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M Alhenc-Gelas

Publications and source records attributed to M Alhenc-Gelas.

At least 19 recordsLinked to original sources
PubMed2004

The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case-control study.

BACKGROUND: The FIIG20210A polymorphism has been associated with arterial wall thickness and atherothrombotic diseases in selected subgroups. The FVArg506Gln polymorphism does not seem to be associated with arterial diseases. Few data are available on these polymorphisms and the risk of peripheral arterial disease (PAD). OBJECTIVES: To study the association between the FIIG20210A and FVArg506Gln polymorphisms and PAD and its clinical severity. To examine the potential interactions with traditional vascular risk factors. PATIENTS AND METHODS: We studied 184 consecutive male patients under 70 years of age with symptomatic PAD and 330 age-matched male controls free of symptomatic PAD and with no cardiovascular history. We evaluated the FIIG20210A and FVArg506Gln polymorphisms in all subjects. RESULTS: Mean age was 57.1 +/- 7.2 years (cases) and 56.7 +/- 7.6 years (controls). The FII20210A allele was more frequent in PAD patients with odds ratios (OR) of 3.77 (1.39-10.2) in univariate analysis and 4.30 (1.3-14.7) after adjustment for diabetes, smoking, hypertension and hypercholesterolemia. In smokers or past smokers the magnitude of the association was markedly increased but there was no evidence of an interaction between tobacco exposure and FIIG20210A. In case subjects, the FII20210A allele was also associated with critical ischemia [OR = 4.1 (1.1-15.7), P = 0.039 in multivariate analysis]. FVArg506Gln was not associated with PAD [OR = 0.65 (0.27-1.54) and 0.77 (0.28-2.1) in univariate and multivariate analyses, respectively]. CONCLUSIONS: The FIIG20210A gene polymorphism may be a risk factor for PAD and its severity. In contrast, the FVArg506Gln polymorphism is not associated with PAD.

Aged↗
PubMed2004

Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives.

Oral contraceptive (OC) use is associated with an increased risk of venous thromboembolism. Previous data reported higher thrombotic risk in women using third-generation combined OC than in those using second generation OC. The difference could be explained by differential effects of progestagens on plasma sensitivity to activated protein C (APC). The main purpose of this cross-sectional study was to assess the influence of a progestagen-only OC (chlormadinone acetate) as well as the effect of several combined OC with different progestagen components on APC resistance. The effect of APC on endogenous thrombin potential (ETP) was investigated in the plasma of healthy women using either combined OC (n=82) or progestagen-only OC (n=28), and in non-users (n=64). Carriers of factor V Leiden were excluded. Compared with non-users, there was no significant change in APC resistance in women using progestagen-only OC. Women who used combined OC were less sensitive to APC than non-users (P < 0.001) and the difference was significantly more pronounced in women using third-generation OC (n=41) than in those who used second-generation OC containing levonorgestrel (n=22) (P < 0.05). Compared with OC containing levonorgestrel, use of norethisterone-containing OC (n = 9) was associated with an increased resistance to APC (P < 0.05). Women who used cyproterone-containing OC (n = 10) were less sensitive to APC than those using third-generation OC (P < 0.05) or second-generation OC containing levonorgestrel (P < 0.05). Protein S, factor II and FVIII levels explained in part the OC-related changes in APC sensitivity variations. ETP-based APC resistance may contribute to explain why different brands of OC can be associated with different levels of thrombogenicity.

Activated Protein C Resistance↗
PubMed2003

Familial thrombophilia is an oligogenetic disease: involvement of the prothrombin G20210A, PROC and PROS gene mutations.

Population-based case-control studies and cases previously published suggest that the prothrombin G20210A mutation is a weak risk factor for thrombosis, leading to clinical expression mainly in the presence of other risk factors. We report the results of plasma and genetic analyses performed in a 13-year-old symptomatic boy homozygous for the 20210A allele and in his family, which are in accordance with this suggestion. These analyses demonstrated the presence of several PROC (R-5W, R87H) and PROS (R60C, T103N) gene mutations in this family. These additional mutations have modulating effects on clinical expression of the G20210A mutation. The present family study illustrates the concept of 'mild' mutation and the hypothesis that familial thrombophilia is a multifactorial disease.

Adolescent↗
PubMed2003

[Genetics of venous thromboembolism].

