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A Tosetto

Publications and source records attributed to A Tosetto.

At least 19 recordsLinked to original sources
PubMed2006

Association of protein S p.Pro667Pro dimorphism with plasma protein S levels in normal individuals and patients with inherited protein S deficiency.

A dimorphism in PROS1 gene (c.A2,001G, p.Pro667Pro) has been associated with significantly reduced levels of both free and total protein S in carriers of the GG genotype. It is not known how the GG genotype could influence PS levels in normals, whether it could influence the levels of protein S in carriers of mutations in PROS1 gene and whether this genotype acts as an isolated or additive risk factor for venous thrombosis. With this as background, we evaluated the association of p.Pro667Pro dimorphism with free and total protein S centrally measured in a panel of 119 normal controls, 222 individuals with low protein S and 137 individuals with normal PS levels belonging to 76 families with protein S deficiency enrolled in the ProSIT study. Transient expression of recombinant wild type protein S and p.Pro667Pro protein S was performed to evaluate the role of the A to G transition at position 2001 in vitro. The p.Pro667Pro polymorphism was also expressed together with a p.Glu67Ala variant to assess a possible influence on protein S levels in protein S deficient subjects. Free and total protein S levels were significantly lower in normal women. In normal women only was the GG genotype associated with significantly lower free protein S levels in comparison to AA and AG genotypes (P=0.032). No significant influence of GG genotype was observed in patients, either with known mutations or with low protein S levels. These data were confirmed by in vitro transient expression, showing no difference in secretion levels of the p.Pro667Pro variant (even in association with the p.Glu67Ala mutation), compared to the wild type protein S. The genotype in itself was neither a significant risk factor for venous thrombosis nor a risk modifier in patients with known mutations.

Adolescent↗
PubMed2006

Prothrombin A19911G polymorphism and the risk of venous thromboembolism.

BACKGROUND: The A > G polymorphism at position 19911 of the prothrombin gene is associated with increased plasma prothrombin levels but its role as a risk factor for venous thromboembolism (VTE) is not established. OBJECTIVE: To investigate the role of prothrombin 19911 A > G polymorphism in the risk of VTE in patients with heterozygous prothrombin 20210GA or factor (F) V Leiden and in those without thrombophilia. PATIENTS AND METHODS: Case-control study of 793 patients with prothrombin 20210 GA (n = 167) or FV Leiden (n = 198), and without thrombophilia (n = 428), and of 795 healthy individuals with the corresponding coagulation profile, investigated for the presence of prothrombin 19911 A > G. Plasma prothrombin levels were measured in 342 individuals. RESULTS: Prothrombin 19911 A > G did not increase the risk of VTE in carriers of prothrombin 20210 GA [odds ratio (OR) 1.2, 95% CI (95% CI) 0.8-1.8] but significantly increased the risk in carriers of FV Leiden (OR 2.1, 95% CI 1.3-3.4) and in patients without thrombophilia (OR 1.5, 95% CI 1.0-2.2). Higher plasma prothrombin levels in carriers of prothrombin 19911 A > G polymorphism than in non-carriers were found among individuals without thrombophilia (P =0.05) and with FV Leiden (P = 0.07), but not in carriers of prothrombin 20210 GA (P = 0.2). CONCLUSIONS: Prothrombin 19911 A > G polymorphism was independently associated with a 1.5-fold increased risk of VTE and increased 2-fold the risk of VTE associated with FV Leiden, both increases statistically significant. No effect was observed in carriers of prothrombin 20210 GA, perhaps because this polymorphism has a stronger influence on plasma prothrombin levels than the prothrombin 19911 polymorphism.

Adenine↗
PubMed2006

Cognitive impairment and carotid atherosclerosis in a general Italian midlife and old population.

The authors describe the design and the general, ultrasonographic, neuropsychological methodology of an observational epidemiological population survey, named REMEMBER (Registry Evaluation Memory in Buttrio e Remanzacco) conducted in the northeast of Italy in a randomized stratified sample of 1,026 subjects (554 F and 472 M) aged 55-98 years. The study was planned as cross-sectional and longitudinal survey of cognitive impairment, cardiovascular risk factors, carotid atherosclerosis in a midlife and older Italian population sample. The objectives of the first phase are to assess the prevalence of the different types of dementia, the cognitive impairment non-dementia, the cardiovascular risk factors, the carotid intima-media thickness and arterial distensibility, and of depression. The conclusions of this study will make it possible to organize preventive and interventional strategies for these epidemic conditions.

Aged↗
PubMed2006

A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD).

BACKGROUND: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. OBJECTIVES: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. PATIENTS AND METHODS: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. RESULTS: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. -1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. CONCLUSIONS: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.

