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Biomedical subjects

P Simioni

Publications and source records attributed to P Simioni.

At least 73 records · Page 4Linked to original sources
PubMed1996

Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.

BACKGROUND: It has been reported that women with an inherited deficiency of antithrombin, protein C, or protein S have an increased risk for developing venous thromboembolic disease during pregnancy and the postpartum period. However, because the available data on risk are flawed, it is difficult to define a rational, efficacious, and safe policy about prophylaxis for venous thromboembolism in these women. OBJECTIVE: To determine the frequency of venous thromboembolism during pregnancy and the postpartum period in women with heritable deficiencies of anticoagulant factors. DESIGN: Retrospective cohort study. SETTING: University outpatient clinics in the Netherlands and Italy. PARTICIPANTS: 129 otherwise asymptomatic female family members of patients with a history of venous thromboembolism and an established deficiency of antithrombin, protein C, or protein S. MEASUREMENTS: Medical history, with specific attention to episodes of venous thromboembolism and obstetric history, was taken. The anticoagulant factor status of the study participants was determined. If a patient had an episode of venous thromboembolism, subsequent pregnancies in that patient were not analyzed. RESULTS: Of the 129 women who participated in the study, 60 had anticoagulant factor deficiency and 69 did not. In the nondeficient group, 198 pregnancies occurred; 1 of these (0.5%) was complicated by an episode of venous thromboembolism during the postpartum period. In the deficient group, 169 pregnancies occurred; 7 of these (4.1%) were complicated by an episode of venous thromboembolism during the third trimester of pregnancy (2 pregnancies [1.2%]) and the postpartum period (5 pregnancies [3.0%]). The risk for venous thromboembolism was increased eightfold in deficient women compared with nondeficient women (hazard ratio, 8.0 [95% CI 1.2 to 184]). CONCLUSIONS: Anticoagulant factor-deficient women have an increased risk for venous thromboembolism during pregnancy and the postpartum period. Although data from an appropriate randomized clinical trial are lacking, the frequency of venous thromboembolism seen in deficient women might justify the use of anticoagulative prophylaxis during the third trimester of pregnancy and the postpartum period.

Adolescent↗
PubMed1996

An antifibrinolytic mechanism describing the prothrombotic effect associated with factor VLeiden.

Factor Va is the essential cofactor in prothrombinase-dependent activation of prothrombin. Resistance of Factor VaLeiden to inactivation by activated protein C (APC) contributes to thrombotic tendencies in subjects with the variant due, in part, to the inability to terminate thrombin production which increases both fibrin accretion and the frequency of thrombus formation. A reduced ability to inhibit thrombin generation, however, may lead to the stabilization of a clot through the activation of thrombin activatable fibrinolysis inhibitor (TAFI). This hypothesis was tested by determining the profibrinolytic effect of APC on lysis time using clots formed with plasma from either homozygous normal (n = 4) or homozygous factor VLeiden (n = 4) subjects. Clots were formed in the presence of tissue-type plasminogen activator, thrombin, phosphatidylcholine/phosphatidylserine vesicles, Ca2+, and various concentrations of APC. Approximately 10-fold more APC was required to reduce lysis time from 140 to 50 min in clots containing factor VLeiden compared to normal factor V. This effect was specific to the form of factor V present in plasma since identical results were obtained in an appropriately reconstituted purified system, which included both TAFI and either form of factor V purified from pooled plasma. In the absence of TAFI, APC did not affect clot lysis in experiments with either normal factor V or factor VLeiden. During the various lysis assays performed with purified components, clots were solubilized and the proteolytic alterations in factor V/Va were assessed by Western blotting using a specific factor Va heavy chain monoclonal antibody. The heavy chain of factor VaLeiden persisted for as long as 60 min, in the presence of 6.3 n APC indicating sustained activity of factor VaLeiden during the lysis assay. In contrast, no factor Va heavy chain was present after the first 5.0 min in clots formed in the presence of normal factor V and 6.3 n APC. These combined data indicate that factor VaLeiden specifically attenuates the profibrinolytic effect of APC. Thus, an impaired TAFI-dependent profibrinolytic response to APC in APC-resistant individuals appears to be an additional factor contributing to the prothrombotic tendencies in subjects with factor VLeiden.

Carboxypeptidase B2↗
PubMed1996

Compound heterozygous protein C deficiency resulting in the presence of only the beta-form of protein C in plasma.

