The prognostic impact of non-driver gene mutations and variant allele frequency in primary myelofibrosis.

Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.

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.

Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing.

Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.

Application of IPSET-thrombosis in 1366 Patients Prospectively Followed From the Spanish Registry of Essential Thrombocythemia.

The International Prognostic Score of thrombosis in Essential Thrombocythemia (IPSET-thrombosis) and its revised version have been proposed to guide thrombosis prevention strategies. We evaluated both classifications to prognosticate thrombosis in 1366 contemporary essential thrombocythemia (ET) patients prospectively followed from the Spanish Registry of ET. The cumulative incidence of thrombosis at 10 years, taking death as a competing risk, was 11.4%. The risk of thrombosis was significantly higher in the high-risk IPSET-thrombosis and high-risk revised IPSET-thrombosis, but no differences were observed among the lower risk categories. Patients allocated in high-risk IPSET-thrombosis (subdistribution hazard ratios [SHR], 3.7 [95% confidence interval, CI, 1.6-8.7]) and high-risk revised IPSET-thrombosis (SHR, 3.2 [95% CI, 1.4-7.45]) showed an increased risk of arterial thrombosis, whereas both scoring systems failed to predict venous thrombosis. The incidence rate of thrombosis in intermediate risk revised IPSET-thrombosis (aged >60 years, JAK2-negative, and no history of thrombosis) was very low regardless of the treatment administered (0.9% and 0% per year with and without cytoreduction, respectively). Dynamic application of the revised IPSET-thrombosis showed a low rate of thrombosis when patients without history of prior thrombosis switched to a higher risk category after reaching 60 years of age. In conclusion, IPSET-thrombosis scores are useful for identifying patients at high risk of arterial thrombosis, whereas they fail to predict venous thrombosis. Controlled studies are needed to determine the appropriate treatment of ET patients assigned to the non-high-risk categories.

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis.

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.

BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.

Teachers' conceptions about approaches of activities in nature in the physical education classroom / Concepções dos professores sobre a abordagem das atividades na natureza na aula de educação física

ABSTRACT The objective is to understand the conceptions that Physical Education teachers have about Activities in Nature (ACN) that occur in the school context. The research is based on the interpretive paradigm with qualitative methodology, in which a semi-structured interview was applied to 12 high school Physical Education teachers in the city of Talca-Chile. The results indicate that these activities, among other things, contribute to a greater environmental awareness on the part of students, enabling the realization of different bodily practices in the natural environment. It is concluded that teachers need more training in the area, as the ACN become a pedagogical strategy that privileges autonomy, reflection and the development of values, fundamental issues for the integral development of young people and adolescents.

RESUMO O objetivo é compreender as concepções que os professores de Educação Física têm sobre as Atividades em Contato com a Natureza (ACN) que ocorrem no contexto escolar. A pesquisa se baseia no paradigma interpretativo com metodologia qualitativa, em que foi aplicada uma entrevista semiestruturada a 12 professores de Educação Física do ensino médio da cidade de Talca-Chile. Os resultados indicam que essas atividades, entre outras coisas, contribuem para uma maior consciência ambiental por parte dos alunos, possibilitando a realização de diferentes práticas corporais no ambiente natural. Conclui-se que os professores necessitam de maior formação na área, visto que as ACN tournarm-se uma estratégia pedagógica que privilegia a autonomia, a reflexão e o desenvolvimento de valores, questões fundamentais para o desenvolvimento integral de jovens e adolescentes.

Efectos de un programa multicomponente sobre medidas antropométricas, condición física y calidad de vida relacionada con la salud en personas mayores / Effects of a multicomponent program on anthropometric measures, physicalfitness and health-related quality of life in older people

