Essential Thrombocythemia Research Articles

Abstract TP224: Timing of Ischemic and Hemorrhagic Stroke With Myeloproliferative Neoplasm Diagnosis Among Veterans

Myeloproliferative Neoplasms (MPNs) are rare acquired stem cell disorders, consisting of Essential Thrombocythemia (ET), Polycythemia Vera (PV), and Primary Myelofibrosis (PMF), complicated by thrombohemorrhagic events such as stroke. The timing of ischemic stroke (IS) and hemorrhagic stroke (HS) in relation to MPN diagnosis among Veterans remains undefined. We utilized the Veterans Affairs Informatics and Computing Infrastructure database from 1/1/2006 - 1/26/2023 and included 586,555 Veterans from Illinois, the state most representative of the US population. ICD-9 and -10 codes identified Veterans with stroke and MPN. Fisher’s exact test was utilized to compare MPNs vs. non-MPNs. There were 237 MPNs and 15,221 non-MPNs with IS while there were 26 MPNs and 1,567 non-MPNs with HS (Table 1). There were no differences in age of stroke diagnosis among MPNs vs. non-MPNs. There were higher rates of hypertension, smoking, and heart failure among MPNs vs. non-MPNs with IS. Majority of IS was diagnosed either more than 3 months before MPN diagnosis (N=115, 48.5%) or more than 5 years after diagnosis (N=98, 41.4%). Among MPNs with HS, stroke was predominantly diagnosed (N=14, 53.8%) more than 3 months before and (N=7, 26.9%) within 3 months of MPN diagnosis (Figure 1). Among MPNs there was recurrence of stroke among 45.18% of IS and 40% of HS. Although MPN are infrequent causes of stroke, these findings suggest continued surveillance for MPN and workup for driver mutations after a stroke diagnosis. This study also suggests consideration for dual antiplatelet therapy for MPNs with cardiovascular risk factors to prevent IS and a multidisciplinary approach between neurology and hematology.

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.

Red Blood Cell Contribution to Thrombosis in Polycythemia Vera and Essential Thrombocythemia.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.

Genomic classification and outcomes of young patients with polycythemia vera and essential thrombocythemia according to the presence of splanchnic vein thrombosis and its chronology

To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9–4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4–24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.

CALR mutation burden in essential thrombocythemia and disease outcome

AbstractAmong 281 patients with essential thrombocythemia and calreticulin (CALR) mutation, we found a variant allele frequency of ≥60% to be associated with significantly shortened myelofibrosis-free survival, mostly apparent with CALR type-1 and CALR type-indeterminate mutations.

One thousand patients with essential thrombocythemia: the Florence-CRIMM experience

We describe 1000 patients with essential thrombocythemia seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Florence, Italy, between 1980 and 2023: median age 59 years (18–95), females 65%, JAK2/CALR/MPL-mutated 66%/19%/4%, triple-negative (TN) 11%. Extreme thrombocytosis (ExT, platelets ≥1000 × 109/L) in 16%, leukocytosis (leukocytes >11 × 109/L) in 16%, and at least one cardiovascular risk factor in 52% of cases. JAK2-mutated patients were older (median 62 years) and CALR-mutated and TN (53 years for both) younger (p < 0.001). Female gender clustered with TN (76%) and JAK2 (67%) vs CALR (46%) mutations (p < 0.001). ExT clustered with CALR (type-2 more than type-1), TN and MPL, and leukocytosis with JAK2 mutation (p < 0.001). In multivariable analysis, risk factors for arterial thrombosis-free survival were age ≥60 years (HR 2.0; p < 0.001) and JAK2 mutation (HR 1.3; p = 0.02) with borderline significance for male gender (p = 0.08) and cardiovascular risk factors (p = 0.08); for venous thrombosis-free survival, JAK2 mutation (HR 1.9; p = 0.03) with borderline significance for venous thrombosis history (p = 0.07); for overall survival, older age (p < 0.001), male gender (HR 1.9; p < 0.001), absolute neutrophil count (ANC) ≥ 8 × 109/L (HR 1.8; p = 0.01), absolute lymphocyte count (ALC) < 1.7 × 109/L (HR 1.2; p = 0.03); for myelofibrosis-free survival, CALR mutation (HR 2.7; p < 0.001, particularly for CALR type 1/1-like, HR 3.3) and MPL mutation (HR 3.9; p = 0.001); for leukemia-free survival, older age (p = 0.03). Cytoreductive therapy appeared to mitigate both venous (HR 0.3; p = 0.01) and arterial thrombosis (HR 4; p = 0.04); there was a trend for aspirin in preventing arterial thrombosis recurrence. The current study provides real-world observations in essential thrombocythemia, representing a valid source document for interpreting current literature and planning future studies.