ABO Blood-Group System↗
PubMed2006

Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study.

OBJECTIVES: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). PATIENTS AND METHODS: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. RESULTS: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. CONCLUSIONS: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases.

Adolescent↗
PubMed2005

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Adult↗
PubMed2005

Age-adjusted reference limits for carotid intima-media thickness as better indicator of vascular risk: population-based estimates from the VITA project.

BACKGROUND: An increase of carotid intima-media thickness (CIMT) has been demonstrated to be associated in many studies with the subsequent risk of cardio- and cerebrovascular events, but the threshold level of CIMT for an increased risk at different ages remains uncertain. OBJECTIVES: We aimed at establishing optimal reference limits associated with a definite increased vascular risk in the general population. METHODS: A cohort of 2580 subjects was enrolled in a population-based cross-sectional survey. CIMT was measured on both left and right common carotid arteries, and age-specific, percentile-based reference ranges for CIMT were computed together with the Framingham risk score. RESULTS: A significant, steady increase of CIMT reference ranges was observed within different age strata. CIMT levels were linearly related with an increase of the Framingham risk score, but after age-adjustment only the upper CIMT quintile was associated with a higher Framingham risk score. CONCLUSIONS: Age-specific reference limits provide better estimate of vascular risk in the population and correlation with established risk factors.

Age Distribution↗
PubMed2005

The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study.

OBJECTIVE: The aim of this study was the validation of the criteria defining a significant mucocutaneous-bleeding history in type 1 von Willebrand disease (VWD). SUBJECTS AND METHODS: To avoid selection bias, 42 obligatory carriers (OC) of type 1 VWD were identified from a panel of 42 families with type 1 VWD enrolled by 10 expert centers. OC were identified by the presence of an offspring and another first degree relative with type 1 VWD (affected subjects, AFF). A standardized questionnaire was administered to evaluate hemorrhagic symptoms at the time of first examination, using a bleeding score ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion). Sensitivity, specificity, diagnostic likelihood ratios, positive and negative predictive values for the diagnosis of type 1 VWD were calculated from the data collected in OC and in 215 controls. RESULTS: Having at least three hemorrhagic symptoms or a bleeding score of 3 in males and 5 in females was very specific (98.6%) for the bleeding history of type 1 VWD, although less sensitive (69.1%). None of the misclassified OC had life-threatening bleeding episodes after diagnosis. CONCLUSIONS: We suggest that the use of a standardized questionnaire and bleeding score may be useful for the identification of subjects requiring laboratory evaluation for VWD.

Adult↗
PubMed2003

Prevalence and risk factors of non-fatal venous thromboembolism in the active population of the VITA Project.

Cost-effective strategies for the identification of subjects at risk of venous thromboembolism (VTE) in the active population are still lacking. Our objectives were to identify risk factors for venous thromboembolism in active subjects. We analyzed data from a population-based sample of 15055 Caucasians aged 18-65 years randomly selected from the census list of the township of Vicenza, Italy. A validated methodology was used to retrospectively identify subjects with previous VTE. Body mass index (BMI), smoking, oral contraceptive use, previous superficial vein thrombophlebitis (SVT) and familial history of VTE, all at the age of first thrombosis, were ascertained by direct interview and by review of available medical records. Ninety-two deep vein thromboses [prevalence: 61.1/10000, 95% confidence interval (CI) 49.2-74.9], three upper deep vein thrombosis (prevalence: 1.9/10000, 95% CI 0.4-5.8) and 21 pulmonary embolism (prevalence: 13.9/10000, 95% CI 8.6-21.3) were identified. After age and sex adjustment, clinically identifiable risk factors were: history of SVT [odds ratio (OR) = 6.8], oral contraceptive use (OR = 4.7), family history of VTE (OR = 4.5), smoking (OR = 1.7) and BMI above the third tertile (OR vs. mid-tertile 2.9). While previous SVT and BMI were associated with VTE in all circumstantial situations (surgery/trauma, pregnancy or idiopathic VTE), for oral contraceptive use, positive family history and smoking the degree of association varied significantly depending on the situation. Non-fatal VTE affects 0.7% of the subjects belonging to an active population, 56% of cases being potentially preventable. In 30% of VTE cases, at least two easily recognizable risk factors are present. Clinical assessment of risk factors remains the mainstay of VTE prevention.

Adolescent↗
PubMed2001

Congenital absence of the inferior vena cava: a rare risk factor for idiopathic deep-vein thrombosis.