Venous thrombo-embolic disease is a multifactorial disease which arises in situations of thrombosis risk with poorly understood genetic and/or acquired risk factors. Constitutional anomalies concerning five coagulation proteins (antithrombin, protein C, protein S, factor V and prothrombin) are established risk factors for which the harmful role has been demonstrated in thrombophilic families and/or in case-control studies. New studies (twin studies, GAIT study) which use joint subjects and appropriate statistical methods are aimed at a better understanding of the genetic component and the environmental component of thrombotic risk. They have allowed demonstration of the importance of the contribution of heredity to the variability of the coagulation parameter concentration and the variability of susceptibility to thrombosis, and have implied the influence of genes with pleiotrophic effect. The identification of these new loci will allow a better evaluation of the components of thrombotic risk and perhaps lead to individualised preventive therapeutic management.

Estrogens↗
PubMed2001

Association of circulating cellular adhesion molecules with menopausal status and hormone replacement therapy. Time-dependent change in transdermal, but not oral estrogen users.

The incidence of coronary heart disease is lower in premenopausal than in postmenopausal women, and estrogen use may be cardioprotective among postmenopausal women. Cellular adhesion molecules (CAM) are involved in the early stage of atherosclerosis, and short-term administration of oral estrogen decreased plasma concentrations of their soluble forms in postmenopausal women. However, data evaluating transdermal estrogen are sparse and long-term effect of hormone replacement therapy (HRT) on CAM is unknown. Therefore, we have investigated the association of circulating CAM (cCAM) with menopausal status and long-term HRT. Plasma levels of intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), P-selectin, E-selectin, C-reactive protein (CRP), and fibrinogen were measured in 74 premenopausal women, 60 postmenopausal women not using HRT, 30 postmenopausal women using opposed oral estrogen therapy, and 30 postmenopausal women using opposed transdermal estrogen therapy. All women were apparently healthy and aged between 45 and 54 years. Duration of HRT ranged from 3 to 96 months. Postmenopausal women not receiving HRT had 24% higher mean levels of cICAM-1 than premenopausal women (318 vs. 255 ng/ml, P < .001). In postmenopausal women, users of oral estrogen had 16% lower, and users of transdermal estrogen had 17% lower mean levels of cICAM-1 than non-users (268 and 264 vs. 318 ng/ml, P = .001 for both comparisons). Furthermore, in users of transdermal route, the lowering effect of estrogen on cICAM-1 was dependent on treatment duration, while no time-dependent effect was seen in oral estrogen users. Users of transdermal estrogen had lower cVCAM-1 and P-selectin levels than postmenopausal non-users (327 vs. 364 ng/ml (P = .05) and 18 vs. 23 ng/ml (P = .05). There was no difference in CRP and E-selectin levels between the groups. Adjustment for age and body mass index (BMI) made no substantial change in the results. These data suggest that oral and transdermal estrogen may play a long-term cardioprotective role through favourable changes in endothelial function.

Administration, Cutaneous↗
PubMed2001

Factors V leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis.

PURPOSE: Factor V Leiden and factor II 20210A are inherited disorders of the clotting system that occur frequently in patients with deep vein thrombosis. We conducted this study to determine whether these factors are also common in patients with pulmonary embolism. SUBJECTS AND METHODS: We determined the prevalence of factor V Leiden and factor II 20210A in 773 consecutive patients with objectively documented symptomatic deep vein thrombosis or symptomatic pulmonary embolism, or with a combination of these disorders. RESULTS: Isolated symptomatic deep vein thrombosis occurred in 345 patients; isolated symptomatic pulmonary embolism occurred in 236; and both anomalies occurred in 192. Factor V Leiden was present in 21 (9%) of the patients with isolated symptomatic pulmonary embolism, in 30 (16%) with both manifestations, and in 63 (18%) with isolated symptomatic deep vein thrombosis (P = 0.007). Factor V Leiden was more common among patients with deep vein thrombosis (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.2 to 3.7; P = 0.006) or both pulmonary embolism and deep vein thrombosis (OR = 1.8; 95% CI: 1.0 to 3.3; P = 0.07) than among patients with isolated pulmonary embolism. Factor V Leiden was less common in massive pulmonary embolism (5% [7 of 127]) than in submassive pulmonary embolism (13% [21 of 155], P = 0.03). We found no significant difference in the prevalence of factor II 20210A among the three groups. CONCLUSION: Factors V Leiden and II 20210A vary in prevalence among patients with pulmonary embolism and deep vein thrombosis, suggesting that the risk of pulmonary embolization may vary among patients who have different causes of venous thromboses.

