Essential Thrombocythemia Research Articles

Portal hypertension (PHT) results from increased intrahepatic vascular resistance and augmented portal venous blood flow. Although cirrhosis remains the predominant etiology of PHT, non-cirrhotic PHT also requires clinical attention. This article reports a rare case of PHT with portal vein thrombosis and gastroesophageal varices secondary to essential thrombocythemia (ET). An 82-year-old female patient was admitted due to "hematemesis and melena," abdominal computed tomography revealed ascites, altered liver morphology, mild splenomegaly and PHT. The patient was admitted with a diagnosis of "decompensated cirrhosis." She maintained normal liver function over a 6-month follow-up, subsequently, the condition progressed to portal vein thrombosis, leading to gastrointestinal bleeding. Laboratory assessments at this stage revealed normal levels of albumin, liver enzymes, bilirubin, and coagulation factors, with no ascites formation, inconsistent with decompensated cirrhosis. ET was diagnosed based on Bone Marrow Aspiration and Biopsy, the JAK2 mutation was identified with a variant allele frequency of 42.2%. PHT and thrombosis in this case were attributed to ET. The patient was treated with hydroxyurea and ruxolitinib, endoscopic injection cyanoacrylate/sclerotherapy and endoscopic variceal ligation were performed. Post-discharge, oral antitumor agents and aspirin for antiplatelet therapy were prescribed, with outpatient follow-up. ET can also lead to PHT, portal vein thrombosis, and esophageal varices. Clinicians should consider these possibilities when dealing with such patients.

Mutant calreticulin (CALR) activates the thrombopoietin (TPO) receptor MPL, thereby inducing the development of essential thrombocythemia and primary myelofibrosis. Mutant CALR, due to a frameshift mutation, loses the endoplasmic reticulum (ER) retention signal, the KDEL sequence and is released extracellularly. To examine the significance of the loss of the KDEL sequence in mutant CALR-induced MPL activation, a series of constructs were prepared, including mutant CALR plus KDEL (mutant CALRKDEL), mutant CALR plus the Venus tag and KDEL (mutant CALRVenus-KDEL), and wild-type CALR minus KDEL (CALR WTΔKDEL). UT-7/TPO cells expressing mutant CALRKDEL exhibited autonomous cell growth in the absence of TPO, accompanied by the extracellular secretion of mutant CALRKDEL and subsequent activation of MPL. In contrast, UT-7/TPO cells expressing mutant CALRVenus-KDEL did not exhibit autonomous cell growth or MPL activation without TPO as well as the reduced extracellular secretion of mutant CALRVenus-KDEL. These results suggest that the loss of KDEL function in mutant CALR is closely linked to MPL activation and the extracellular secretion of mutant CALR. While UT-7/TPO cells expressing CALR WTΔKDEL did not exhibit autonomous cell growth, they were responsive to mutant CALR proteins added exogenously, as evidenced by STAT5 activity. Furthermore, CALR WTΔKDEL conferred mutant CALR sensitivity to MPL by recognizing the N-glycans of MPL while maintaining it in an immature form, which may bind to mutant CALR. In conclusion, deletion of the ER retention signal KDEL from CALR is a prerequisite for the expression of the immature form of MPL, which can interact with secreted mutant CALR.

Cytoreductive treatment differentially affects platelet size and cytoskeletal megakaryocyte organization during thrombopoiesis in myeloproliferative neoplasms.

The Triple A model has recently been developed and validated in essential thrombocythemia (ET) and polycythemia vera (PV).However, external validation in diverse populations remains unclear. The purpose of this study was to externally validate the Triple A prognostic model in a Turkish cohort of patients with ET and PV. A retrospective analysis was conducted at two centers in Bursa, Türkiye, involving patients diagnosed with ET or PV under the World Health Organization (WHO) 2016/2022 criteria between 2014 and 2024. While the Triple A model has significantly separated the ET patients with a median follow-up of 47months (p = 0.015), no significant difference was observed in PV patients in terms of survival (p = 0.87). For thrombosis-free survival (TFS), Fine and Gray's competing risk analysis showed a significant separation with the Triple A model in ET (p = 0.017). While the Triple A model was validated as a practical prognostic tool in ET, it demonstrated limited utility in PV. Further multicenter studies are needed to refine risk stratification in PV.

