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A Tosetto

Publications and source records attributed to A Tosetto.

At least 37 records · Page 2Linked to original sources
PubMed1999

Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism.

BACKGROUND: Resistance to activated protein C due to the factor V R506Q (Leiden) mutation is the most common clotting abnormality in patients with venous thromboembolism. OBJECTIVE: To evaluate the risk for venous thromboembolism associated with the factor V Leiden mutation or with resistance to activated protein C in the general population. DESIGN: Cross-sectional survey. SETTING: General community of Vicenza, Italy. PATIENTS: A population-based sample of 15,109 white persons 18 to 65 years of age who were randomly selected from the census list. MEASUREMENTS: Sequential validated approach based on participants' reports and Doppler ultrasonography. Resistance to activated protein C was investigated in all participants; 2134 participants with resistance to activated protein C were screened for the factor V Leiden mutation. RESULTS: Carriers of the factor V Leiden mutation had a relative risk of 3.3 (95% CI, 1.7 to 6.1) for venous thromboembolism before 65 years of age. The fraction of cases attributable to the factor V Leiden mutation was 6.6%. By 65 years of age, 5.7% of carriers of the mutation had had venous thromboembolism, mostly after surgery. Participants with a reduced response to activated protein C were at higher risk even if they did not carry the mutation (odds ratio, 1.7 [CI, 1.0 to 2.7]); the attributable risk for venous thromboembolism was 5.1%. CONCLUSIONS: The factor V Leiden mutation and resistance to activated protein C are important, independent risk factors for venous thromboembolism. Screening strategies for the factor V Leiden mutation in patients undergoing surgery or experiencing major trauma cannot be recommended, but phenotypic evaluation of resistance to activated protein C should be encouraged in patients with venous thromboembolism.

Activated Protein C Resistance↗
PubMed1999

Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis.

Pseudohomozygosity for activated protein C resistance (APC-r) is a rare condition due to the association of heterozygous FV Leiden mutation and partial type I FV deficiency. To assess the risk of venous thromboembolism in these subjects, seven families including 11 pseudohomozygotes and 45 relatives were examined. Among the relatives, 16 were heterozygous FV Leiden carriers, nine showed partial FV deficiency and 20 no abnormalities. Deep vein thrombosis occurred in 4/11 (36.3%) pseudohomozygous patients versus 6/16 (37. 4%) FV Leiden carriers and 1/20 (5%) normal relatives. Pseudohomozygotes and FV Leiden carriers had a significantly increased risk of venous thrombosis in comparison to normal relatives (RR 8.8 and 5.7, respectively). There was no difference between the thrombotic risk of pseudohomozygous subjects and of FV Leiden carriers (RR 1.6, 95% CI 0.43-5.7). Furthermore, there was no difference in thrombosis-free survival between pseudohomozygotes and 45 consecutive FV Leiden heterozygous outpatients, suggesting that a referral bias may explain the apparent younger age of thrombosis in the pseudohomozygotes in comparison to relatives with FV Leiden heterozygosity (27 years v 54 years; P = 0.01). Pseudohomozygosity for APC resistance carries a significantly higher risk for venous thromboembolism in comparison to normal subjects, but probably not in comparison to heterozygous FV Leiden carriers.

Activated Protein C Resistance↗
PubMed1999

The VITA project: prothrombin G20210A mutation and venous thromboembolism in the general population.

Recently a new identified genetic variant in the 3'-untranslated region of the prothrombin gene (G20210A allele) associated with increased plasma prothrombin levels has been linked to an increased risk of venous thromboembolism (VTE). Most of our knowledge on the G20210A allele as a risk factor for VTE derives from a population-based case-control study and from studies on selected series of VTE patients. To determine the importance of the G20210A allele as a causative risk factor for VTE in the general population, we analyzed the cross-sectional data of the Vicenza Thrombophilia and Atherosclerosis (VITA) Project. One hundred sixteen cases of VTE, ascertained in a random fashion within the general population aged 18-65, were age and sex-matched with 232 healthy subjects. Heterozygosity for the G20210A allele was present in 4.3% of VTE cases and in 3.4% of controls, indicating a marginal increase of VTE risk in carriers of the allele (odds ratio: 1.26; 95% CI 0.4-3.9). However, the VTE risk was substantially higher in subjects with idiopathic VTE before age 45 or with recurrent, idiopathic VTE (odds ratio: 2.8; 95% CI 0.6-13.8) or in subjects with a family history of VTE (odds ratio: 7.6; 95% CI 1.8-32.8). Accordingly, our results suggest that the G20210A allele associates with VTE only in selected cases, and that screening for this genetic variant is not warranted for all patients with VTE.