INTRODUCCIÓN: El envejecimiento provoca, entre otros cambios, disminución de la masa muscular y reducción de la independencia funcional. La práctica regular de actividad física es considerada una herramienta esencial para lograr un envejecimiento saludable. OBJETIVO: Analizar los efectos de un programa de entrenamiento multicomponente sobre medidas antropométricas, condición física y calidad de vida relacionada con la salud en personas mayores independientes funcionalmente. MATERIAL Y MÉTODOS: Estudio pre-experimental (con pre y post evaluación) que contó con 17 personas mayores (13 mujeres y 4 hombres) con una edad media de 72,5 años. Se evaluaron medidas antropométricas básicas (peso corporal, estatura bípeda e índice de masa corporal [IMC]), condición física a través del Senior Fitness Test y la calidad de vida relacionada con la salud por medio de la encuesta SF-36. Se realizaron comparaciones pre y post intervención a través de las pruebas t de Student y Wilcoxon considerando un p < 0,05. RESULTADOS: Luego de 12 semanas de intervención las personas mayores reportaron una reducción significativa (p < 0,001) del peso corporal e IMC. Aumento significativo (p < 0,05) en las pruebas relacionadas con la fuerza del tren inferior y superior, capacidad cardiorrespiratoria, agilidad y equilibrio dinámico, y una reducción significativa (p < 0,05) en la distancia entre manos (para la flexibilidad del tren superior) y entre manos y pie (para la flexibilidad del tren inferior). Además, se presentó un aumento significativo (p < 0,05) en siete dimensiones de la calidad de vida relacionada con la salud (i.e. función física, rol físico, salud general, vitalidad, función social, rol emocional y salud mental) y una reducción significativa (p = 0,000) del dolor corporal. CONCLUSIONES: Existe una reducción significativa del peso corporal e IMC y un aumento significativo de la condición física y calidad de vida relacionada con la salud en personas mayores luego de 12 semanas de participación en un programa de entrenamiento multicomponente

INTRODUCTION: Aging causes, among other changes, a decrease in muscle mass and a reduction in functional independence. Regular physical activity is considered an essentialtool for healthy aging. AIM: To analyze the effects of a multicomponent training program on anthropometric measures, physical fitness and health-related quality of life in independent older people. MATERIAL AND METHODS: Pre-experimental study (withpre- and post-evaluation) that included 17 older people (13 women and 4 men) with a mean age of 72.5 years. Basic anthropometric measures, physical fitness through the Senior Fitness Test, and health-related quality of life were evaluated through the SF-36 survey. Pre- and post-intervention comparisons were made through Student's t test and Wilcoxon considering a p <0.05. RESULTS: After 12-weeks of intervention, older people reported a significant reduction (p <0.001) in body weight and BMI. Significant increase (p <0.05) in tests related to lower and upper body strength, cardiorespiratory capacity, agility and dynamic balance, and a significant reduction (p < 0.05) in the distance between hands (for upper body flexibility) and between hands and feet (for lower body flexibility). In addition, there was a significant increase (p <0.05) in seven dimensions of health-related quality of life (i.e. physical function, physical role, general health, vitality, social function, emotional role and mental health) and a significant reduction (p = 0.000) in body pain. CONCLUSIONS: There is a significant reduction in bodyweight and BMI and a significant increase in physical fitness and health-related quality of life in older people after 12-weeks of participation in a multi-component training program

Patients' perceptions with dabigatran in patients with atrial fibrillation previously treated with vitamin K antagonists.

Aim: To analyze the perception of anticoagulation with dabigatran in patients with nonvalvular atrial fibrillation previously treated with vitamin K antagonists over a 6-month period. Materials & methods: This is a prospective, noninterventional, noncontrolled, multicenter study. To assess patients' perceptions, PACT-Q2 questionnaire was completed. Results: Six hundred and fifty nine patients (73.1 ± 9.4 years, CHA2DS2-VASc 3.6 ± 1.6) were included. At baseline, the convenience and satisfaction scores were 60.9 ± 24.9 and 49.9 ± 17.7, respectively. The scores significantly increased along the study. Convenience score was higher in males and in patients with low-moderate thromboembolic risk. Satisfaction score was higher in females. Only 8.0% of patients discontinued dabigatran (3.7% due to side effects). Conclusion: Convenience and satisfaction scores for nonvalvular atrial fibrillation patients treated with dabigatran at 6 months were significantly better than with previous vitamin K antagonists.

