Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings

Objective

To calculate the prevalence of common gain of function gene mutations in patients with different clinical manifestations of venous thromboembolism.

Design and setting

Case–control study in two hospitals in Italy.

Participants

387 patients with venous thromboembolism and 286 controls.

Main measures

Factor V (FV) Leiden, factor II (FII) A20210 and JAK2 V617F mutations.

Results

Among patients with deep vein thrombosis in one leg, 23 (20.9%) carried FV Leiden and FII A20210 mutations. Similar figures were observed in patients with cerebral vein thrombosis (CVT; n = 9; 20.0%) and in patients presenting with splanchnic vein thrombosis (SVT; n = 26; 18.7%). A lower prevalence was obtained in patients with retinal vein thrombosis (n = 11; 11.8%). The JAK2 F617 mutant allele was found in 27 (21.1%) patients with SVT, but in none of the patients presenting with a thrombotic event from different districts. 13 of the 27 JAK2 V617F‐positive subjects with SVT were previously known to have a myeloproliferative disease (MPD). Three other patients had a diagnosis of MPD after the occurrence of the thrombotic event.

Conclusion

Carriership of FV Leiden or FII A20210 mutations identifies an at‐risk condition for venous thrombosis in the lower extremities, SVT or CVT. In patients with SVT, screening for the JAK2 V617F mutation may be useful in recognising patients who should be carefully observed for the subsequent development of overt MPD. Thus, genetic tests may play a different role, various clinical manifestations of venous thromboembolism being associated with distinct risk profiles.Venous thrombosis is the third most common cardiovascular affliction after ischaemic heart disease and stroke.¹ It is common in Caucasians, affecting 1 in 1000 individuals every year, and is strongly associated with life‐threatening pulmonary embolism. The pathogenesis of venous thrombosis is multifactorial, involving acquired and genetic factors. In addition to circumstantial predisposing factors (eg, surgery, pregnancy, immobilisation and malignancy), genetic predisposition due to molecular abnormalities of components of the coagulation pathway have been found in subjects who had had thromboembolic disease.² Abnormalities within the gene loci encoding for natural anticoagulants (antithrombin, protein C and protein S) and for fibrinogen have been shown to be rather uncommon risk factors for venous thrombosis.³ In patients of European ancestry, common gain‐of‐function mutations within the gene of the coagulation factor V (FV Leiden mutation) and the factor II (FII) gene (a G→A transition at nucleotide position 20210) have been shown to account for a large number of cases of thromboembolism.^2,3 Recently, the JAK2 V617F mutation, an acquired somatic event occurring in most patients with polycythaemia vera (PV) and in about half of the patients with essential thrombocythaemia (ET) or myelofibrosis (MF),^4,5,6,7,8 has been found in a high proportion of patients with Budd–Chiari syndrome⁹ and in patients without cirrhosis with portal and mesenteric venous thrombosis, a heterogeneous group of disorders.¹⁰Thus, the high frequency of common mutations in patients presenting with venous thromboembolism raised the hypothesis that it can be considered as a feasible and practical approach for the identification of predisposing genetic risk factors. Genetic test results can better inform individuals about their risk of recurrence and appropriated tailored strategies for the prevention of venous thrombosis.However, depending on the different clinical manifestations of venous thromboembolism, the prevalence of inherited coagulation abnormalities varies, suggesting pathogenic differences.^11,12,13 These data support the hypothesis that mechanistic differences are involved in the pathogenesis of thrombosis in different clinical settings. Thus, before considering whether it is advisable to investigate a subject for inherited risk factors, we need to know the prevalence of these risk factors in different clinical settings.We, therefore, calculated the prevalence of inherited thrombophilic risk factors in a large cohort of patients referred for a thrombophilic investigation with different clinical manifestations of venous thromboembolism.     

