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P Simioni

Publications and source records attributed to P Simioni.

At least 55 records · Page 3Linked to original sources
PubMed1999

Asymptomatic homozygous nt 20210 G to A prothrombin polymorphism in two blood donors belonging to two different kindreds.

The nucleotide (nt) 20210 G to A prothrombin polymorphism has been associated with an increased incidence of thrombosis, particularly venous thrombosis. The increased incidence of thrombosis resulted from an increase in prothrombin levels. Two homozygous patients with this abnormality were found to be completely asymptomatic. In one of the two cases there was no thrombosis even after the additional risk factor of oral contraceptive therapy for several months. Prothrombin activity and antigen as assayed by several methods were at the upper limits of normalcy in one case and slightly elevated in the other. The two cases described in this article do not rule out the possibility that this prothrombin abnormality be associated, given special acquired circumstances, with thrombosis. However, they indicate that extreme caution is needed to avoid an inaccurate conclusion. The fact that homozygous patients may remain asymptomatic indicates that the prothrombotic defect is very mild, if any.

Adult↗
PubMed1999

Incidence of venous thromboembolism in families with inherited thrombophilia.

The risk of spontaneous or risk-period related venous thromboembolism in family members of symptomatic carriers of antithrombin (AT), protein C (PC) or protein S (PS) defects, as well as of the Factor V Leiden mutation is still undefined. We performed a retrospective cohort study in family members (n = 793) of unselected patients with a documented venous thromboembolism and one of these deficiencies to make an estimate of this risk. The annual incidences of total and spontaneous venous thromboembolic events in carriers of AT, PC or PS defects (n = 181) were 1.01% and 0.40%, respectively, as compared to 0.10% and 0.04% in non-carriers, respectively (relative risks both 10.6). In carriers of Factor V Leiden (n = 224), the annual incidences of total and spontaneous venous thromboembolism were 0.28% and 0.11%, respectively, as compared to 0.09% and 0.04% in non-carriers, respectively (relative risks 2.8 and 2.5). Additional risk factors (immobilisation, surgery and trauma: oral contraceptive use; and pregnancy/ post-partum) increased the risk of thrombosis in carriers of AT, PC and PS defects as compared to non-carriers (relative risks 8.3, 6.4 and 8.2, respectively). Oral contraceptive use and pregnancy/ post-partum period increased the risk of thrombosis in carriers of Factor V Leiden to 3.3-fold and 4.2-fold, respectively, whereas other risk factors had only a minor effect. These data lend some support to the practice of screening family members of symptomatic carriers of a AT, PC and PS deficiency. For family members of symptomatic carriers of Factor V Leiden, screening does not seem to be justified except for women in fertile age.

Adolescent↗
PubMed1999

The risk of fetal loss in family members of probands with factor V Leiden mutation.

In order to investigate the risk of fetal loss in carriers of factor V Leiden who are family members of probands with this mutation, we performed a retrospective cohort study including 109 women who had been pregnant at least once and were family members of 61 probands with venous thromboembolism and a single identified factor V Leiden mutation. The rate of pregnancies ending in unexplained fetal loss, early miscarriage, late miscarriage or stillbirth in women with the factor V Leiden was compared with that of women with normal genotype. In the 65 women who were carriers of factor V Leiden 31 of the 191 pregnancies (16.2% per pregnancy) resulted in unexplained fetal loss, as compared to 13 of the 121 pregnancies (10.7% per pregnancy) in the 44 non-carriers (relative risk, 1.5; 95% CI, 0.8-3.2). After the first trimester of pregnancy, 25 pregnancies (13.1% per pregnancy) among carriers of factor V Leiden ended in fetal loss, as compared to 7 (5.8% per pregnancy) among females with normal genotype (relative risk, 2.3; 95% CI, 1.01 to 5.1). We conclude that carriers of factor V Leiden who are family members of probands with this mutation have a statistically significant and clinically important risk of late miscarriage or stillbirth. Studies addressing the benefit-to-risk ratio of adopting routinary thromboprophylactic measures following the first trimester of pregnancy in these women are strongly indicated.

Cohort Studies↗
PubMed1998

Platelet-derived factor Va/Va Leiden cofactor activities are sustained on the surface of activated platelets despite the presence of activated protein C.