Identification of daily environmental noise patterns in two different urban sites in Santiago, Chile / Análisis de ruido ambiental en Santiago, Chile

Background: Environmental noise can cause auditory and non-auditory adverse effects. Aim: To identify daily environmental noise patterns in two urban sites of Metropolitan Santiago. Material and Methods: Continuous measurements of environmental noise in two sites of Metropolitan Santiago were analyzed by means of hierarchical cluster analysis. One site was a main street with heavy traffic and the second was a street from a neighborhood with intense nocturnal activity. The first phase of analysis consisted of clustering noise profiles with similar shapes according to the average linkage method, with correlation as the similarity measure. The second phase grouped the profiles with similar shapes into sub-clusters that also had similar absolute noise levels, using the complete linkage method, with absolute distance as the similarity measure. Results: Two noise patterns were identified for the first site, one for weekdays (Monday to Friday) and another for weekends (Saturday and Sunday). For the second site five different patterns were identified (Monday to Wednesday, Thursday, Friday, Saturday, and Sunday). Also different patterns appeared for summer compared to the rest of the year. The noise levels of both sites were high. Conclusions: The detected noise levels can be annoying, cause sleep disturbances and increase the risk for hypertension and cardiovascular diseases, among other effects.

Antecedentes: El ruido ambiental puede tener efectos adversos auditivos y no auditivos. Objetivo: Identificar patrones diarios de ruido ambiental en dos sectores urbanos de Santiago, Chile. Material y Métodos: Se analizaron mediciones continuas de ruido ambiental realizadas en dos emplazamientos urbanos de Santiago, Chile, mediante análisis de cluster jerárquico. Los dos lugares fueron una avenida principal con alto tráfico vehicular y una calle en un barrio con intensa actividad nocturna. La primera fase del análisis agrupó perfiles de ruido con formas similares de acuerdo al método de vinculación promedio, usando la correlación como medida de similitud. La segunda fase agrupó los perfiles con formas similares en subclusters que también tuvieran niveles de ruido similares, usando el método de vinculación completa, con la distancia absoluta como medida de similitud. Resultados: Se identificaron dos patrones para el primer emplazamiento, uno para días de semana (lunes a viernes) y otro para fines de semana (sábado y domingo). Para el segundo emplazamiento se identificaron cinco patrones diferentes (lunes a miércoles, jueves, viernes, sábado, y domingo), así como patrones distintos para el verano en comparación con el resto del año. Los niveles de ruido en ambos lugares fueron altos. Conclusiones: Los niveles de ruido detectados podrían producir molestias, perturbación del sueño, incremento de riesgo de hipertensión y enfermedades cardiovasculares, entre otros efectos.

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

Identification of daily environmental noise patterns in two different urban sites in Santiago, Chile.

BACKGROUND: Environmental noise can cause auditory and non-auditory adverse effects. AIM: To identify daily environmental noise patterns in two urban sites of Metropolitan Santiago. MATERIAL AND METHODS: Continuous measurements of environmental noise in two sites of Metropolitan Santiago were analyzed by means of hierarchical cluster analysis. One site was a main street with heavy traffic and the second was a street from a neighborhood with intense nocturnal activity. The first phase of analysis consisted of clustering noise profiles with similar shapes according to the average linkage method, with correlation as the similarity measure. The second phase grouped the profiles with similar shapes into sub-clusters that also had similar absolute noise levels, using the complete linkage method, with absolute distance as the similarity measure. RESULTS: Two noise patterns were identified for the first site, one for weekdays (Monday to Friday) and another for weekends (Saturday and Sunday). For the second site five different patterns were identified (Monday to Wednesday, Thursday, Friday, Saturday, and Sunday). Also different patterns appeared for summer compared to the rest of the year. The noise levels of both sites were high. CONCLUSIONS: The detected noise levels can be annoying, cause sleep disturbances and increase the risk for hypertension and cardiovascular diseases, among other effects.

Idarucizumab, but not procoagulant concentrates, fully restores dabigatran-altered platelet and fibrin components of hemostasis.