Adult↗
PubMed2001

[The biological distribution of thrombosis in the year 2000].

Acquired or genetic risk factors for thrombosis are present in about fifty per cent of the patients with venous thromboembolic disease. In order to evaluate the contribution of genetic defects in the pathogenesis of thrombosis, the laboratory investigation will include search for the factor V Leiden and prothrombin Leiden mutations, and for antithrombin, protein C and protein S hereditary deficiencies. Search for antiphospholipid antibodies and factor VIII plasma levels measurements will be also performed.

Antibodies, Antiphospholipid↗
PubMed2001

Venous thromboembolic disease: risk factors and laboratory investigation.

The etiology of venous thromboembolic disease has been the subject of several recent discoveries, particularly on genetic predisposing factors. The laboratory investigation that may help to evaluate the risk for individual patients includes the measurements of coagulation inhibitors (antithrombin, protein C, and protein S) in plasma assays, the search for the factor V Leiden mutation by the plasma activated protein C resistance test (always to be confirmed by DNA analysis when abnormal), and the search for the prothrombin gene mutation by DNA analysis. Among acquired abnormalities, the most frequently involved are phospholipid-dependent autoantibodies associated or not with a subset of antibodies having an anticoagulant effect in vitro (lupus anticoagulant). Other coagulation abnormalities such as increased FVIII, FIX, or FXI levels or hyperhomocysteinemia have been suggested to be risk factors for thrombosis, although additional studies are required to definitively assess their role.

Activated Protein C Resistance↗
PubMed2001

Deep venous thrombosis and thrombophilia: indications for testing and clinical implications.

In the past 3 decades, numerous biological abnormalities linked with deep venous thrombosis have been described. Among the different possibilities, it is crucial to order tests that can modify the therapeutic attitude towards the patient and/or his family. A combined clinical and laboratory approach taking into account the history of the patient and his family, the prevalence of the defects, and also the accuracy of the tests should allow tailoring a laboratory testing program to each patient. It is essential to keep in mind that the more difficult task is not to perform the tests but to consider who will benefit from testing both for prevention and therapy of venous thromboembolism. This article provides answers to some of these issues. These answers should, however, be considered as tentative and provisional because new findings and study results will certainly modify them in the near future.

Activated Protein C Resistance↗
PubMed2001

Thrombomodulin promoter mutations, venous thrombosis, and varicose veins.

We analyzed the distal promoter region of the thrombomodulin (TM) gene (nucleotides -300 to -2052) in subjects from the Paris Thrombosis Study (PATHROS), a French case-control study of venous thrombosis, to identify polymorphisms that might modify TM gene expression. Eight novel mutations were found in the 40 DNA samples initially screened. Two of these mutations (-1748G/C and -1208/-1209 del TT) were frequent. One rare transition (-1166G/A) might have functional consequences owing to its position. These 3 mutations were screened for in the entire study population of 327 patients and 398 controls. None of the 3 was significantly associated with thrombosis. Interestingly, the -1208/-1209 TT deletion was associated with varicose veins in the patients. This mutation was in tight linkage disequilibrium with the +1418 C/T change in the coding sequence, a known polymorphism that predicts an Ala 455 Val substitution in the sixth epidermal growth factor-like TM module, a domain previously implicated in the proliferative functions of TM. This linkage suggests that the Ala 455 Val mutation may promote changes in these functions and thus be involved in varicose vein formation.

Adult↗
PubMed2000

Hypercoagulable states in primary upper-extremity deep vein thrombosis.

BACKGROUND: There are very few data on the prevalence of coagulation abnormalities in primary deep vein thrombosis of the upper limbs. OBJECTIVE: To determine if coagulation abnormalities play a role in effort-related and/or idiopathic (non-effort-related) upper-extremity deep vein thrombosis (UEDVT). METHODS: Fifty-one consecutive patients (21 men and 30 women) who had effort-related (n = 20) or idiopathic (n = 31) UEDVT over an 18-year period (median age at diagnosis, 32 years; age range, 15-86 years) were routinely reexamined. Plasma was screened for antithrombin, protein C, and protein S deficiencies and for antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies). The DNA was screened for factor V Leiden and for prothrombin gene G20210A mutations. RESULTS: The median age (35 vs. 28 years), the proportion of women (81% [25/31] vs. 25% [5/201), the proportion of patients with a personal and/or family history of thromboembolism (42% [13/31] vs. 15% [3/20]), and the proportion of patients with at least 1 coagulation abnormality (42% [13/31] vs. 15% [3/20]) were higher in the idiopathic UEDVT group than in the effort-related UEDVT group. The odds ratio of having a coagulation abnormality was 4.09 (95% confidence interval, 0.99-16.78; P = .06) in the idiopathic UEDVT group compared with the effort-related UEDVT group. CONCLUSION: Hypercoagulable states appear to play a significant role in idiopathic but not in effort-related UEDVT.