We investigated the role of the thrombin-activated platelet in modulating the rate and extent of activated protein C (APC)-catalyzed inactivation of platelet-derived factor Va and factor VaLeiden. Platelet-derived factor Va and factor VaLeiden were inactivated by APC at near identical rates; however, complete inactivation of the cofactors was never achieved. Greater residual cofactor activity remained when using thrombin-activated platelets compared with that observed with synthetic phospholipid vesicles and platelet-derived microparticles, suggesting that thrombin-activated platelets protect the cofactors from APC-catalyzed inactivation. This apparent protection was not due to (1) an insufficient number of membrane binding sites for APC or factor Va; (2) the destruction of these sites; or (3) the presence of a platelet-associated APC inhibitor. Results from a plasma-based clotting assay (with or without APC) with platelets or PCPS vesicles added to induce clot formation indicated that, even in the presence of high concentrations of APC, platelets offered protection of the cofactor by delaying cleavage at Arg506. This resulted in incomplete proteolysis of the heavy chain, suggesting that platelets can also protect plasma-derived factor Va from APC-catalyzed inactivation. However, additional experiments indicated that the plasma-derived cofactor, bound to thrombin-activated platelets, was completely inactivated by APC, suggesting that the plasma and platelet-derived cofactor pools represent different substrates for APC. Collectively, these results indicate that platelets sustain procoagulant events by providing a membrane surface that delays cofactor inactivation and by releasing a cofactor molecule that displays an APC resistant phenotype. Thus, at sites of arterial injury, the factor VLeiden mutation may not as readily predict arterial thrombosis, because the normal and variant platelet-derived cofactors are equally resistant to APC at the activated platelet surface.

Blood Platelets↗
PubMed1998

Hemorrhagic and thrombotic disorders due to factor V deficiencies and abnormalities: an updated classification.

The recent description of a factor V abnormality (factor V Leiden) associated with an increased incidence of thrombosis has considerably increased interest in this clotting factor. The discovery of this new clinical entity indicated the need for an updated classification of factor V defects. These should be divided into hemorrhagic and thrombotic disorders. A proper classification of hemorrhagic disorders should include: 1) homozygous and heterozygous 'true' factor V deficiency; and 2) combined factor V and factor VIII deficiencies. The latter should be subdivided in Type I (association type) and Type II (common defect). A suitable classification of the thrombotic factor V defects should include: 1) homozygous and heterozygous factor V Leiden; and 2) combined heterozygous factor V Leiden and heterozygous 'true' factor V deficiency. The presence of thrombosis in these latter patients, often as severe as those seen in homozygous patients with activated protein C (APC) resistance, allows important considerations on the functions of factor V. It would seem that half the normal level of factor V activity and antigen is unable to protect against thrombosis in patients with heterozygous APC resistance. An accurate evaluation of factor V activity and antigen is indicated in all patients with suspected factor V defects. The first suspicion may be obtained by the presence of a mild prolongation of prothrombin time and of partial thromboplastin time. The suspicion should then be immediately confirmed by specific factor V activity and antigen assays. This approach is of great importance even for the presumptive diagnosis of pseudohomozygosis for APC resistance. In fact, in these cases, factor V activity is about 50% of normal, whereas factor V antigen is 100% of normal. In heterozygous 'true' factor V deficiency both activity and antigen are about 50% of normal.

Clinical Laboratory Techniques↗
PubMed1998

Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant.

A recently discovered variant in the prothrombin gene (20210A) has been found in approximately 5-10% of patients with venous thromboembolism. It has been shown that patients with this variant present with high levels of prothrombin in plasma and this is maintained to be the most likely mechanism by which the risk of thrombosis is increased. We have evaluated prothrombin antigen levels in 50 carriers of the 20210A allele and compared with non-carriers. 327 subjects were subdivided according to deficiency status and previous thrombosis. 30 symptomatic and 20 asymptomatic carriers had increased mean prothrombin levels as compared to symptomatic (n=178) or asymptomatic (n=99) non-carriers. The percentage of subjects with prothrombin levels above cut-off values of 1.15u/ml or 1.30u/ml was significantly higher in carriers of the prothrombin variant as compared to non-carriers, regardless of a previous thrombosis. However, among non-carriers the percentage of those with prothrombin levels above cut-off values was significantly higher in the group of symptomatic as compared to asymptomatic individuals. In conclusion, increased prothrombin antigen levels, as detected by a specific ELISA, were found among 50 symptomatic and asymptomatic carriers of the 20210A prothrombin variant as well as among a large group of symptomatic non-carriers. The data are in agreement with those found by using functional tests for the determination of prothrombin levels in these patients.