About 30% of human plasma protein C (PC) is of lower molecular weight than the predominant alpha-form. The minor beta-form arises as a consequence of the lack of glycosylation at Asn329. Although the functional role of Asn329 has been investigated by in vitro mutagenesis, until now no naturally occurring mutations have been reported at this site. We describe here the case of two identical twin sisters compound heterozygous for two novel PC mutations: Cys78-->Stop inherited from the maternal side and Asn329-->Thr inherited from the paternal side, associated with the presence of only the beta-form of PC in plasma. The Cys78-->Stop substitution is predicted to abolish PC synthesis from one allele, whereas the Asn329-->Thr substitution results in the reduced synthesis of a beta PC variant with decreased functional activity. PCN329T from the two monovular twin sisters was purified and its active form APCN329T was assessed for its ability to inactivate factor Va. Whereas no differences were observed between the activation rates of normal PC and PCN329T, APCN329T inactivated human factor Va with a rate slower than the normal APC. This is the first report of a PC defect involving glycosylation of the molecule. This defect results in the presence of only the beta-form of PC in human plasma and is responsible for the reduced anticoagulant activity observed.

Adult↗
PubMed1996

Fibronectin and antithrombin as markers of pre-eclampsia in pregnancy.

INTRODUCTION: The differential diagnosis between pre-eclampsia and chronic hypertension is not easy, but is essential to proper management of a pregnancy. Patients presenting pre-pregnancy hypertension can be treated conservatively, if not a superimposed pre-eclampsia occurs, controlling pressure pharmacologically and completing the pregnancy with a natural delivery. In pre-eclampsia, hypertension is merely the visible sign of a process of endothelial damage and coagulation cascade activation which is often destined to emerge clinically on a dramatic scale. MATERIALS AND METHODS: The study involved 18 women with physiological pregnancies, 19 with pre-eclampsia and 13 with chronic hypertension since superimposed pre-eclampsia. The following laboratory tests were performed: PT, PTT, AT-III, proteins C and S, platelet count, D-dimer, fibrinogen and plasma fibronectin. The three groups were compared using the Kruskall Wallis test, the median test and, for multiple comparisons, the Mann-Whitney test. A 'P' value of < 0.01 was considered as statistically significant. RESULTS: The values for plasma fibronectin were higher in the pre-eclampsia group (410 mg/l (253-727)) than in controls (262 mg/l (183-385)) (P < 0.01) and values for AT-III were lower in the pre-eclampsia group (73% (40-100)) than in controls (93% (80-126) (P < 0.01) (Table 2). The groups with chronic hypertension revealed no such significant differences, however, in relation to the control group (fibronectin = 296 mg/l (198-530), AT-III = 86% (75-103)). CONCLUSIONS: Measuring antithrombin and fibronectin to monitor any onset of pre-eclampsia can help the obstetrician to avoid important diagnostic and therapeutic errors.

Adult↗
PubMed1996

Prothrombin fragment 1+2 and thrombin-antithrombin complex levels in patients with inherited APC resistance due to factor V Leiden mutation.

Inherited activated protein C (APC) resistance is a newly described pathological condition associated with familial thrombophilia. A recent report on family with APC resistance showed increased levels of prothrombin fragment 1 + 2 (F1 + 2) in the affected individuals. No data concerning thrombin-antithrombin complex (TAT) levels in patients with inherited APC resistance are presently available. The aim of this study was to assess the plasma levels of F1 + 2 and TAT in patients with inherited APC resistance due to factor V (F.V) Leiden mutation and to evaluate F1 + 2 and TAT levels in symptomatic and asymptomatic patients with the defect ('carriers') as compared to their family members having no evidence of F.V Leiden mutation ('non-carriers'). One hundred and twenty-nine individuals belonging to 30 families with inherited APC resistance due to F.V Leiden mutation were studied. F1 + 2 and TAT levels were determined using two commercially available ELISA kits and cut-off values were defined as the higher limits of normal ranges obtained in healthy volunteers. Out of the 129 family members investigated, 36 were non-carriers, 85 were heterozygous and eight homozygous for F.V Leiden mutation. Thrombosis had occurred in 2/36 (6%) non-carriers, in 36/85 (42.3%) heterozygous and in 5/8 (63%) homozygous. Median levels of F1 + 2 and TAT were above cutoff values in carriers, whereas they were below in non-carriers. An overall percentage of 68.8% of carriers exhibited F1 +2 levels above the cut-off value as compared to 38.9% of non-carriers. For TAT, an overall percentage of 63.4% of carriers presented with levels above the cut-off compared with 28% of non-carriers. In conclusion, patients with inherited F.V Leiden mutation may exhibit increased levels of F1 + 2 and TAT. There are no differences in F1 + 2 and TAT median levels among symptomatic and asymptomatic carriers. The percentage of carriers of F.V Leiden with levels of F1 + 2 and TAT above cut-off appears to be higher than that found in other clotting inhibitors defects and in this respect the defect might be considered different. However, these findings and the presence of high percentage of non-carriers presenting with increased F1 + 2 and TAT levels may suggest the possible coexistence in these families of other unknown defects predisposing to thrombosis.