One thousand patients with essential thrombocythemia: the Mayo Clinic experience

We describe 1000 patients with essential thrombocythemia seen at the Mayo Clinic between 1967 and 2023: median age 58 years (18–90), females 63%, JAK2/CALR/MPL-mutated 62%/27%/3%, triple-negative (TN) 8%, extreme thrombocytosis (ExT; platelets ≥1000 × 109/L) 26%, leukocytosis (leukocyte count >11 × 109/L) 20%, and abnormal karyotype 6%. JAK2-mutated patients were older (median 71 years), and CALR mutated (52 years), and TN (50 years) younger (p < 0.01). Female gender clustered with TN (73%) and JAK2 (69%) vs. CALR/MPL (49%/47%) mutations (p < 0.01). ExT clustered with CALR (type-2 more than type-1) and TN and leukocytosis with JAK2 mutation (p < 0.01). In multivariable analysis, risk factors for overall survival were older age (p < 0.01), male gender (HR 1.8), absolute neutrophil count (ANC) ≥ 8 × 109/L (HR 1.6), absolute lymphocyte count (ALC) < 1.7 × 109/L (HR 1.5), hypertension (HR 1.7), and arterial thrombosis history (HR 1.7); for leukemia-free survival, ExT (HR 2.3) and abnormal karyotype (HR 3.1); for myelofibrosis-free survival, ANC ≥ 8 × 109/L (HR 2.3) and MPL mutation (HR 3.9); for arterial thrombosis-free survival, age ≥60 years (HR 1.9), male gender (HR 1.6), arterial thrombosis history (HR 1.7), hypertension (HR 1.7), and JAK2 mutation (HR 1.8); for venous thrombosis-free survival, male gender (HR 1.8) and venous thrombosis history (HR 3.0). Associations between ExT and leukemic transformation and between ANC and fibrotic progression were limited to JAK2-mutated cases. Aspirin therapy appeared to mitigate both arterial (HR 0.4) and venous (HR 0.4) thrombosis risk. HR-based risk models delineated patients with median survivals ranging from 10 years to not reached and 20-year leukemia/myelofibrosis incidences from 3%/21% to 12.8%/49%. The current study provides both novel and confirmatory observations of essential thrombocythemia.

Expression of JAK2 V617F Mutation in BCR - ABL Negative Myeloproliferative Neoplasms

OBJECTIVE: To detect the presence of JAK2V617F mutation in BCR - ABL negative myeloproliferative neoplasms and to stratify high risk patients for targeted therapy.PLACE AND DURATION OF STUDY: Department of Haematology, Armed forces institute of Pathology (AFIP), Rawalpindi, from Dec 2023 to Oct 2023.STUDY DESIGN: Descriptive cross sectional studyMETHODOLOGY: A total of 40 consecutive patients of BCR - ABL 1 negative myeloproliferative disorders were included in the study after being diagnosed according to WHO defined haematological criteria for each disorder and performing bone marrow examination under aseptic measures. Informed consent and ethical approval were obtained from each individual. All patients had their blood samples examined for the G-T point mutation (V617F) in the JAK2 gene located on chromosome 9, utilizing allele-specific real-time qualitative polymerase chain reaction (RT-qPCR). Results were analyzed by using SPSS version 22.RESULTS: Out of total 40 patients included in our study 21(52.5%) had Polycythemia Vera (PV), 15 (37.5%) had Primary myelofibrosis (PMF) and 4 (10%) had Essential thrombocythemia (ET). JAK2 mutation was found in 20 (95.2%) patients of PV, 9 (60%) patients of PMF and 2 (50%) patients of ET with a significant p-value of ˂ 0.001.CONCLUSIONS: JAK2 V617F is a useful clinical marker for establishing diagnosis and separating high risk patients for specific targeted therapy.