Adult↗
PubMed1998

Molecular bases of pseudo-homozygous APC resistance: the compound heterozygosity for FV R506Q and a FV null mutation results in the exclusive presence of FV Leiden molecules in plasma.

Pseudo-homozygous APC resistance, the condition resulting from compound heterozygosity for FV R506Q (FV Leiden) and quantitative FV deficiency, provides a natural model to study the interaction between procoagulant and anticoagulant defects. This paper reports a complete FV characterization of a pseudo-homozygous APC resistant thrombotic patient. The expression of the patient's non-Leiden gene was found to be severely impaired both at the mRNA and protein levels. In particular, only FV Leiden molecules were detected in the patient's plasma by immunoblotting, which accounts for the observed marked APC resistance. Analysis of the FV cDNA obtained by reverse transcription of platelet RNA revealed that the mRNA of the non-Leiden gene was extremely reduced in amount. A PAC clone containing the whole FV gene was used to design primers for a complete FV exon scanning. A 2-bp insertion at nucleotide 3706 in the large exon 13 of the non-Leiden gene, predicting a frame-shift and premature termination of protein synthesis, was identified as responsible for the FV defect. Failure to find any case of pseudo-homozygous APC resistance in a large sample (6,804) of blood donors suggests that this condition is extremely rare among normal controls and that its detection is favoured by the thrombotic risk that it may confer.

Aged↗
PubMed1997

Recurrence of venous thromboembolism in patients with familial thrombophilia.

BACKGROUND: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.

Anticoagulants↗
PubMed1997

An in vitro analysis of the combination of hemophilia A and factor V(LEIDEN).

The classification of factor VIII deficiency, generally used based on plasma levels of factor VIII, consists of severe (<1% normal factor VIII activity), moderate (1% to 4% factor VIII activity), or mild (5% to 25% factor VIII activity). A recent communication described four individuals bearing identical factor VIII mutations. This resulted in a severe bleeding disorder in two patients who carried a normal factor V gene, whereas the two patients who did not display severe hemophilia were heterozygous for the factor V(LEIDEN) mutation, which leads to the substitution of Arg506 --> Gln mutation in the factor V molecule. Based on the factor VIII level measured using factor VIII-deficient plasma, these two patients were classified as mild/moderate hemophiliacs. We studied the condition of moderate to severe hemophilia A combined with the factor V(LEIDEN) mutation in vitro in a reconstituted model of the tissue factor pathway to thrombin. In the model, thrombin generation was initiated by relipidated tissue factor and factor VIIa in the presence of the coagulation factors X, IX, II, V, and VIII and the inhibitors tissue factor pathway inhibitor, antithrombin-III, and protein C. At 5 pmol/L initiating factor VIIa x tissue factor, a 10-fold higher peak level of thrombin formation (350 nmol/L), was observed in the system in the presence of plasma levels of factor VIII compared with reactions without factor VIII. Significant increase in thrombin formation was observed at factor VIII concentrations less than 42 pmol/L (approximately 6% of the normal factor VIII plasma concentration). In reactions without factor VIII, in which thrombin generation was downregulated by the addition of protein C and thrombomodulin, an increase of thrombin formation was observed with the factor V(LEIDEN) mutation. The level of increase in thrombin generation in the hemophilia A situation was found to be dependent on the factor V(LEIDEN) concentration. When the factor V(LEIDEN) concentration was varied from 50% to 150% of the normal plasma concentration, the increase in thrombin generation ranged from threefold to sevenfold. The data suggested that the analysis of the factor V genotype should be accompanied by a quantitative analysis of the plasma factor V(LEIDEN) level to understand the effect of factor V(LEIDEN) in hemophilia A patients. The presented data support the hypothesis that the factor V(LEIDEN) mutation can increase thrombin formation in severe hemophilia A.

Factor V↗
PubMed1997

Increased tissue factor-initiated prothrombin activation as a result of the Arg506 --> Gln mutation in factor VLEIDEN.