Congenital absence of the inferior vena cava (AIVC) is a rare vascular defect, commonly reported as a fortuitous finding. The presence of AIVC in patients with DVT is underestimated because AIVC cannot be detected by compression B-mode ultrasonography. By use of computed tomography, we diagnosed four cases of AIVC in young patients with idiopathic DVT over a 5 year period. Based on the occurrence of DVT in patients below 30 years in our area during the same period, we estimate that AIVC is present in about 5% of cases of DVT in young patients. Computed tomography or angiography should be used for the diagnosis of idiopathic DVT in young patients.

Adolescent↗
PubMed2001

Phenotypic APC resistance in carriers of the A20210 prothrombin mutation is associated with an increased risk of venous thrombosis.

We hypothesized that increased prothrombin levels associated with G20210A prothrombin gene mutation could affect the results of activated protein C (APC) resistance phenotype and increase the risk of venous thrombosis (VT). The increasing addition of purified prothrombin in plasma of 90 normal subjects resulted in a parallel significant increase of APC resistance. Significantly different mean n-APC-SR in 879 GG20210 subjects compared to 27 heterozygous carriers of isolated G20210A mutation was observed (1.0 +/- 0.12 vs. 0.95 +/- 0.11; P = 0.02) in a random sample of 906 normal population subjects. Twenty-seven families with VT and isolated G20210A mutation consecutively diagnosed during 1998-1999 were evaluated. Mean n-APC-SR was significantly lower in the 80 G20210A carriers compared to 58 GG 20210 relatives investigated, even after sex and age adjustment (0.92 +/- 0.08 vs. 1.05 +/- 0.13; P < 0.0001). A strong relationship between plasma prothrombin level and n-APC-SR was observed in the families. When n-APC-SR values were grouped in tertiles, the odds ratio for VTE, after exclusion of the index cases and adjustment for 20210 status, for subjects in the lowest tertile (n-APC-SR 0.73-0.90) was 4.58 (95% CI 0.78-26.88) compared to upper tertile (n-APC-SR 1.01-1.30). In conclusion, in subjects with G20210A mutation APC resistance is significantly increased, correlates with plasma prothrombin level and the carriers with the lowest APC resistance values have an increased risk of VTE.

3' Untranslated Regions↗
PubMed2000

The A20210 allele in the prothrombin gene enhances the risk of venous thrombosis in carriers of inherited protein S deficiency.

Sixteen families with inherited protein S deficiency and venous thromboembolism (VT) were screened for the presence of factor V (FV) Leiden mutation and for the G20210A allele in the prothrombin gene. While FV Leiden was not detected in any of the families, protein S deficiency and prothrombin mutation were present in five families. To assess the risk of VT in carriers of the combined defects, a total of 92 members of the 16 families, including propositi, were examined. Thirty subjects were normal, 40 showed protein S deficiency, 10 the prothrombin mutation and 12 showed both abnormalities. When index cases were excluded, thrombosis history were present in 40.7% of protein S-deficient patients, 75% of patients with combined abnormality, one out of the 10 (10%) with prothrombin mutation and only one (3.3%) of the normal subjects. Relatives with combined defects showed the highest incidence rate of VT in comparison with normal relatives (rate ratio = 32.4), those with protein S deficiency an intermediate degree (rate ratio = 15.7), and G20210A relatives the lowest (rate ratio = 3.4). Relatives with combined defects had an increased risk of VT in comparison with relatives with protein S deficiency (incidence rate ratio 2.1; 95% confidence interval, 0.7-5.41; P = 0.1). In conclusion, the presence of the prothrombin mutation seems to increase the risk of VT carriers of protein S deficiency, although additional families are required to fully estimate the magnitude of risk.

Adult↗
PubMed2000

The VITA Project: heritability of resistance to activated protein C. Vincenza Thrombophilia and Arteriosclerosis.

Resistance to activated protein C (APC) is a risk factor for venous thromboembolism also in absence of the FV Leiden mutation. To evaluate the influence of genetic factors on APC resistance, we evaluated the heritability of the APC resistance phenotype in 1,519 sib-parent pairs randomly selected from the VITA Project. After adjustment for known influencing factors, a high heritability coefficient (0.58) was observed and parental response to APC was the single most important factor in predicting the corresponding phenotype in sibs. In 32 parent-sib pairs in which phenotypic resistance to APC unrelated to FV Leiden was present in both parents and sibs, no additional mutation on the 306-aminoacid residue of FV (FV Cambridge and FV Hong Kong) was found. In these 32 parent-sib pairs, FVIII:C and vWf:Ag levels were not significantly increased and there was no excess prevalence of the R2 allele of exon 13 of FV gene. This study suggests that the response to APC is significantly influenced by genetic factors also at a population level, but the responsible mechanisms are still undefined.

Activated Protein C Resistance↗