Inherited polygenic effects on common hematological traits influence clonal selection on JAK2V617F and the development of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are chronic cancers characterized by overproduction of mature blood cells. Their causative somatic mutations, for example, JAK2V617F, are common in the population, yet only a minority of carriers develop MPN. Here we show that the inherited polygenic loci that underlie common hematological traits influence JAK2V617F clonal expansion. We identify polygenic risk scores (PGSs) for monocyte count and plateletcrit as new risk factors for JAK2V617F positivity. PGSs for several hematological traits influenced the risk of different MPN subtypes, with low PGSs for two platelet traits also showing protective effects in JAK2V617F carriers, making them two to three times less likely to have essential thrombocythemia than carriers with high PGSs. We observed that extreme hematological PGSs may contribute to an MPN diagnosis in the absence of somatic driver mutations. Our study showcases how polygenic backgrounds underlying common hematological traits influence both clonal selection on somatic mutations and the subsequent phenotype of cancer.

JAK2V617F drives gut microbiota differences in patients with myeloproliferative neoplasms.

Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are myeloproliferative neoplasms (MPN). Inflammation is involved in the initiation, progression, and symptomology of the diseases. The gut microbiota impacts the immune system, infection control, and steady-state hematopoiesis. We analyzed the gut microbiota of 227 MPN patients and healthy controls (HCs) using next-generation sequencing. We expanded our previous results in PV and ET patients with additional PV, pre-MF, and MF patients which allowed us to compare MPN patients collectively, MPN sub-diagnoses, and MPN mutations (separately and combined) vs. HCs (N = 42) and compare within MPN sub-diagnoses and MPN mutation. MPN patients had a higher observed richness (median, 245 [range, 49-659]) compared with HCs (191.5 [range, 111-300; p = .003]) and a lower relative abundance of taxa within the Firmicutes phylum; for example, Faecalibacterium (6% vs. 14%, p < .001). The microbiota of CALR-positive patients (N = 30) resembled that of HCs more than that of patients with JAK2V617F (N = 177). In JAK2V617F-positive patients, only minor differences in the gut microbiota were observed between MPN sub-diagnoses, illustrating the importance of this mutation. The gut microbiota in MPN patients differs from HCs and is driven by JAK2V617F, whereas the gut microbiota in CALR patients resembles HCs more.

Myeloproliferative Neoplasms: Diseases Mediated by Chronic Activation of Signal Transducer and Activator of Transcription (STAT) Proteins.

Myeloproliferative neoplasms (MPNs) are hematopoietic diseases characterized by the clonal expansion of single or multiple lineages of differentiated myeloid cells that accumulate in the blood and bone marrow. MPNs are grouped into distinct categories based on key clinical presentations and distinctive mutational hallmarks. These include chronic myeloid leukemia (CML), which is strongly associated with the signature BCR::ABL1 gene translocation, polycythemia vera (PV), essential thrombocythemia (ET), and primary (idiopathic) myelofibrosis (PMF), typically accompanied by molecular alterations in the JAK2, MPL, or CALR genes. There are also rarer forms such as chronic neutrophilic leukemia (CNL), which involves mutations in the CSF3R gene. However, rather than focusing on the differences between these alternate disease categories, this review aims to present a unifying molecular etiology in which these overlapping diseases are best understood as disruptions of normal hematopoietic signaling: specifically, the chronic activation of signaling pathways, particularly involving signal transducer and activator of transcription (STAT) transcription factors, most notably STAT5B, leading to the sustained stimulation of myelopoiesis, which underpins the various disease sequalae.

