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.     

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.     

Blood pressure and cardiovascular involvement in children with neurofibromatosis type1

We evaluated blood pressure in a sample of patients with neurofibromatosis type 1 (NF1), using ambulatory blood pressure monitoring (ABPM), to determine whether ABPM, when compared with casual BP recordings, allowed the detection of a higher risk for hypertension. We also evaluated the correlation between BP and vascular abnormalities. We studied 69 NF1 patients (36 males and 33 females) with a mean age of 11±4 years, divided into group A, with 24-h mean systolic blood pressure (SBP) or diastolic blood pressure (DBP) <95th percentile, and group B, with mean SBP or DBP >95th percentile. Standard electrocardiography and M-mode, two-dimensional echocardiography were performed and all patients were in sinus rhythm. ABPM identified 11 hypertensive patients (16%); 5 had a mean SBP >95th percentile, 3 mean SBP–DBP >95th percentile, and 3 a mean DBP >95th percentile. Laboratory and other investigations to exclude secondary hypertension were normal. Cardiac abnormalities were found in 13 of the 69 patients (18.8%) with NF1. There were no significant clinical and cardiac differences between the normotensive and hypertensive group. Our data emphasize the importance of periodic ABPM in NF1 patients to diagnose hypertension early and avoid target organ damage and increased mortality.     

Trauma-induced systemic inflammatory response versus exercise-induced immunomodulatory effects

Accidental trauma and heavy endurance exercise, both induce a kind of systemic inflammatory response, also called systemic inflammatory response syndrome (SIRS). Exercise-related SIRS is conditioned by hyperthermia and concomitant heat shock responses, whereas trauma-induced SIRS manifests concomitantly with tissue necrosis and immune activation, secondarily followed by fever. Inflammatory cytokines are common denominators in both trauma and exercise, although there are marked quantitative differences. Different anti-inflammatory cytokines may be involved in the control of inflammation in trauma- and exercise-induced stress. Exercise leads to a balanced equilibrium between inflammatory and anti-inflammatory responses. Intermittent states of rest, as well as anti-oxidant capacity, are lacking or minor in trauma but are high in exercising individuals. Regular training may enhance immune competence, whereas trauma-induced SIRS often paves the way for infectious complications, such as sepsis.     

Unilateral Dichotomy of Nipple (Intraareolar Polythelia) and Areola: Report of a Case and Surgical Correction

An unusual case of intraareolar polythelia with two nipples is presented. The dichotomy affected not only the nipple, but also the areola. No other breast malformation existed. Surgical correction was performed by transposition flaps sutured to one another in the center of the areola. The anatomic and functional results were satisfactory.     

Digital cineradiology in the diagnosis and surgical treatment of pharyngo-oesophageal junction motor disorders

The aim of the study was to report our experience with the use of radiology in functional disorders of the cricopharyngeal muscle and their surgical therapy using digital cineradiology. Five-hundred and seventy dysphagic patients underwent dynamic study of the oral and pharyngeal phases of swallowing (Videofluoroscopic Swallowing Study, VFSS). A motor disorder of the cricopharyngeal muscle was diagnosed by videofluorography in 19 patients: the disorder was mild in 8, moderate in 7 and severe in 4. Two of these underwent cricopharyngeal myotomy, with an improvement in their dysphagia and swallowing mechanisms. VFSS provides a morphological and functional view of the aero-digestive tracts: this is essential in the diagnosis of cricopharyngeal dysfunction and is capable of revealing the related laryngeal penetration and tracheal aspiration. VFSS must always include an oesophageal phase study because of the known clinical and physico-pathological correlations between the gastro-oesophageal junction and the upper oesophageal sphincter. On the basis of our experience we believe that VFSS could be used as a primary investigation, followed by motility studies, and that it may be a useful complementary procedure both in the diagnosis of pharyngo-oesophageal junction motor disorders and with a view to surgical indications.     