Adult↗
PubMed1996

A new global test for the evaluation of the protein C-protein S system.

We have developed a simple screening assay for evaluating the global activity of the protein C/protein S system. The new test consists of measuring the prothrombin time (PT) with bovine thromboplastin before and after activation of the PC present in the plasma sample by PROTAC, derived from Agkistrodon contortrix snake contortrix venom. Prolongation of the PT was directly related to the activity of the PC/PS system. One hundred and nineteen thrombophilic patients including 36 with PC deficiency, 22 with PS defect, 35 with APC resistance and 26 with other genetic defects predisposing to thrombosis were tested with the new assay together with 112 healthy subjects. The new test showed a high sensitivity for detection of inherited defects related to the PC/PS system (92%, 91% and 97% for PC defects, PS defects and APC resistance, respectively). Since it can be performed automatically the test could be used to screen for patients predisposed to thrombosis due to impairment of the PC/PS system and those patients who might eventually require more extensive evaluation of the PC/PS system by single component assays.

Adult↗
PubMed1996

Thromboembolic disease developing during oral contraceptive therapy in young females with antiphospholipid antibodies.

The role of oral contraceptives as a triggering factor for thrombosis in patients with lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACA) has not yet been established. We describe the cases of three women aged 19, 29 and 48 years who developed venous thrombosis after 16 +/- 3.4 (mean +/- SD) cycles of oral contraceptives. They were all asymptomatic before taking the pill. Two patients subsequently developed venous and/or arterial recurrence of thrombosis. Laboratory studies performed after the diagnosis of thrombosis, showed the presence of LA and elevated levels of ACA (IgG and IgM) in all three patients. None of these patients had autoimmune diseases and therefore appeared to have a primary antiphospholipid antibody syndrome. The three patients belonged to a group of 45 young females who experienced their first thrombotic event while taking the pill. This group had a similar prevalence (8%) for antithrombin deficiency and antiphospholipid antibodies. We surmise that some of the women who developed venous thrombosis while taking the pill might have an undetected primary antiphospholipid syndrome.

Adult↗
PubMed1996

Homozygous patients with APC resistance may remain paucisymptomatic or asymptomatic during oral contraception.

The effect of oral contraceptive therapy was studied in five patients with homozygous activated protein C resistance. Patients with this congenital abnormality, in contrast to those with antithrombin, protein C or protein S deficiencies, showed only a mild thrombotic tendency. In fact, only two of six observations (one patient took the pill on two separate occasions many years apart) showed deep vein thrombosis. No patient had pulmonary embolism. Two additional patients had a superficial vein thrombosis of the legs. In two instances, a superficial vein thrombosis and a deep vein thrombosis, concomitant risk factors were present (immobilization and surgery for an ovarian cyst, respectively). However, compared with heterozygous for the same abnormality, the symptomatic homozygous patients with APC resistance appeared to develop thrombosis after a shorter period of oral contraception.

Adult↗
PubMed1996

The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.

Hereditary deficiencies of the naturally occurring anticoagulants are well recognized conditions predisposing to recurrent venous thromboembolism. Since thrombotic phenomena have been implied as a cause of abortion and stillbirth, we hypothesized that these deficiencies increase the risk of fetal demise. A group of 129 female subjects who had been pregnant at least once and who had a family member with documented venous thrombosis associated with a deficiency of AT, PC or PS were studied. We first assessed the obstetric history and subsequently determined the deficiency status. In the 60 deficient subjects 42 (22.3%) of the 188 pregnancies resulted in miscarriage or stillbirth as compared to 23 (11.4%) of the 202 pregnancies in the 69 non-deficient subjects. The relative risk of abortion and stillbirth per pregnancy for deficient women as compared to non-deficient women was 2.0 (95% C.I. 1.2-3.3).

Abortion, Spontaneous↗
PubMed1996

"Pseudo homozygous" activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds.

Two unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F.V defect and F.V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F.V Leiden mutation, the measurement of the responsiveness of patients' plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so-called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F.V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F.V, instead of protecting from thrombotic risk due to heterozygous F.V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F.V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F.V Leiden mutation based on the APC-resistance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged.

Adolescent↗
PubMed1996

Mutations which introduce free cysteine residues in the Gla-domain of vitamin K dependent proteins result in the formation of complexes with alpha 1-microglobulin.