Background: Myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are chronic leukemias associated with cardiovascular (CV) disease (CVD), including pulmonary hypertension (PH). Prior studies utilizing echocardiography for identifying PH in MPNs have suggested an association between PH and adverse outcomes. However, right heart catheterization (RHC) is required for diagnosis and hemodynamic profiling of PH. Data on RHC-proven PH in MPNs are sparse. Methods: We conducted a multicenter study of patients with MPN who underwent RHC. PH, defined as mean pulmonary artery pressure (mPAP) > 20 mmHg, was hemodynamically characterized into isolated pre-capillary (pre-cap), isolated post-capillary (post-cap), and combined pre- and post-capillary (Cpc-PH). Outcomes were heart failure hospitalization (HFH) or CV death, and all-cause death. Multivariable Cox proportional hazards regression was performed. To model total number of HFH, multivariable negative binomial regression was performed. Results: 85 patients were included, 70 (82.4%) had PH, 37 (43.5%) were female, and 68 (80.0%) were White. Among PH patients, 30 (42.9%) had pre-cap PH, 12 (17.1%) post-cap PH, and 28 (40.0%) Cpc-PH. Age, gender, time from MPN to RHC, MPN type and driver and non-driver mutations did not differ between patients with or without PH. Patients with PH were more likely to have prior HFH (35.7% vs 0%, p = 0.006). After a median follow-up of 31.4 months, HFH or CV death occurred in 57 (67.1%) patients and death in 49 (57.6%). After adjustment, pre-cap (aHR 2.69, 95% CI 1.00 – 7.27) and post-cap PH were associated with increased risk of HFH or CV death (aHR 4.12, 95% CI 1.26 – 13.50) versus no PH. After multivariable negative binomial regression, any PH (IRR 3.36, 95% CI 1.31 – 8.63), pre-cap PH (IRR 4.11, 95% CI 1.60 – 10.58) and post-cap PH (IRR 5.06, 95% CI 1.63 – 15.67) were associated with increased total HFH. Conclusions: Among patients with MPN who underwent RHC, PH is common and appears to be predominantly isolated pre-capillary and Cpc-PH. Isolated pre- and isolated post-capillary PH were associated with increased HFH. Our study is confounded by selection bias, and therefore prospective studies of PH as diagnosed with RHC are needed in MPNs.

Introduction . Essential thrombocythemia (ET) is a type of clonal myeloproliferative neoplasm, which is characterized by uncontrolled proliferation of megakaryocytes. It is associated with an increased number of large and giant megakaryocytes in the bone marrow, leading to thrombocytosis and a high risk of both thrombosis and bleeding. Unlike in adults, pediatric patients with ET often do not experience any clinical manifestations of the disease. However, based on data from adult studies, it is possible that ET and polycythemia vera in children can also lead to both thrombotic and hemorrhagic complications. Changes in the hemostatic system are an important factor that can contribute to these risks. The aim of this study was to evaluate the state of blood coagulation system in children with thrombocytosis and erythrocytosis using standard coagulation tests, aggregometry, global hemostasis assays, levels of von Willebrand factor antigen (vWF:Ag) and activity and markers of endothelial dysfunction. Materials and methods . Activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, antithrombin III, D-dimer, vWF:Ag and activity RCo of von Willebrand factor, platelet aggregation with adenosine diphosphate (ADP), collagen, ristocetin, thromboelastography and thrombodynamics, endothelin-1 and thrombomodulin levels. The concentration of procoagulant micropartocles derived from the patients' plasma was estimated by flow cytometry. 59 patients diagnosed with ET were enrolled in this study. 13 children with secondary thrombocytosis and 23 with erythrocytosis were enrolled as the control groups. Results. The results of routine coagulation tests, as well as measurements of antithrombin III activity, D-dimer levels, vWF:Ag, thrombomodulin and endothelin-1, were within the normal range in most patients. The decrease in platelet aggregation was observed after stimulation with ADP in 29 % of patients, with collagen in 37 %, and with ristocetin in 47 %. A statistically significant correlation was found between the decrease in platelet aggregation and the increase in platelet counts. Increased aggregation was seen with ADP and collagen in only 11 and 18 % of patients, respectively, which may indicate a potential prothrombotic tendency and microcirculatory abnormalities in patients with ET. Acquired von Willebrand syndrome was present in 54 % of patients. Analysis showed that among patients with extreme thrombocytosis (> 1500 × 109/L), all had acquired von Willebrand disease. In addition, in patients with extreme thrombocytosis, there was an increase in parameters of thromboelastography, such as angle α and maximum amplitude, as well as clot growth rates in the thrombodynamics test. Correlation analysis showed significant dependences (p < 0.05) between the parameters of thromboelastography and thromobodynamics on both platelet count and number of procoagulant microvesicles. Conclusions . Despite the differences in clinical manifestations in children with ET, a close correlation has been identified between increased platelet counts and changes in their aggregation function, as well as, between increased platelet counts and changes in global hemostasis assays. All patients with hemorrhagic symptoms had laboratory signs of acquired von Willebrand syndrome.