3' Untranslated Regions↗
PubMed1998

Low risk of venous thrombosis in two families with combined type I plasminogen deficiency and factor V R506Q mutation.

Two families with type I plasminogen deficiency and APC resistance are reported. The proposita of family A suffered from ischemic stroke when taking estrogen-progesterone-containing oral contraceptive. Several hemostatic challenges in the past (ovariectomy, appendectomy, and two pregnancies) were without thrombosis. Plasminogen activity and antigen (60 and 58%, normal range 72-136 and 69-135%, respectively) were reduced, and an increased APC resistance (APC-SR= 1.55; normal range 1.8-3.00) associated with G --> A change at 1,691 nucleotide position in exon 10 of FV gene (FV Leiden) was observed. The asymptomatic son had isolated plasminogen deficiency (activity 57% and antigen 60%) whereas the asymptomatic daughter had isolated APC resistance (APC-SR = 1.61) and FV Leiden mutation. The proposita of family B, referred for superficial thrombophlebitis, had low plasminogen levels (activity 55% and antigen 53%) and APC resistance (APC-SR = 1.5) whereas the asymptomatic mother and the brother had isolated APC resistance (APC-SR = 1.62 and 1.8, respectively) and the asymptomatic father isolated plasminogen deficiency (activity 61% and antigen 62%). These data suggest that the combination of plasminogen deficiency and APC resistance probably does not significantly increase the risk of venous thrombosis. However, larger experience with additional cases is needed to definitely assess the magnitude of thrombotic risk in these families.

Blood Coagulation↗
PubMed1998

No treatment for low-risk thrombocythaemia: results from a prospective study.

Essential thrombocythaemia (ET) is a chronic myeloproliferative disorder characterized by the occurrence of thromboembolic episodes, particularly in patients aged > 60 years or with a previous history of thrombosis, and/or by haemorrhages in patients with an exceedingly high platelet count. In these subgroups of patients the use of cytoreductive therapy is beneficial in terms of risk/benefit ratio. Only limited anecdotal data are available on the thrombotic or haemorrhagic risk and survival in young asymptomatic ET patients with a platelet count < 1500 x 10(9)/l. Therefore the optimal management of these patients is unknown. To assess the incidence of thrombosis and haemorrhages in this group of patients we carried out a prospective observational study in a cohort of 65 patients with ET, aged < 60 years, with no history of thrombosis or haemorrhage and platelet count < 1500 x 10(9)/l, and in 65 age- and sex-matched controls. Patients were not treated with cytoreductive therapy until the occurrence of thrombosis or haemorrhage. Arterial or venous thrombotic events were objectively documented both in cases and in controls. The median follow-up was 4.1 years, with an incidence of thrombosis in patients and controls of 1.91 and 1.50 cases/100 patient-years, respectively. The age- and sex-adjusted risk rate ratio was 1.43 (95% CI 0.37-5.4). Only three minor haemorrhagic episodes occurred in patients, with an incidence of 1.12 cases/100 patient-years. Pregnancy and surgery were not associated with thrombosis in these patients. We conclude that the thrombotic risk in young ET patients, with no thrombotic history and a platelet count < 1500 x 10(9)/l, is not increased compared to the normal population and that a conservative therapeutic approach should therefore be considered in these patients.

Adolescent↗
PubMed1998

Additional genetic risk factors for venous thromboembolism in carriers of the factor V Leiden mutation.

Only a minority of subjects with factor V (FV) Leiden mutation develop venous thromboembolism (VTE), suggesting that additional genetic risk factors may be present in symptomatic carriers. We screened 157 unrelated carriers of the FV Leiden mutation with a first episode of VTE and 291 unrelated asymptomatic FV carriers for the presence of two frequent mutations, i.e. G20210A of the prothrombin gene and C677T of the methylenetetrahydrofolate reductase gene. Carriers with other inherited or acquired thrombophilia-associated abnormalities were excluded from analysis. Heterozygotes for the G20210A mutation were more prevalent among symptomatic carriers than in asymptomatic carriers (10.8% v 2.7%, P<0.0001); homozygotes for the C677T mutation were also more prevalent in symptomatic carriers (21.6% v 14.4%, P = 0.05). Factor V Leiden carriers who had had a VTE episode during oral contraceptive intake were more frequently carriers of the G20210A mutation (14.3%, P = 0.03). These results further support the idea that VTE in carriers of FV Leiden results from interaction with additional genetic or circumstantial risk factors, and that an accurate search for such factors is required to identify carriers at risk.

