19.0 % of the matched controls (9141/47,964) developed arterial thrombosis, 11.6 % of MPN patients (1397/11,991) and 6.4 % of the matched controls (3099/47,964) developed venous thrombosis and 18.7 % of MPN patients (2251/11,991) and 12.1 % of the matched controls (5836/47,964) developed hemorrhage. 4.9 % of MPN patients (597/11,991) and 0.1 % of matched controls (50/47,964) developed leukemia. The overall risk of developing thrombosis, hemorrhage, leukemic transformation was higher in MPN patients (adjusted hazard ratio [aHR] 1.695, 95 % confidence interval [CI]: 1.629-1.765 for arterial thrombosis, aHR 1.963, 95 % CI: 1.838-2.096 for venous thrombosis, and aHR 1.714, 95 % CI: 1.630-1.802 for hemorrhage) than in the controls. Patients with MPNs had a 10-year cumulative incidence of leukemic transformation of 6.2 %. CONCLUSION: The patients with MPNs have a higher risk of thrombosis, hemorrhage, and leukemic transformation than matched controls. Strategies are warranted to reduce the risk of thrombosis, hemorrhage, and leukemic transformation in MPN patients.

In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone-deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight-treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109 /L, WBC ≤10 × 109 /L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.

Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics. We investigated NLR on mortality stratified by prevalent and incident MPN, essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), comorbidity burden (CCI-score), and the Triple-A risk score using hazard ratio (HR) and 95% confidence interval (95%CI). NLR 1-1.9 was the reference level. During a median follow-up of 11.2 years, 197,802 deaths were recorded. All-cause mortality increased for a stepwise increasing NLR with a HR (95%CI) for NLR ≥ 6 of 2.06(2.03-2.09) for the whole population and 2.93(2.44-3.50) in prevalent MPN. ET, PV, and MF had a HR (95%CI) for NLR ≥ 2 of 2.14(1.71-2.69), 2.19(1.89-2.54), and 2.31(1.91-2.80). Results were similar for incident MPN. Mortality was higher for stepwise increasing NLR and CCI-score(pinteraction < 2×10-16), with a HR for NLR ≥ 6 of 2.23(2.17-2.29), 4.10(4.01-4.20), and 7.69(7.50-7.89), for CCI-score 0, 1-2, or ≥3. The Triple-A risk score demonstrated alignment with NLR. Increasing NLR and comorbidity burden were associated with lower survival in individuals without MPN but were even worse in prevalent and incident MPN, ET, PV, and MF.

Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Clinical Features and Long-Term Outcomes of a Pan-Canadian Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms: A Canadian MPN Group Study.

Myeloproliferative neoplasms (MPNs) are a group of chronic hematologic malignancies that lead to morbidity and early mortality due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs and are used commonly to guide therapeutic decisions, including allogenic stem cell transplant, in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively examined in this population. We conducted a retrospective review of patients evaluated at eight Canadian centers for MPN patients diagnosed at ≤45 years of age. In total, 609 patients were included in the study, with median overall survival of 36.8 years. Diagnosis of prefibrotic or overt PMF is associated with the lowest OS and highest risk of AP/BP transformation. Thrombotic complications (24%), including splanchnic circulation thrombosis (9%), were frequent in the cohort. Mutations in addition to those in JAK2/MPL/CALR are uncommon in the initial disease phase in our AYA population (12%); but our data indicate they may be predictive of transformation to post-ET/PV myelofibrosis.

Broad Next-Generation Integrated Sequencing of Myelofibrosis Identifies Disease-Specific and Age-Related Genomic Alterations.