Insights into the role of JAK2-I724T variant in myeloproliferative neoplasms from a unique cohort of New Zealand patients

ABSTRACT Objectives: This study aimed to compile bioinformatic and experimental information for JAK2 missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline JAK2-I724T, recently found to be common in New Zealand Polynesians, associates with MPN. Methods: For all JAK2 variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of JAK2-I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with JAK2-V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software. Results: Several non-V617F JAK2 variants previously reported in MPN had REVEL scores greater than 0.5, suggesting pathogenicity. JAK2-I724T (REVEL score 0.753) was more common in New Zealand Polynesian MPN patients (n = 2/27; 7.4%) than in other New Zealand patients (n = 0/84; 0%) but less common than expected for healthy Polynesians (n = 56/377; 14.9%). Patients carrying I724T (n = 2), one with polycythaemia vera and one with essential thrombocythaemia, had high-risk MPN. Both patients with JAK2-I724T were also positive for JAK2-V617F, found on the same allele as I724T, as well as separately. In silico modelling did not identify noticeable structural changes that would give JAK2-I724T a gain-of-function. Conclusion: Several non-canonical JAK2 variants with high REVEL scores have been reported in MPN, highlighting the need to further understand their relationship with disease. The JAK2-I724T variant does not drive MPN, but additional investigations are required to exclude any potential modulatory effect on the MPN phenotype.

A germline JAK2 exon12 mutation and a late somatic CALR mutation in a patient with essential thrombocythemia.

It has been discovered that Janus kinase 2 (JAK2) exon12 mutations lead to the polycythemia vera (PV) phenotype, while somatic mutations of calreticulin (CALR) are associated with essential thrombocythemia (ET) or primary myelofibrosis. In this article, we report a case of ET with coexistence of JAK2 exon12 and CALR mutations. The objective of this study was to elucidate the pathogenicity mechanism of a JAK2 exon12 mutation (JAK2N533S) and the role of the coexistence of mutations on the hematological phenotype. We designed a colony analysis of tumor cells obtained from this patient, and attempted to identify mutant genes using DNA from hair follicles. Mutation impairment prediction and conservative analysis were conducted to predict the mutation impairment and structure of JAK2N533S. In addition, we conducted a functional analysis of JAK2N533S by constructing Ba/F3 cell models. Three distinct tumor subclones, namely JAK2N533Shet+/CALRtype1het +, JAK2N533Shet+/CALR wt, and JAK2N533Shet+/CALRtype1hom +, were identified from the 17 selected erythroid and 21 selected granulocyte colonies. The analysis of hair follicles yielded positive results for JAK2N533S. According to the bioinformatics analysis, JAK2N533S may exert only a minor effect on protein function. Functional studies showed that JAK2N533S did not have a significant effect on the proliferation of Ba/F3 cells in the absence of interleukin-3 (IL-3), similar to wild-type JAK2. Notably, there were no increased phosphorylation levels of JAK2-downstream signaling proteins, including signal transducer and activator of transcription 3 (STAT3) and STAT5, in Ba/F3 cells harboring the JAK2N533S. Our study revealed that the JAK2N533Shet+/CALRtype1het+ subclone was linked to a significant expansion advantage in this patient, indicating that it may contribute to the development of the ET phenotype. We further demonstrated that JAK2N533S, as a noncanonical JAK2 exon12 mutation, is a germline mutation that may not exert an effect on cell proliferation and protein function. These results and the present body of available data imply that certain noncanonical JAK2 mutations are not gain-of-function mutations leading to the development of myeloproliferative neoplasms.