Factor V↗
PubMed1997

The VITA project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism.

We evaluated the hypothesis that a common polymorphism of the methylenetetrahydrofolate reductase gene (C677T), which results in increased levels of plasma homocysteine, may be a putative risk factor for venous thromboembolism (VT). Sixty-five cases of VT and 130 controls, both identified within the framework of an epidemiologic survey on thrombophilia, the Vicenza Thrombophilia and Arteriosclerosis (VITA) Project, were genotyped for the mutation. No increased risk of VT was found in carriers of the mutation. We conclude that screening for the C677T mutation of the methylenetetrahydrofolate reductase gene should not be recommended in unselected patients with VT.

Adult↗
PubMed1997

Low prevalence of thrombophilic coagulation defects in patients with deep vein thrombosis of the upper limbs.

While many studies have demonstrated the pathogenetic role of inherited deficiency of natural clotting inhibitors in patients in the development of deep vein thrombosis of lower limbs, no data are available on the prevalence of these abnormalities in patients with upper vein thrombosis. In this study, antithrombin III, protein C, protein S, plasminogen, resistance to activated protein C and factor V Leiden mutation were assayed in 27 consecutive patients with thrombosis of upper extremities. Only two patients (7.4%) showed a congenital defect (one patient with deficiency of protein C, confirmed by family study, and one patient with factor V Leiden mutation). Anticardiolipin antibodies were also measured and four patients (14.8%) had increased levels, confirmed on a subsequent occasion 3 months later. Eighteen out of 27 (67%) had a predisposing or triggering factor, thus emphasizing the role of physical stress in the development of upper vein thrombosis. At variance with what is observed in deep vein thrombosis of the lower limbs, inherited clotting abnormalities seem to be rarely responsible for upper vein thrombosis, whereas anticardiolipin antibodies and cancer are implicated in a significant proportion of cases.

Adolescent↗
PubMed1997

Inherited abnormalities of blood coagulation in juvenile stroke. A case-control study.

The nature of the relationship between inherited abnormalities of the clotting system and the occurrence of cerebrovascular accidents in young subjects is controversial. To evaluate the risk of cerebrovascular disease associated with such abnormalities, we analyzed a series of 23 consecutive patients in a case-control study with ischemic stroke proven by computerised tomography and aged below 45 years at admission, and a control group of 115 age- and sex-matched controls from the general population. No differences in antithrombin, protein C, protein S, heparin cofactor II, plasminogen or response to activated protein C were observed between cases and controls. None of the patients had a history of personal or familial thrombosis, and none had a reduction in the considered clotting factor below the reference range. We conclude that abnormalities of the clotting system are not associated with the occurrence of cerebrovascular abnormalities in the young and that routine screening for inherited thrombophilia is not appropriate in young patients with cerebrovascular disease.

Adult↗
PubMed1997

The VITA project: phenotypic resistance to activated protein C and FV Leiden mutation in the general population. Vicenza Thrombophilia and Atherosclerosis.

Resistance to activated protein C (APC) has been recently identified as a common abnormality of the clotting system that significantly increases the risk of venous thromboembolism. The distribution of plasma response to APC in the general population and the variables potentially influencing it are however unknown. In this study, we analyzed the data from the first 4,000 subjects enrolled in the Vicenza Thrombophilia and Atherosclerosis (VITA) Project to identify the demographic and laboratory variables affecting the plasma response to APC. Plasma response to APC, expressed as APC-ratio, was significantly influenced not only by the presence of the FV Leiden mutation but also by the aPTT ratio, triglycerides, fibrinogen and cholesterol level and by pill use, ABO blood group, gender, smoke, body-mass index and age. The effect of these variables was independent of the presence of the FV Leiden mutation, and adjustment for their effect improved the discriminating efficiency of the APC-ratio for the presence of the FV Leiden mutation. Notwithstanding adjustment, the APC ratio was unsuitable for screening purposes in the general population (positive predictive value 82.7%).

Anticoagulants↗
PubMed1997

[Prevention of hemorrhage and dental treatment of patients with congenital or acquired coagulopathies].