PURPOSE: Myeloproliferative neoplasms (MPN) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR, and MPL are considered drivers of Bcr-Abl-ve MPN, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF), and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear. EXPERIMENTAL DESIGN: To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1,711 genes for mutations along with whole transcriptome RNA sequencing of 137 patients with MPN. RESULTS: In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N = 106) and ET/PV/PrePMF (N = 31), respectively. Overt MF had more mutations compared with ET/PV/prePMF (5 vs. 4 per subject, P = 0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2, and U2AF1) and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2, and NF1 were exclusive to MF. Advancing age, higher DIPSS, and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2, and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells. CONCLUSIONS: Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression and potential targets for therapeutic intervention.

Spatial Mapping of Hematopoietic Clones in Human Bone Marrow.

Clonal hematopoiesis (CH) is the expansion of somatically mutated cells in the hematopoietic compartment of individuals without hematopoietic dysfunction. Large CH clones (i.e., >2% variant allele fraction) predispose to hematologic malignancy, but CH is detected at lower levels in nearly all middle-aged individuals. Prior work has extensively characterized CH in peripheral blood, but the spatial distribution of hematopoietic clones in human bone marrow is largely undescribed. To understand CH at this level, we developed a method for spatially aware somatic mutation profiling and characterized the bone marrow of a patient with polycythemia vera. We identified the complex clonal distribution of somatic mutations in the hematopoietic compartment, the restriction of somatic mutations to specific subpopulations of hematopoietic cells, and spatial constraints of these clones in the bone marrow. This proof of principle paves the way to answering fundamental questions regarding CH spatial organization and factors driving CH expansion and malignant transformation in the bone marrow. SIGNIFICANCE: CH occurs commonly in humans and can predispose to hematologic malignancy. Although well characterized in blood, it is poorly understood how clones are spatially distributed in the bone marrow. To answer this, we developed methods for spatially aware somatic mutation profiling to describe clonal heterogeneity in human bone marrow. See related commentary by Austin and Aifantis, p. 139.

Thromboembolic events, major bleeding and mortality in essential thrombocythaemia and polycythaemia vera-A matched nationwide population-based study.

Thromboembolic events and bleeding are known complications in essential thrombocythaemia (ET) and polycythaemia vera (PV). Using multiple Swedish health care registers, we assessed the rate of arterial and venous events, major bleeding, all-cause stroke and all-cause mortality in ET and PV compared to matched controls. For each patient with ET (n = 3141) and PV (n = 2604), five matched controls were randomly selected. In total, 327 and 405 arterial or venous events were seen in the group of ET and PV patients respectively. Compared to corresponding controls, the rate of venous thromboembolism, major bleeding and all-cause mortality per 100 treatment years was significantly increased among both ET (0.63, 0.79 and 3.70) and PV patients (0.94, 1.20 and 4.80). The PV patients also displayed a significantly higher rate of arterial events and all-cause stroke compared to controls. When dividing the cohort into age groups, we found a significantly higher rate of arterial and venous events in all age groups of PV patients, and the rate of all-cause mortality was significantly higher in both ET and PV patients in all ages above the age of 50. This study confirms that PV and ET are diseases truly marked by thromboembolic complications and bleeding.

Transcription factor 3 is dysregulated in megakaryocytes in myelofibrosis.

Transcription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical "MF-like" morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets.

What is the context? We investigated TCF3 (transcription factor 3), a gene that regulates megakaryocyte development, for genomic and proteomic changes in myelofibrosis.Myelofibrosis is the aggressive phase of a group of blood cancers called myeloproliferative neoplasms, and abnormalities in development and maturation of megakaryocytes is thought to drive the development of myelofibrosis.What is new? We report detection of three novel TCF3 mutations in megakaryocytes and decreases in TCF3 protein and gene expression in primary megakaryocytes and platelets from patients with myelofibrosis.This is the first association between loss of TCF3 in megakaryocytes from patients and myelofibrosis.What is the impact? TCF3 dysregulation may be a novel mechanism that is responsible for the development of myelofibrosis and better understanding of this pathway could identify new drug targets.

[How I manage polycythemia]. / Comment j'explore une polyglobulie.

Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a myeloproliferative neoplasm known as polycythemia vera, or be secondary to excess erythropoietin (EPO) or decreased in plasma volume. Faced with polycythemia, the search for JAK2 mutations and measurement of serum EPO levels can guide toward the etiology. In polycythemia vera, thromboembolic events are the most lethal complications and unfortunately often the initial manifestation of the disease. The condition can also progress to myelofibrosis or acute leukemia. Management aims at reducing the hematocrit below 45 %, in order to limit, but not completely prevent, thrombo-embolic complications. This article elaborates on the clinical considerations around this biological anomaly, relevant complementary examinations, and briefly the therapeutic management.

La polyglobulie est suspectée lorsque le taux d'hémoglobine et/ou d'hématocrite est au-dessus des normes définies selon le sexe et l'âge. Cette anomalie biologique peut survenir à la suite d'une néoplasie myéloproliférative appelée polycythemia vera (PV), être secondaire à un excès d'érythropoïétine (EPO) ou à une diminution du volume plasmatique. Face à une polyglobulie, la recherche de mutations du gène JAK2 et un dosage d'EPO sérique permettront d'orienter vers l'étiologie. En cas de PV, les phénomènes thrombo-emboliques sont les complications les plus léthales et sont malheureusement souvent la première manifestation de la maladie. La maladie peut également évoluer en myélofibrose ou en leucémie aiguë. La prise en charge vise à réduire le taux d'hématocrite en-dessous de 45 %, afin de limiter, sans les empêcher complètement, les complications thrombo-emboliques. Dans cet article, nous développons la réflexion clinique autour de cette anomalie biologique, les examens complémentaires pertinents dans ce domaine et, brièvement, la prise en charge thérapeutique.

Ischemic stroke as an initial performance of polycythemia vera in young adults: A case report and literature review.

INTRODUCTION: As the second leading cause of death and disability worldwide, stroke is mainly caused by atherosclerosis and cardiac embolism, particularly in older individuals. Nevertheless, in young and otherwise healthy individuals, the causes of stroke can be more diverse and may include conditions such as patent foramen ovale, vasculitis, coagulopathies, genetic factors, or other undetermined causes. Although these other causes of stroke account for a relatively small proportion compared to ischemic stroke, they are becoming increasingly common in clinical practice and deserve attention. Here, we present a rare female patient with polycythemia vera (PV) who was admitted to the hospital as a stroke patient without any previous medical history. PATIENT CONCERNS: A 40-year-old young woman felt sudden dizziness and slow response. After 4 days of being admitted, she developed blurry vision on the right. DIAGNOSES: Cranial magnetic resonance imaging revealed aberrant signals in the left temporal and parietal lobe, as well as multiple small focal signal abnormalities were observed in the left frontal lobe. Magnetic resonance angiography revealed partial stenosis of the left internal carotid artery. The patient's blood routine examination revealed a significant elevation in complete blood counts, particularly the increase in red blood cells, as well as prolonged clotting time. An abdominal ultrasound and abdomen computed tomography showed splenomegaly. The outcome of the genetic testing was positive for the Janus kinase JAK2 exon V617F mutation (JAK2/V617F). The patient was diagnosed with PV-related stroke. INTERVENTIONS: The patient was treated with phlebotomy, cytoreductive therapy, and low-dose aspirin antiplatelet therapy and was regularly followed up in hematology and neurology clinics after discharge. OUTCOMES: The patient's red blood cell, leukocyte, and thrombocyte counts had fully normalized, with her hemoglobin level measuring at 146 g/L and hematocrit value at 43%. Furthermore, there had been a significant improvement in neurological symptoms. LESSONS: PV, a rare hematological disorder, can present with ischemic stroke as the initial performance, and the diagnosis mainly relies on routine blood tests, bone marrow biopsies, and genetic test. Therefore, clinicians should pay attention to PV, a low-prevalence disease, when encountering stroke in youth.