The effect of the Arg506 --> Gln mutation in factor VLEIDEN on thrombin generation was evaluated in a reconstituted system using the purified components of the tissue factor (TF) pathway to thrombin and the components of the protein C pathway. Recombinant full-length tissue factor pathway inhibitor (RTFPI) was included in the system because of a previously observed synergistic inhibitory effect of TFPI and the protein C pathway on TF-initiated thrombin generation. Thrombin generation initiated by 1.25 pM factor VIIa.TF in the absence of the protein C pathway components occurs following an initiation phase, after which prothrombin is quantitatively converted to 1.4 microM thrombin. The factor VLEIDEN mutation did not influence thrombin generation in the reconstituted model in the absence of the protein C pathway. In the presence of 2.5 nM TFPI, 65 nM protein C, and 10 nM recombinant soluble thrombomodulin (Tm), thrombin generation catalyzed by normal factor V was abolished after the initial formation of 25 nM thrombin. In contrast, persistent thrombin generation was observed in the presence of factor VLEIDEN in the same system, although the rate of thrombin generation was slower compared with the reaction without protein C and Tm. The rate of thrombin generation with factor VLEIDEN increased with time and ultimately resulted in quantitative prothrombin activation. When the TFPI concentration was reduced to 1.25 nM, thrombin generation is still curtailed in the presence of normal factor V. In contrast, under similar conditions using factor VLEIDEN, the protein C pathway totally failed to down-regulate thrombin generation. The dramatic effect of a 50% reduction in TFPI concentration on the inhibitory potential of the protein C pathway on thrombin generation catalyzed by factor VLEIDEN suggests that the observed synergy between TFPI and the protein C pathway is directly governed by the TFPI concentration and by cleavage of the factor Va heavy chain at Arg506. This cleavage appears to have a dramatic regulatory effect in the presence of low concentrations of TFPI. Markedly increased thrombin generation in the presence of both 1.25 nM TFPI and factor VLEIDEN was also observed when antithrombin-III was added to the system to complete the natural set of coagulation inhibitors. Protein S (300 nM) had a minimal effect in the model on the inhibition of thrombin generation by protein C, Tm, and TFPI, with either normal factor V or factor VLEIDEN. Protein S also failed to significantly potentiate the action of the protein C pathway in the presence of antithrombin-III in reactions employing normal factor V or factor VLEIDEN. The absence of an effect of protein S in the model, which employs saturating concentrations of phospholipid, suggests that the reported interactions of protein S with coagulation factors are not decisive in the reaction. Altogether the data predict that TFPI levels in the lower range of normal values are a risk factor for thrombosis when combined with the Arg506 --> Gln mutation in factor VLEIDEN.

Animals↗
PubMed1997

Accuracy of two newly described D-dimer tests in patients with suspected deep venous thrombosis.

Accumulating evidence suggests that the ELISA determination of D-Dimer might be a useful tool for the exclusion of deep vein thrombosis (DVT) of lower extremities, because of its high sensitivity and negative predictive value. However, conventional ELISA assay is time-consuming and, therefore, is not suitable for emergency use. To evaluate the accuracy of two rapid assays recently described, 126 consecutive outpatients with the clinical suspicion of DVT underwent the NycoCard D-Dimer and the Instant I.A. D-Dimer determination, using venography as the reference test. In all patients, the conventional ELISA assay was also performed. Venography confirmed the presence of DVT in 30 patients (23.8%), and ruled out the diagnosis in the remaining 96. Instant I.A D-Dimer was positive in 28 patients with DVT (sensitivity, 93.3%), and negative in 90 subjects free from thrombosis (specificity, 93.8%). Nycocard D-Dimer correctly identified 27 patients with DVT (sensitivity 90.0%), and was negative in 77 subjects free from thrombosis (specificity, 80.2%). Sensitivity, specificity, negative and positive predictive values of both tests did not differ from those found with the classic ELISA method. In conclusion, both Instant I.A. D-Dimer and Nycocard D-Dimer assays show a great potential for clinical use.

Adult↗
PubMed1997

The risk of recurrent venous thromboembolism in patients with an Arg506-->Gln mutation in the gene for factor V (factor V Leiden).