Ropeginterferon alfa-2b in hydroxyurea-intolerant or hydroxyurea-refractory essential thrombocythaemia (SURPASS ET): a multicentre, open-label, randomised, active-controlled, phase 3 study.

Can ropeginterferon SURPASS resistance in essential thrombocythaemia?

Essential thrombocytosis (ET) is one of the myeloproliferative neoplasms (MPNs) which increase the probability of thrombosis and bleeding. ET is usually discovered as an incidental finding on blood workup and in rare cases, will present as vascular events such as stroke. Our patient, a 77-year-old female, a case of acute cerebral infarct presented with numbness and severe weakness of left upper and lower extremity. Serial complete blood count showed an elevated platelet count. Bone marrow aspiration studies showed increased number of enlarged megakaryocytes. She was diagnosed as a case of ET and maintained on Aspirin 80 mg per tablet once a day and Hydroxyurea 500 mg per tablet once a day. Keywords: Essential thrombocytosis, Myeloproliferative neoplasms, Acute cerebral infarct, Aspirin, Hydroxyurea

Introduction: This study was aimed to identify the discrepancies in treatment goals and concerns regarding disease management between patients with myeloproliferative neoplasms (MPNs) and hematologists. Methods: A study was conducted among patients with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), and hematologists in China. Results: Data from 1,645 respondents with ET, PV, and MF and 715 hematologist respondents were analyzed. Cure of disease and healthy blood counts as treatment goals were reported more by almost half of the respondents with MPNs than by hematologists. However, prevention of thrombotic events, delayed transformation of disease, improvement of symptoms and better quality of life, and reduction in spleen size were less reported by respondents with MPNs than by hematologists. In multivariate analyses, education, comorbidities, symptom burden, disease duration, and annual out-of-pocket expenses for treatment were significantly associated with the treatment goals of respondents with MPNs. However, female physicians and senior professors paid more attention to these goals. Regarding concerns on MPN-related issues, more respondents with MPNs paid more attention to disease knowledge and restrictions in daily life compared to hematologists, whereas the majority of physicians attached importance to medication-related issues. Conclusion: The perceptions of patients with MPNs and hematologists differed in terms of treatment goals and concerns of management of MPNs. Sociodemographic and clinical variables were associated with the respondents’ perspectives on MPNs. Therefore, sufficient patient-physician communication is suggested to improve treatment satisfaction and compliance.