BACKGROUND: Comparative studies on the restoration of hemostasis with different reversal agents after dabigatran therapy have not been performed. We compared the efficacy and prothrombotic potential of the specific antidote idarucizumab with that of previously recommended non-specific procoagulant concentrates. STUDY DESIGN AND METHODS: We explored the in vitro effects of dabigatran (184 ng/mL) on fibrin and platelet-aggregate formation onto a damaged vessel under flow conditions (600 s-1 ). The reversal mechanisms and efficacy of idarucizumab (0.3-3 mg/mL) were compared with that of the non-specific procoagulant concentrates aPCC (25-75 U/Kg), PCC (70 U/Kg), or rFVIIa (120 µg/Kg). Generation of thrombin and prothrombin fragment (F1 + 2), and thromboelastometry parameters of clot formation were measured. RESULTS: Dabigatran caused pronounced reductions in fibrin (87%) and platelet interactions (36%) with damaged vessels (p < 0.01) and significantly impaired thrombin generation and thromboelastometric parameters (delayed dynamics and reduced firmness). Idarucizumab completely normalized rates of fibrin and platelet coverage to baseline values in flow studies; and reversed the alterations in thrombin generation, F1 + 2 and thromboelastometry parameters produced by dabigatran. In comparison, aPCC and PCC only partially compensated for the dabigatran-induced alterations in fibrin deposition, but were unable to fully restore them to baseline values. Reversal with aPCC or PCC improved the majority of alterations in coagulation-related tests, but tended to overcompensate thrombin generation kinetics and significantly increased F1 + 2 levels. CONCLUSION: Idarucizumab antagonizes alterations of direct and indirect biomarkers of hemostasis caused by dabigatran. In our studies, idarucizumab was clearly more efficacious than strategies with non-specific procoagulant concentrates and devoid of the excessive procoagulant tendency observed with the latter.

Essential thrombocythaemia with mutation in MPL: clinicopathological correlation and comparison with JAK2V617F-mutated and CALR-mutated genotypes.

AIM: To characterise the clinical and histological features of MPL-mutated essential thrombocythaemia (ET). PATIENTS AND METHODS: Bone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases with MPL mutation, 98 JAK2V617F-mutated and 35 CALR-mutated. Clinical and histological features were compared among the three genotypes included in the current 2016 WHO classification and among the different types of MPL mutations. RESULTS: Patients with MPL-mutated ET were significantly older than those with the other genotypes. Haematological values at diagnosis were similar among MPL-mutated and CALR-mutated ET, with both genotypes showing higher platelet counts and lower haemoglobin values than ET with JAK2V617F genotype. In the bone marrow, the median number of megakaryocytes was higher in MPL and CALR than in JAK2V617F genotype (16, 19 and 14 megakaryocytes per ×20 power field, respectively, p=0.004). Histological features of prefibrotic myelofibrosis were rarely observed in MPL genotype, whereas sinusoidal hyperplasia, dense clusters of megakaryocytes and reticulin fibrosis were more frequent in CALR-mutated ET, with 11% of such cases fulfilling WHO 2016 histological criteria of prefibrotic myelofibrosis. With a median follow-up of 3.5 years, no significant differences were seen among genotypes regarding survival, vascular complications or myelofibrotic transformation. There were no significant differences in the clinical data or in the histological characteristics depending on the type of MPL mutation. CONCLUSION: MPL and CALR ET genotypes share clinical and histological characteristics. In contrast to CALR genotype, features of prefibrotic myelofibrosis are uncommon in MPL-mutated ET.

Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms.

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.

Betrixaban: a direct oral inhibitor of activated factor X for the prophylaxis of venous thromboembolism in patients hospitalized for acute medical illness.

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a serious clinical and public health concern. Hospitalization is a major risk factor for developing VTE. Hospital-associated events account for more than 50% of all cases of VTE. Heparins have demonstrated to be efficacious in the prevention of VTE in medically ill patients. Despite the demonstrated efficacy and safety of the available direct oral anticoagulants in the prevention and treatment of different thromboembolic conditions, their net benefit in the prevention of VTE in hospitalized medically ill patients has not been fully confirmed. Betrixaban is an oral, specific and direct inhibitor of human coagulation factor Xa with demonstrated efficacy and safety for the prevention of VTE in patients undergoing total knee replacement and in patients with nonvalvular atrial fibrillation. Recent studies have successfully evaluated betrixaban 80 mg once daily in the prevention of VTE in acute medically ill patients in a large phase III trial. This review will address preclinical pharmacology and main aspects of the clinical development of betrixaban as an antithrombotic agent, with specific attention to recent studies on the prophylaxis of VTE in a specific population of patients hospitalized for acute medical illnesses.