BACKGROUND: A recently discovered mutation in coagulation factor V (Arg506-->Gln, referred to as factor V Leiden), which results in resistance to activated protein C, is found in approximately one fifth of patients with venous thromboembolism. However, the risk of recurrent thromboembolism in heterozygous carriers of this genetic abnormality is unknown. METHODS: We searched for factor V Leiden in 251 unselected patients with a first episode of symptomatic deep-vein thrombosis diagnosed by venography. The patients were followed prospectively for a mean of 3.9 years to determine the frequency of recurrent venous thrombosis and pulmonary embolism. RESULTS: Factor V Leiden was found in 41 of the patients (16.3 percent; 95 percent confidence interval, 11.8 to 20.9 percent). The cumulative incidence of recurrent venous thromboembolism after follow-up of up to eight years was 39.7 percent (95 percent confidence interval, 22.8 to 56.5 percent) among carriers of the mutation, as compared with 18.3 percent (95 percent confidence interval, 12.3 to 24.3 percent) among patients without the mutation (hazard ratio, 2.4; 95 percent confidence interval, 1.3 to 4.5; P<0.01). CONCLUSIONS: The risk of recurrent thromboembolic events is significantly higher in carriers of factor V Leiden than in patients without this abnormality. Large trials assessing the risk-benefit ratio of long-term anticoagulation in carriers of the mutation who have had a first episode of venous thromboembolism are indicated.

Adult↗
PubMed1997

Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications.

BACKGROUND: Little is known about the clinical, diagnostic, and prognostic aspects of upper-extremity deep vein thrombosis (UEDVT). OBJECTIVES: To identify the clinical and laboratory parameters associated with this disease, to assess the diagnostic accuracy of ultrasonographic methods for its detection, and to establish the frequency of both early and late complications. PATIENTS AND METHODS: After a careful history was taken, 58 consecutive patients with signs and symptoms that were clinically suggestive of UEDVT underwent the determination of antithrombin III and protein C and S levels and resistance to activated protein C and lupuslike anticoagulants. Compression ultrasonography, color flow Doppler imaging, and Doppler ultrasonography were performed prior to venography. Patients with confirmed UEDVT underwent objective tests to detect a pulmonary embolism and were followed up prospectively to record recurrent thromboembolic events and postthrombotic sequelae. RESULTS: Findings from venography confirmed UEDVT in 27 patients (47%). Central venous catheters, thrombophilic states, and a previous leg vein thrombosis were statistically significantly associated with UEDVT. Sensitivity and specificity of compression ultrasonography (96% and 93.5%, respectively) and color flow Doppler imaging (100% and 93%, respectively) were comparable and better than those of Doppler ultrasonography (81% and 77%, respectively). Objective findings suggestive of a pulmonary embolism were recorded in 36% of the patients with UEDVT. After a mean follow-up of 2 years, 2 patients with UEDVT experienced recurrent thromboembolic events, and 4 had postthrombotic sequelae. CONCLUSIONS: Symptomatic UEDVT is associated with central venous catheters, thrombophilic states, and a previous leg vein thrombosis. Both compression ultrasonography and color flow Doppler imaging are accurate methods for its detection. A pulmonary embolism is a common complication of the disease. Finally, this disorder may recur and may be followed by postthrombotic sequelae.

Adult↗
PubMed1997

Factor V antigen levels in APC resistance, in factor V deficiency and in combined APC resistance and factor V deficiency (pseudohomozygosis for APC resistance).

Factor V antigen levels were measured in 40 patients with factor V deficiency (11 homozygous and 29 heterozygous), in 38 patients with factor V Leiden mutation (16 homozygous and 22 heterozygous) and in three patients with combined heterozygous factor V deficiency and heterozygous factor V Leiden mutation (so-called pseudohomozygosis for APC resistance). Twenty normal subjects of both sexes served as controls. Factor V antigen levels compared well with factor V activity in normal subjects and in all groups of patients. They were normal both in homozygous and heterozygous APC resistance patients. Factor V antigen determination may be useful for the diagnosis of pseudohomozygosis for APC resistance. These patients have a phenotypic picture similar to homozygous APC resistance, but show a factor V antigen level about half the normal value since they are compound heterozygotes for factor V deficiency and APC resistance. In contrast, homozygous patients for APC resistance show normal factor V activity and antigen levels.

Drug Resistance↗
PubMed1997

Protein S deficiency and pregnancy: is there a case for ylaxis?

Pregnancy reduces protein S to 40-50% of normal levels, but it is not clear whether lower protein S levels raise the risk of developing thrombo-embolism during pregnancy. This case report describes a primigravida with a documented protein S deficiency who delivered at 38 weeks of gestation with no thrombo-embolic complications.

Adult↗