The management of essential thrombocythemia (ET) relies on risk stratification; therefore, easily applicable risk scores with improved prognostic value are in demand. Triple A risk score (AAA model) is a novel model incorporating Age, Absolute neutrophil, and Absolute lymphocyte counts. In this study, we aimed to evaluate the predictive performance of Triple A score in ET for survival and its complications in an independent cohort, in addition to refining the model by incorporating absolute monocyte count and neutrophil/lymphocyte ratio (NLR). Demographic, clinical, and laboratory data of 565 ET patients were retrospectively collected. Based on Triple A score, 250 patients were classified as low-, 228 as intermediate-1, 37 as intermediate-2, and 50 as high-risk. Over a median follow-up of 6 years, 10.3% patients developed thrombosis, 4.4% experienced bleeding, 5.1% had post-ET myelofibrosis, and 10.9% died. There were significant differences in overall survival (p<0.001) and thrombosis-free survival (p=0.0003) across risk groups. Monocytosis (>800 x 106/L) was associated with increased mortality (p=0.033) and its prevalence increased progressively with higher Triple A scores (p<0.001). Elevated NLR was also linked to a higher risk of mortality (p<0.001), and moreover, NLR-monocyte-age based risk score demonstrated significant differences in survival risk (p<0.0001). Consequently, Triple A score is an easy-to-use and reliable tool for predicting survival and thrombosis in ET. Incorporating monocytosis into Triple A (AAA+A model) may further enhance its prognostic accuracy. NLR also demonstrated prognostic value both independently and as component of NLR-monocyte-age based model, highlighting its potential as a robust tool for risk stratification.

Integrated one-pot RPA-CRISPR/Cas13a platform enables ultrasensitive and field-deployable JAK2 V617F detection for myeloproliferative neoplasm diagnosis.

OB756 is a novel oral selective JAK2 inhibitor targeting the JAK-STAT pathway. This study assessed its safety and efficacy in patients with essential thrombocythemia (ET) who were resistant to or intolerant of hydroxyurea or intolerant of interferon. This phase 2, single-arm, open-label, multicenter clinical trial evaluated the efficacy and safety of OB756 in patients with ET who were intolerant of or resistant to hydroxyurea, or intolerant of interferon. The primary end point was the complete hematologic response (CHR) rate at week 24, whereas secondary end points included hematologic response (HR), the proportion of patients with ≥35% spleen volume reduction at week 24, molecular response, and safety. At week 24, the CHR was 22% (11 of 50) based on intention-to-treat analysis. Among evaluable patients, the HR rate reached 65.6% at week 24. At week 24, 94.7% of patients (36 of 38) experienced spleen volume reduction, with 50.0% achieving ≥35% reduction. Additionally, 74.2% of patients (23 of 31) had a ≥50% reduction in myeloproliferative neoplasm symptom assessment form total symptom score. Among evaluable patients, 84.7% (11 of 13) had a reduction in JAK2-V617F allele burden post-treatment. In terms of safety, most treatment-related adverse events (TEAEs) were grade 1-2. Grade ≥3 hematologic TEAEs included anemia (10%) and neutropenia (6%). The incidence of grade ≥3 infections was 16% and grade ≥3 thrombotic events was 2%. Overall, OB756 was well-tolerated and demonstrated acceptable efficacy, offering a promising therapeutic option for ET patients who are resistant to or intolerant of hydroxyurea or intolerant of interferon.

Pegbing® (peginterferon alfa-2b), a pegylated interferon-alpha, is approved for the treatment of chronic hepatitis B (CHB) and C. One of its adverse effects is platelet (PLT) suppression. It is currently being repurposed for the treatment of essential thrombocythemia (ET), a rare myeloproliferative disorder characterized by abnormally elevated PLT levels and associated with significant unmet clinical needs. The drug repositioning strategy of Pegbing® from CHB to ET aims to accelerate development and reduce costs. Through the application of pharmacometrics, the existing data from CHB patients were leveraged to inform dose selection and clinical trial design for ET patients. The pharmacokinetic/pharmacodynamic (PK/PD) model of Pegbing® for PLT and white blood cell (WBC) inhibition was established using data from a phase II trial conducted in CHB patients who received Pegbing®, and validated with data from a phase III trial. The PK/PD relationship was extrapolated to ET patients by adjusting baseline PLT and WBC levels using real-world data from ET patients receiving off-label treatment with Pegbing®. According to the parameter distribution and correlation from the extrapolated PK/PD relationship, 1,000 virtual ET patients were generated to form an in silico clinical trial, revealing that baseline PLT and WBC levels were key factors for hematologic response. Pegbing® 180 μg is expected to be an appropriate dose for future development, with an overall complete hematologic response rate of 62.3%. A higher maintenance dose may be required in patients with severe ET. Moreover, this study provides a valuable reference for drug repositioning between two indications with significant differences.