Selective attention deficits reflect increased genetic vulnerability to schizophrenia

BACKGROUND: Impairment in attention is prominent in schizophrenia and may be a valuable genetic indicator for vulnerability to this disease. AIMS: We set out to characterize the attention deficits that may be associated with genetic liability to schizophrenia. METHODS: We compared attention performance in 55 people with schizophrenia, 95 of their first-degree relatives, and 61 unrelated controls. We also segregated presumed obligate carriers of genetic risk (POCs, N=12) and compared their performance with that of controls. RESULTS: Although the relatives of people with schizophrenia did not significantly differ from the normal controls on the tasks of attention, their scores were significantly ordered such that patients>relatives>normal controls during tasks of sustained and selective attention as measured by the Jonckheere-Terpstra Test (p<.05). Additionally, POCs were significantly worse than normal controls during selective attention tasks such as the Stroop (p=.03) and Letter Cancellation Task (p=.04). CONCLUSIONS: Heterogeneity in the first-degree relatives may have diluted the attention deficits present in those who are at genetic risk for schizophrenia. On the other hand, our findings in the more homogeneous group of POCs suggest that selective attention may be an indicator of genetic liability for schizophrenia.     

Lipopolysaccharide delays demyelination and promotes oligodendrocyte precursor proliferation in the central nervous system

Systemic infection can influence the course in many diseases of the central nervous system (CNS) such as multiple sclerosis (MS), yet the relationship between infection outside the CNS and potential damage and/or protection within the CNS is still not understood. Activation of microglia is a characteristic feature of most CNS autoimmune disorders, including MS, and both protective and degenerative functions of microglia have been proposed. Hence, we analyzed the effects of a systemic inflammatory reaction induced by peripheral treatment with lipopolysaccharide (LPS) on microglial reaction and cuprizone induced de- and remyelination. We found that LPS administration delayed demyelination, which was linked with inhibition of microglial proliferation and reduced numbers of activated microglia. The phenotype of microglia changed as an increase of Toll-like receptor 4 was found. During remyelination, LPS treatment delayed the onset of myelin protein re-expression, but later there was a beneficial effect via an increase of proliferating oligodendrocyte precursor cells (OPC) and mature oligodendrocytes. Moreover, the expression of ciliary neurotrophic factor was increased in response to LPS, a growth factor known to mediate OPC proliferation. Additional experiments showed that the time window to induce LPS effects was limited and associated with the presence of microglia. In conclusion, LPS delayed demyelination and caused beneficial effects on remyelination via increasing the proliferation of OPC. These differences seem to be an effect of LPS induced microglial modulation and indicate that exposure to certain infectious agents within a given time window may be beneficial in promoting tissue repair.     

Reference charts for weight gain and body mass index during pregnancy obtained from a healthy cohort

Objective. To create reference charts for weight gain and body mass index (BMI) in pregnancy derived from longitudinal data obtained in a representative sample of the Argentinean population.

Methods. A prospective cohort of 1439 healthy pregnant women was selected from antenatal clinics in seven different urban regions in Argentina. Serial anthropometric measurements were made at weeks 12, 16, 20, 24, 28, 32, 36 and in the last pre-natal control. Centile curves of body weight and BMI by gestational age were developed using the LMS method.

Results. Mean weight gain at 38 weeks of gestation was 11.9 ± 4.4 kg. There were no differences in total weight gain between women who enter pregnancy with low, normal or overweight; only those women with a pre-pregnancy BMI in the range of obesity showed a significantly lower weight gain (10.2 ± 4.8 kg). At 12 weeks of pregnancy, BMI values of the 10th, 50th and 90th centiles were 19.3, 22.8 and 29.0, and at 38 weeks these values were 23.3, 27.4 and 33.8, respectively.

Conclusion. This BMI for gestational age chart, based on women who delivered normal birth weight infants and processed with modern statistical methods, represents an improvement in pre-natal care monitoring.