Approach to the Diagnosis and Management of Essential Thrombocytosis in a Resource-Limited Setting

Essential thrombocytosis (ET) is a myeloproliferative neoplasm (together with polycythemia vera, chronic myelogenous leukemia, and primary myelofibrosis) characterized by clonal proliferation of megakaryocytes, usually due to the presence of JAK2, CALR, or MPL mutations. Whereas a bone marrow aspirate and genetic testing for these mutations are necessary for an accurate diagnosis of ET, in resource-limited settings, these are often either inaccessible or limited by prohibitive costs. A nuanced clinical approach is necessary to diagnose and manage ET in these settings. In this study, we present a case of ET diagnosed and managed in a resource-limited rural setting in Kenya with hydroxyurea and aspirin. We highlight the importance of individualized therapeutic targets, the challenges with dose adjustments in the setting of hydroxyurea-induced neutropenia, and how extrapolated data from the use of hydroxyurea elsewhere may help guide such dose adjustments. Finally, we propose a rationalized approach to treating ET in a resource-limited clinical setting.

Newly identified roles for PIEZO1 mechanosensor in controlling normal megakaryocyte development and in primary myelofibrosis.

Mechanisms through which mature megakaryocytes (Mks) and their progenitors sense the bone marrow extracellular matrix to promote lineage differentiation in health and disease are still partially understood. We found PIEZO1, a mechanosensitive cation channel, to be expressed in mouse and human Mks. Human mutations in PIEZO1 have been described to be associated with blood cell disorders. Yet, a role for PIEZO1 in megakaryopoiesis and proplatelet formation has never been investigated. Here, we show that activation of PIEZO1 increases the number of immature Mks in mice, while the number of mature Mks and Mk ploidy level are reduced. Piezo1/2 knockout mice show an increase in Mk size and platelet count, both at basal state and upon marrow regeneration. Similarly, in human samples, PIEZO1 is expressed during megakaryopoiesis. Its activation reduces Mk size, ploidy, maturation, and proplatelet extension. Resulting effects of PIEZO1 activation on Mks resemble the profile in Primary Myelofibrosis (PMF). Intriguingly, Mks derived from Jak2V617F PMF mice show significantly elevated PIEZO1 expression, compared to wild-type controls. Accordingly, Mks isolated from bone marrow aspirates of JAK2V617F PMF patients show increased PIEZO1 expression compared to Essential Thrombocythemia. Most importantly, PIEZO1 expression in bone marrow Mks is inversely correlated with patient platelet count. The ploidy, maturation, and proplatelet formation of Mks from JAK2V617F PMF patients are rescued upon PIEZO1 inhibition. Together, our data suggest that PIEZO1 places a brake on Mk maturation and platelet formation in physiology, and its upregulation in PMF Mks might contribute to aggravating some hallmarks of the disease.

Impact of Hydroxyurea to Treat Haematological Disorders on Male Fertility: Two Case Reports and a Systematic Review.

Hydroxyurea (HU) is a cytoreductive agent used as standard treatment option for sickle cell anaemia/disease (SCD), essential thrombocythemia (ET), and polycythaemia vera (PV). Despite its overall good safety profile, its use also in relatively young patients raises an interest on its potential impact on spermatogenesis. To perform a systematic review of all published articles investigating fertility in male patients affected by SCD, ET, and PV and treated with HU. Two paradigmatic case reports of patients affected by PV and ET, respectively, have been also reported. PubMed, EMBASE, and Cochrane databases were queried for all the published studies indexed up to November 15th, 2022. A combination of the following keywords was used: "hydroxyurea," "fertility," "male," "sperm," "sickle cell anaemia," "sickle cell disease," "essential thrombocythemia," "polycythaemia vera." Of 48 articles identified, 8 studies, involving 161 patients, were eligible for inclusion. Overall, the number of spermatogonia per round cross section of seminiferous tubule were decreased in patients with SCD compared to healthy males. HU treatment was always associated with a worsening of semen parameters, even up to azoospermia. Notably, treatment discontinuation was associated with an improvement of semen parameters and a trend toward normalization in the case of PV and ET, with a less clear amelioration in men with SCD. In both our patients with either PV or ET, HU discontinuation was associated with a significant improvement of spermatogenesis with successful spontaneous pregnancies. Published evidence do not consistently report normalization of spermatogenesis after HU discontinuation in SCD cases. Conversely, the literature almost consistently reported an improvement of semen parameters at the discontinuation of HU therapy in PV and ET cases. Our real-life two cases confirmed those findings. The willing of fatherhood and the need for effective fertility treatment warrant further research to improve work-up management in men with hematological disorders.