We have previously described a genetic factor IX variant (Cys18-->Arg) for which we demonstrated that it had formed a heterodimer with alpha 1-microglobulin through formation of a disulphide bond with the remaining free cysteine residue of the disrupted disulphide bond in the Gla-domain of factor IX. Recently, we observed a similar high molecular weight complex for a genetic protein C variant (Arg-1-->Cys). Both the factor IX and the protein C variants have a defect in the calcium induced conformation. In this study we show that the aminoterminus of this protein C variant is prolonged with one amino acid, cysteine. This protein C variant, as well as protein C variants with Arg9-->Cys and Ser12-->Cys mutations which also carry a free cysteine residue, are shown to be present in plasma as a complex with alpha 1-microglobulin. A prothrombin variant with a Tyr44-->Cys mutation, had not formed such a complex. Furthermore, complexes between normal vitamin K-dependent clotting factors and alpha 1-microglobulin were shown to be present in plasma at low concentrations. The data suggest that the presence of an unpaired cysteine residue in the propeptide or the N-terminal half of the Gla-domain has strongly promoted the formation of a complex with alpha 1-microglobulin in the variants.

Alpha-Globulins↗
PubMed1996

Deep venous thrombosis and lupus anticoagulant. A case-control study.

BACKGROUND: A definite evidence in favour of an association of deep-vein thrombosis (DVT) with lupus anticoagulant (LA) in patients free from systemic lupus erythematosus is still lacking. METHODS: In a case-control study, LA was determined in 176 consecutive outpatients who underwent phlebography because of the first episode of clinically suspected DVT of lower limbs. The association between DVT and LA was described using odds ratios (OR). RESULTS: Contrast venography confirmed the clinical suspicion in 59 patients (33.5%). LA was detected in 5 of the 59 patients with DVT (8.5%), and in none of the 117 subjects with normal venogram (P = 0.007). The OR for having an acute DVT in patients with LA was 10.7 (95% CI: 1.2-94.2). CONCLUSIONS: LA is significantly associated with DVT in symptomatic patients. Further studies are needed to establish the clinical implications of this association.

Adult↗
PubMed1996

Hyperhomocysteinemia and deep-vein thrombosis. A case-control study.

In a case-control study, fasting total homocysteinemia was determined in 208 consecutive outpatients who underwent phlebography because of the first episode of clinically suspected deep-vein thrombosis (DVT) of lower limbs. Contrast venography confirmed the clinical suspicion in 60 patients (28.8%). Hyperhomocysteinemia was detected in 15 of the 60 patients with DVT (25.0%), and in 17 of the 148 subjects without thrombosis (11.5%; p = 0.025). The OR for having an acute DVT in patients with hyperhomocysteinemia was 2.6 (95% CI: 1.1-5.9). It is concluded that high plasma homocysteine levels are significantly associated with DVT in symptomatic patients. Further studies are needed to clarify the clinical implications of this association.

Adult↗
PubMed1995

Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy.

The molecular genetic analysis of protein S deficiency has been hampered by the complexity of the protein S (PROS) gene and by the existence of a homologous pseudogene. In an attempt to overcome these problems, a reverse transcript-polymerase chain reaction (RT-PCR) mutation screening procedure was developed. However, the application of this mRNA-based strategy to the detection of gene lesions causing heterozygous type I protein S deficiency appears limited owing to the high proportion of patients exhibiting absence of mRNA derived from the mutation-bearing allele ("allelic exclusion"). Nevertheless, this strategy remains extremely effective for rapid mutation detection in type II/III protein S deficiency. Using the RT-PCR technique, a G-to-A transition was detected at position +1 of the exon IV donor splice site, which was associated with type I deficiency and resulted in both exon skipping and cryptic splice site utilization. No abnormal protein S was detected in plasma from this patient. A missense mutation (Asn 217 to Ser), which may interfere with calcium binding, was also detected in exon VIII in a patient with type III protein S deficiency. A further three PROS gene lesions were detected in three patients with type I deficiency by direct sequencing of exon-containing genomic PCR fragments: a single base-pair (bp) deletion in exon XIV, a 2-bp deletion in exon VIII, and a G0to-A transition at position -1 of the exon X donor splice site all resulted in the absence of mRNA expressed from the disease allele. Thus, the RT-PCR methodology proved effective for further analysis of the resulting protein S-deficient phenotypes. A missense mutation (Met570 to Thr) in exon XIV of a further type III-deficient proband was subsequently detected in this patient's cDNA. No PROS gene abnormalities were found in the remaining four subjects, three of whom exhibited allelic exclusion. However, the father of one such patient exhibiting allelic exclusion was subsequently shown to carry a nonsense mutation (Gly448 to Term) within exon XII.

Base Sequence↗