Introduction. Thrombosis and bleeding are frequent complications of essential thrombocythemia (ET) and polycythemia vera (PV). Platelet morphofunctional abnormalities in these disorders are poorly understood. Aim: To study the morphofunctional characteristics of platelets in ET and PV. Materials and methods. The study included 39 patients under 18 years of age with an established diagnosis of ET (n = 26) and PV (n = 13). The control group consisted of 40 healthy children. The manifestations of ischemic and hemorrhagic symptoms, hepato-/splenomegaly were evaluated. Platelets were studied using flow cytometry (FC) with activation by a mixture of thrombin and collagen analogues; the activity of the Willebrand factor was measured. Results. Depending on the presence and type of driver mutation, all patients were divided into 3 groups. Group 1 included 16 patients with triple negative (TN) form of ET. Group 2 included 15 patients with JAK2 driver mutation and diagnoses of PV or ET. The third group included 8 patients with CALR driver mutation and a diagnosis of ET. The platelet count was higher in the TN group when compared to the JAK2 group (p = 0.005) and did not differ between the TN and CALR groups (p = 0.98). Hepatomegaly was observed in 36 % of patients, splenomegaly in 56 %. Symptoms of ischemia and/or bleeding were observed in 54 % of patients. Acquired von Willebrand disease syndrome developed in 64 % of patients. According to the results of FC, the size of non-activated platelets was reduced in all groups when compared to the control group (p ≤ 0.01). The reduction in platelet size upon activation was significantly attenuated in JAK2 and CALR (p ≤ 0.0015). Platelet granularity was reduced in TN and CALR groups (p ≤ 0.01) when compared to the control. Morphological abnormalities of platelets, in the form of an increase in their granularity relative to cell size, were detected in 58 % of patients. The decrease in the amount of CD42b on the platelet membrane, due to Shedding and internalization, was significantly attenuated in all patient groups (p ≤ 0.01). The externalization of CD61 on the platelet membrane surface upon activation was attenuated in all groups (p ≤ 0.02). In the JAK2 and CALR groups, the volume/number of platelet dense granules were significantly reduced at rest (p ≤0.02), and upon activation, dense granule degranulation was attenuated (p &lt; 0.001) when compared to the control. Conclusion. Common morphofunctional platelet abnormalities (reduced size, abnormalities in CD42b and CD61 expression) were identified in children and adolescents with ET/PV, independent of the genetic cause.&gt;&lt; 0.001) when compared to the control. Conclusion. Common morphofunctional platelet abnormalities (reduced size, abnormalities in CD42b and CD61 expression) were identified in children and adolescents with ET/PV, independent of the genetic cause.

Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40.

Objective: This study investigated the prevalence of arterial stiffness among individuals diagnosed with myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Methods: We performed a cross-sectional study at Chiang-Mai University Hospital, Thailand, defining arterial stiffness as a mean cardio-ankle vascular index (CAVI) ≥8.0. Patients were compared to age-, sex-, and Thai cardiovascular (CV) risk score-matched controls with CV risk factors. Additional outcomes included the 10-year CV risk in MPN patients, estimated by the Thai CV risk score, and the correlation between plasma C-reactive protein (CRP) levels and CAVI. Results: Eighty participants were included (50 with PV, 24 with ET, 6 with PMF; median age: 63.5 years). Arterial stiffness was present in 63.8% of MPN patients overall, with respective rates for ET, PV, and PMF being 70.8%, 60.0%, and 66.7% (p = 0.655). When compared to matched non-MPN controls with CV risk, prevalence of arterial stiffness did not differ significantly (65.2% vs. 60.9%, p = 0.539). The median estimated 10-year CV risk for patients with MPNs was 13.6% (range 0.7-30.0). No significant association was observed between CRP levels and mean CAVI (R = 0.208, p = 0.073). Conclusions: Arterial stiffness was detected in 63.8% of individuals with MPNs, a prevalence like that of matched non-MPN patients with CV risk factors.