Confirmatory factor analysis and measurement invariance by gender,age and levels of psychological distress of the short TEMPS-A

Background

The Temperament Evaluation of Memphis, Pisa, Paris and San Diego – Autoquestionnaire (TEMPS-A) is a widely used self-reported tool aimed at measuring the affective temperaments that define the bipolar spectrum, with cyclothymic, depressive, irritable, hyperthymic, and anxious subscales. Confirmatory factor analysis (CFA) was rarely used to confirm the expected five-factor model. Measurement invariance was never tested.

Methods

Cross-sectional, survey design involving 649 Italian college students (males: 47%). The short 39-item TEMPS-A and the 12-item General Health Questionnaire (GHQ-12) were used as measures of the affective temperaments and of psychological distress, respectively. CFA was applied to the TEMPS-A. Measurement invariance by gender, age and levels of psychological distress on the GHQ-12 was calculated with the establishment of subsequent equivalence constraints in the model parameters across groups.

Results

The expected five-factor model had the best fit for all CFA indexes. Configural, metric and scalar invariance of the five-factor model of the TEMPS-A was proved across gender, age and levels of psychological distress of the participants. The hyperthymic temperament subscale has low or no links with the other affective temperament subscales, which were interrelated with medium to large effect sizes.

Limitations

College students might be not representative of the general population. No information on the clinical status of the students was available beyond self-report data.

Conclusion

The study proved the measurement invariance of the (short) TEMPS-A, which is a pre-requisite to compare groups or individuals in cross-sectional and longitudinal surveys. Generalizability cannot be assumed without replication of the findings in clinical samples.     

Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: A role for the JAK2 V617F mutation re-evaluation

Introduction

Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN.

Materials and Methods

A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed.

Results

In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation.The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p = 0.032). The thrombosis-free survival was lower in patients with (p = 0.04) or developing later MPN and the JAK2 V617F mutation (p = 0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups.

Conclusions

MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients.     

An EEG index of sensorimotor interhemispheric coupling after unilateral stroke: clinical and neurophysiological study

Brain connectivity has been employed to investigate on post‐stroke recovery mechanisms and assess the effect of specific rehabilitation interventions. Changes in interhemispheric coupling after stroke have been related to the extent of damage in the corticospinal tract (CST) and thus, to motor impairment. In this study, we aimed at defining an index of interhemispheric connectivity derived from electroencephalography (EEG), correlated with CST integrity and clinical impairment. Thirty sub‐acute stroke patients underwent clinical and neurophysiological evaluation: CST integrity was assessed by Transcranial Magnetic Stimulation and high‐density EEG was recorded at rest. Connectivity was assessed by means of Partial Directed Coherence and the normalized Inter‐Hemispheric Strength (nIHS) was calculated for each patient and frequency band on the whole network and in three sub‐networks relative to the frontal, central (sensorimotor) and occipital areas. Interhemipheric coupling as expressed by nIHS on the whole network was significantly higher in patients with preserved CST integrity in beta and gamma bands. The same index estimated for the three sub‐networks showed significant differences only in the sensorimotor area in lower beta, with higher values in patients with preserved CST integrity. The sensorimotor lower beta nIHS showed a significant positive correlation with clinical impairment. We propose an EEG‐based connectivity index which is a measure of the interhemispheric cross‐talking and correlates with functional motor impairment in subacute stroke patients. Such index could be employed to evaluate the effects of training aimed at re‐establishing interhemispheric balance and eventually drive the design of future connectivity‐driven rehabilitation interventions.     

Hyperandrogenemia influences the prevalence of the metabolic syndrome abnormalities in adolescents with the polycystic ovary syndrome

Objective.?The prevalence of the metabolic syndrome (MBS) abnormalities in Italian adolescents with polycystic ovary syndrome (PCOS) was evaluated.

Design.?Retrospective chart review.

Setting.?University outpatient clinic.

Participants.?Fifty-three adolescents with PCOS.