The physiopathology of the hemorrhagic blood coagulation disorders caused by genetic or aquired problems is described. Among the former the most frequent ones include the hemophilia of type A-B and the von Willebrand disease, among the latter the use of oral anticoagulant constitutes the most frequent cause. If the are not subjected to an adequate haemostatic prophylaxis, both patients with hemophilia and von Willebrand disease present a serious haemorrhagic risk as a consequence of dental practice. As far as the use of anticoagulants is concerned, a periodical monitoring of the time of prothrombin (PT) is needed to find the right dosage (TP between 20%-30% or INR--international normalized radio between 2 and 3.5). Values over this range cause an increase of the hemorrhagic risk, while lower values involve an increased risk of thrombotic events. According to the authors the patients with the hemorrhagic diathesis show a precise handicap, caused both by his illness and by environmental elements, such as the fear of doctors for the haemorrhagic complications consequent to a therapeutical operation, fear that often leads to neglect important medical measures, in particular dental measures. The specialized dental surgeon has to mantain a strict cooperation with the hematologist in order to arrange an appropriate procedure of the prophylaxis. As far as the hemostatic prophylaxis is concerned, the use of the dermopressin (DDAVP), in patients with hemophilia A and von Willebrand disease, guarantees the realisation of dental practice without hemorrhagic risk. On the contrary, the use of the tranhexanic acid on patients in an anticoagulant oral treatment gives hemostatic security and makes it possible to carry on the therapy and the out-patient treatment.

Blood Coagulation Disorders↗
PubMed1996

Validated questionnaire for the identification of previous personal or familial venous thromboembolism.

The recognition of previous episodes of venous thromboembolism is of primary importance for the diagnosis of familial thrombophilia. Since there is no validated method to diagnose past venous thromboembolism for epidemiologic purposes, the authors administered a questionnaire to a group of subjects who had had venous thromboembolism in the past and to a group of normal controls. Both cases and controls were less than age 65 years and were identified by the discharge diagnosis International Classification of Diseases codes of records of the Vicenza general hospital, Italy, from 1975 to 1992. Cases were further validated by critical review of pertinent medical records. For each key question, the sensitivity and specificity were computed; questions were then aggregated into sets of maximal sensitivity and specificity. The best diagnostic efficiency (98.2%) was obtained by a set of questions about past symptoms and anticoagulant treatment; this set showed a very high specificity (99.4%), but a low sensitivity (37.1%). A higher sensitivity (71.3%) was obtained without loss of specificity (98.9%) by retaining as positive those subjects who gave a history of venous thromboembolism and anticoagulant treatment or those who had a history of venous thromboembolism and venous reflux at Doppler ultrasound scanning but had no treatment. The combined use of the questionnaire and Doppler scan is suggested for epidemiologic surveys in population.

Female↗
PubMed1996

Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain.

Factor XIII deficiency has been classified into two categories: type I deficiency, characterized by the lack of both the a and b subunits; and type II deficiency, characterized by the lack of the a subunit alone. To clarify the genetic bases of these diseases, previously reported cases of the type I deficiency were examined at the DNA level. DNA sequence analysis showed that a nucleotide triplet (AAC) was inserted within the codon for Tyr-80 in exon III of the gene for a female proband's b subunit, resulting in the creation of a stop codon. Restriction digestion of amplified DNAs confirmed that the proband and her sister were homozygotes, and their family members were heterozygotes of this mutant allele. A truncated protein composed of 79 amino acids could be synthesized by these homozygotes; however, such a protein would not be secreted or it would degrade quickly, because there were normal amounts of the mutant mRNA, but no b subunit was detected in these patients. The a subunit deficiency of these patients must be a secondary to the b subunit deficiency, as their gene for the a subunit was intact, and the a subunit in their platelets was present within normal levels.

Alleles↗
PubMed1996

Factor V gene mutation is a risk factor for cerebral venous thrombosis.

To evaluate the association between coagulation defects and cerebral venous thrombosis, a case-control study was conducted in 25 patients who had no autoimmune, neoplastic or infections disease and 75 healthy individuals. There were no patients with deficiency of protein C or protein S. Four had resistance to activated protein C (APC) and one had APC resistance associated with antithrombin deficiency. APC resistance was investigated by DNA analysis, and diagnosed by the presence of a point mutation in the factor V gene, which predicts replacement of Arg506 with Gln at one of the two APC cleavage sites in activated factor V. The prevalence of APC resistance was 20% in patients and 2.7% in controls. This difference was statistically significant (p = 0.01) and the odds ratio was 9.1. A circumstantial factor predisposing to cerebral venous thrombosis (such as oral contraceptive intake, pregnancy, puerperium, trauma or prolonged immobilization) was reported in 72% of cases. In conclusion, APC resistance is the most frequent coagulation abnormality associated with cerebral venous thrombosis.

Adult↗