Adolescent↗
PubMed2000

Molecular bases of antithrombin deficiency in French families: identification of seven novel mutations in the antithrombin gene.

We have investigated the molecular bases of familial antithrombin deficiency in eight French families. Eight mutations in the antithrombin coding exons were identified, seven of which were novel mutations. In all cases, individuals were heterozygous for the mutation. We found two small frameshift deletions in exon 3a, leading to type I deficiency. Five missense mutations in exons 3b or 5 also caused type I deficiency and their potential consequences on the antithrombin three-dimensional structure were analysed. The last mutation in exon 4 was associated with a type II 'reactive site' deficiency: a dysfunctional antithrombin that is affected in its interaction with thrombin was present in circulation.

Antithrombin III Deficiency↗
PubMed2000

Protective effect of a thrombin receptor (protease-activated receptor 1) gene polymorphism toward venous thromboembolism.

The human protease-activated receptor 1 (PAR-1) is activated by thrombin at the surface of platelets and endothelial cells, 2 cells that are implicated in hemostasis and thrombosis. We studied the PAR-1 gene in a large case-control study from the Paris Thrombosis Study (PATHROS), and the possible implication of polymorphisms in venous thromboembolism was evaluated. Two polymorphisms were found in the 5' regulatory region. The first is a C to T transition that is 1426 nucleotides upstream from the translation start site (-1426 C/T), and the second is a 13-bp insertion repeating the preceding -506 5'-CGGCCGCGGGAAG-3' sequence (-506 I/D, where I indicates insertion and D indicates deletion), a putative cis-acting element of the Ets family. The third polymorphism is an A to T transversion in the intervening sequence (IVS) that is 14 nucleotides upstream from the exon 2 start site (IVS-14 A/T). The distribution of the 3 polymorphisms was otherwise similar in the 250 cases and the 1214 controls. A noteworthy sex heterogeneity led us to analyze men and women separately with regard to the -506 I/D polymorphism. We found that allele I was less frequent in male cases than in male controls (0.154 versus 0.247, P<0.01), with an odds ratio at 0.52 (95% CI 0. 32 to 0.82, P<0.01). Furthermore, a reduction of prothrombin fragment 1+2 levels was observed in homozygous carriers of allele -506 I (P=0.04). Altogether, these data suggested a protective effect in men of -506 I/D polymorphism for venous thromboembolism.

Adult↗
PubMed2000

Thirty-three novel mutations in the protein C gene. French INSERM network on molecular abnormalities responsible for protein C and protein S.

We analyzed the protein C gene (PROC) with the denaturing gradient gel electrophoresis (DGGE) scanning strategy in a series of 129 patients with suspected protein C (PC) deficiency (93 with low plasma PC levels and 36 with borderline level). At least one sequence variation was found in 104 of the 129 patients. Thirty-nine sequence variations (found in 72 patients) were already reported detrimental mutations. Thirty-three were novel sequence variations, of which 19 (found in 25 patients) were probably detrimental. Five novel mutations (A1T, R9H, S11R, S12R and K193Q) were associated with qualitative plasma PC deficiency, suggesting or confirming the functional importance of amino acids at these positions. This strategy confirmed the diagnosis of inherited PC deficiency in 79/93 (84.9%) patients with low plasma PC levels and 14/36 (38.8%) patients with borderline values. In order to explain abnormal PC levels observed in patients who did not carry detrimental mutations, screening for the -1654C/T and -1641A/G PROC promoter polymorphisms known to influence plasma PC concentrations was performed. The frequency of the CG allele associated with lower PC concentrations was slightly but not significantly lower in 82 heterozygotes for detrimental PROC gene mutations than in 36 patients with no identified detrimental mutations.

Adult↗