Interventions.?Subjects underwent a physical evaluation. Fasting blood samples were taken for the evaluation of metabolic parameters.

Main outcome measures.?The prevalence of MBS abnormalities according to de Ferranti criteria was assessed.

Results.?9.4% of adolescents with PCOS had the MBS (three abnormalities). Twelve girls (22.7%) had two abnormalities. Seventeen (32.1%) of PCOS girls have no MBS abnormalities. PCOS adolescents with the MBS were more obese, insulin resistant and they had significantly higher levels of total and free testosterone. The number of metabolic abnormalities correlated with free, total testosterone, free androgen index (FAI) and body mass index (BMI). Groups with two or three abnormalities were not differentiated by BMI, insulin, lipids, blood pressure, but they were differentiated by total and free testosterone and FAI. Adolescents with the MBS have higher total and free testosterone and FAI than girls with two MBS abnormalities.

Conclusions.?The MBS and its components are present in some adolescents with PCOS, placing them at increased risk for cardiovascular disease early in adulthood. Hyperandrogenemia is a risk factor for MBS independent of obesity.     

The institution of a Multi‐disciplinary Italian Breast Unit: Reflections of the first psychosocial research study results on distress and quality of life

Breast cancer affects patients both emotionally and physically. It is time to consider distress as the sixth vital sign in breast cancer patients in Europe. Between 2012 and 2015, our EUSOMA‐certified multi‐disciplinary group conducted a study on emotional distress and quality‐of‐life in breast cancer patients at diagnosis, and observed their trend over the first 8 months of treatment. One hundred and forty‐nine patients concluded the program. The psycho‐oncologist and the breast nurses gave out SF36, Hospital Anxiety and Depression Scale and Distress Thermometer. Our Italian data go along with the reported literature on distress and quality‐of‐life. Despite modern advances, experiencing breast cancer impacts on overall quality‐of‐life.     

如何改善靶向药物在胆管癌中的疗效？

10年中胆管癌(CC)的处理方法已经有了巨大的改变.仅仅在几年前,胆管癌晚期患者还没有效的治疗方案,只有支持治疗.并且在没有有效证据及随机研究结果的情况下,常给予患者姑息化疗. 根据两个随机试验的结果已经建立了一个新的治疗标准:吉西他滨和铂化合物的联合化疗方案已被证明能显著延长胆道肿瘤不能手术切除的患者的生存期[1-2].此外,新治疗方式的发展,包括具有开拓性的靶向性治疗也正开辟治疗CC的新途径[3].毫无疑问,考虑如何针对不同肿瘤类型使用新制剂治疗是个合乎时机的研究主题.一些Ⅱ期靶向药物研究,主要是抗-EGFR和VEGF药物,但是结果仍不明确.     

Occurrence of ocular disease in traumatic brain injury in a selected sample: a retrospective analysis

Primary objective: To determine retrospectively the relative risk of ocular disease in a selected, visually-symptomatic sample of clinic patients having traumatic brain injury (TBI; n = 160) vs. cerebrovascular accident (CVA; n = 60), with all initially presenting at the clinic with symptoms and/or signs of vision dysfunction.

Methods and procedures: To review retrospectively 220 medical records of individuals with TBI (n = 160) vs. CVA (n = 60), as determined by a computer-based query spanning the years 2000-2003, to ascertain the frequency of occurrence of ocular disease in the two major sub-groups of acquired brain injury.

Main outcomes and results: Conditions with high relative risk unique to TBI included corneal abrasion, blepharitis, chalazion/hordeolum, dry eye, traumatic cataract, vitreal prolapse and optic atrophy. This is distinct from those ophthalmic conditions unique to CVA, which included sub-conjunctival haemorrhage and ptosis.

Conclusion: These new findings should alert clinicians to the potential increased frequency of occurrence of specific ocular diseases in a selected, visually-symptomatic population with TBI and their associated rehabilitative and quality-of-life implications.