An Approach to the Investigation of Thrombocytosis: Differentiating between Essential Thrombocythemia and Secondary Thrombocytosis.

Thrombocytosis is a common reason for referral to Hematology. Differentiating between secondary causes of thrombocytosis and essential thrombocythemia (ET) is often clinically challenging. A practical diagnostic approach to identify secondary thrombocytosis could reduce overinvestigation such as next generation sequencing (NGS) panel. All adult patients with thrombocytosis (≥450 × 109/L) who underwent molecular testing at a single tertiary care centre between January 1, 2018 and May 31, 2021 were evaluated. Clinical and laboratory variables were compared between patients with secondary thrombocytosis vs. ET. Clinical variables included smoking, thrombosis, splenectomy, active malignancy, chronic inflammatory disease, and iron deficiency anemia. Laboratory variables included complete blood count (CBC), ferritin, and myeloid mutations detected by NGS. The overall yield of molecular testing was 52.4%; 92.1% of which were mutations in JAK2, CALR, and/or MPL. Clinical factors predictive of ET included history of arterial thrombosis (p < 0.05); active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency were associated with secondary thrombocytosis (p < 0.05). A diagnosis of ET was associated with higher hemoglobin, mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV), while secondary thrombocytosis was associated with higher body mass index, white blood cells, and neutrophils (p < 0.01). A practical approach to investigating patients with persistent thrombocytosis based on clinical characteristics such as active malignancy, chronic inflammatory disease, splenectomy, and iron deficiency may assist in accurately identifying patients more likely to have secondary causes of thrombocytosis and reduce overinvestigation, particularly costly molecular testing.

Repeated Ischemic Stroke due to in situ Thrombus at the Middle Cerebral Artery in a Patient with Essential Thrombocythemia.

Essential thrombocythemia (ET) is a myeloproliferative neoplasm that is a rare cause of ischemic stroke. We herein report a 70-year-old man with JAK2 V617F mutation-positive ET who experienced ischemic stroke twice in 1 month due to transient stenosis. In both events, transient stenosis formed at the same curvature of the right middle cerebral artery, and the thrombus disappeared with the initiation of antiplatelet agents. The formation of in situ thrombus at the curvature of the intracranial vessels may be a unique characteristic of JAK2 V617F mutation-positive ET patients.

Essential thrombocythemia: nutritional management in weight loss and malnutrition.

Essential thrombocythemia is the category of myeloproliferative syndromes, generally characterized by a group of clonal stem cell diseases that present a disturbance in the growth of one or more sets of hematopoietic cells. All long clinical treatment, patients may experience gastrointestinal disorders and other metabolic processes that can lead to weight loss and malnutrition. Cytokine is involved in the control of appetite, digestive, and metabolic processes in the body, it can be assumed that increased stimulation could impair the control of these processes leading to loss of body mass. Effective and systematic nutritional intervention is required to ensure patient compliance with treatment and improved nutritional status.

Recent findings and advances in treatment of myeloproliferative neoplasms

Many novel agents have been developed for BCR::ABL1-negaive myeloproliferative neoplasms (MPN), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Some of these agents not only achieve hematologic complete response, reduce spleen size, and alleviate constitutional symptoms, but also induce molecular response, which means that they reduce the allele burden of driver gene mutations. These agents also prevent and alleviate fibrosis in bone marrow, which reduces the incidence of thrombotic events and disease progression and might improve prognosis. This article discusses the latest findings and promising treatments, including ongoing clinical trials, in PV, ET, and PMF.