Hemopericardium, the accumulation of blood within the pericardial sac, can lead to fatal cardiac tamponade if untreated. Its subtle presentation often obscures classic tamponade signs, complicating timely diagnosis. Essential thrombocythemia (ET), a chronic myeloproliferative neoplasm, predisposes patients to both thrombotic and hemorrhagic complications. While aspirin is effective in reducing thrombotic risks associated with ET, it can also precipitate life-threatening bleeding, such as hemorrhagic cardiac tamponade. A 71-year-old hemodialysis-dependent woman with ET experienced worsening dyspnea and chest tightness 1 month after starting dual antiplatelet therapy. This therapy was initiated immediately following a percutaneous coronary intervention for an acute non-ST elevation myocardial infarction. Computed tomography revealed a massive pericardial effusion, and echocardiography confirmed cardiac tamponade. Ultrasound-guided pericardiocentesis yielded hemorrhagic fluid, establishing the diagnosis of hemorrhagic cardiac tamponade. Pericardiocentesis resolved the effusion, but recurrent non-ST elevation myocardial infarctions and in-stent restenosis necessitated repeated balloon angioplasty. Discontinuation of aspirin and the addition of cilostazol to clopidogrel failed to prevent further complications. The patient later developed pulse ventricular tachycardia in the emergency department, and after her family declined cardioversion, she died. This case exemplifies the complex challenges of managing thrombotic and hemorrhagic risks in ET patients with cardiovascular disease and renal impairment, highlighting the necessity for tailored therapeutic strategies and further research.

Myeloproliferative neoplasms (MPN) are chronic bone marrow malignancies. While the prognosis is generally good, patients can face complications leading to reduced life expectancy. However, no population-based studies have quantified the life expectancy (LEC) and loss in life expectancy (LLE) following MPN. In this population-based study, we included individuals diagnosed with MPN in Sweden aged 50 and older between 2002 and 2021, with follow-up until 2022. We used flexible parametric relative survival models with a period analysis (2012-2021) to estimate LEC and LLE. We also estimated 15-year restricted mean survival time (RMST) and the loss in 15-year restricted mean survival time (LRMST) for each MPN subtype: polycythaemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The average LEC was 11.4 (95% CI, 11.2-11.7) and LLE was 4.3 years (95% CI, 4.1-4.6). For the MPN subtypes, the average 15-year LRMST was 1.8 (95% CI, 1.7-2.0) in PV, 1.3 (95% CI, 1.1-1.4) in ET, and 4.4 years (95% CI, 4.0-4.8) in PMF. Our study shows that life expectancy is lower in all MPN subtypes compared to the general population. By quantifying LEC and LLE, our research offers insights into the impact of MPN on an individual's lifespan beyond the diagnosis.

ABSTRACTPeripheral gangrenes have been sporadically documented as the initial presentation of essential thrombocythemia (ET), as exemplified in the preceding case reports. Nevertheless, the prevalence of vasculitis‐induced skin problems as the primary indication of ET has not been extensively examined. Our case distinguishes itself in this regard, as it proposes a fresh outlook on the etiology of ET. A 52‐year‐old male presented with worsening pain and bruising in the right toes, following auto‐amputation of the left fourth fingertip due to gangrene a month earlier. Examination revealed necrotic wounds on multiple toes. Dorsalis pedis pulses were palpable, and sonography ruled out obstructions. Splenomegaly and thrombocytosis prompted consideration of ET. Marrow analysis confirmed myeloproliferative neoplasia with negative JAK2, CALR, and MPL mutations. Axonal polyneuropathy was evident, and skin biopsy showed leukocytoclastic vasculitis (LCV). The patient was diagnosed with undifferentiated vasculitis, characterized by total signs of ischemia and gangrene of the fingertips, splenomegaly, triple‐negative ET, neuropathy (medium vessel involvement), and cutaneous LCV (small vessel involvement). The patient received prednisolone at a dosage of 1 mg/kg and azathioprine concurrently with hydroxyurea, aspirin, cilostazol, and sildenafil. The results indicate a fresh perspective, suggesting that ET may potentially contribute to the development of LCV. The main takeaway lesson from this atypical manifestation highlights the wide range of clinical manifestations associated with ET and encourages further investigation into the complex relationship between thrombocythemia and vasculitis processes. As we delve deeper into these distinct presentations, we gain a more comprehensive understanding of the diverse aspects of ET pathology.