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Biomedical subjects

M Aiach

Publications and source records attributed to M Aiach.

At least 73 records · Page 4Linked to original sources
PubMed1997

Interdonor variability of platelet response to thrombin receptor activation: influence of PlA2 polymorphism.

Considering that platelet response to thrombin receptor activation might be critical for the development of arterial thrombosis, we measured the dense granule release under stimulation by the thrombin receptor activating peptide (TRAP) in a series of 102 healthy volunteers. The threshold TRAP concentration which initiated a secretion ranged from 3 to 20 microM. A good concordance (79%, k=0.677) between two tests performed at a 1 month interval indicated that platelet response to thrombin receptor activation was characteristic of each individual donor. Since the threshold concentration required to initiate secretion corresponded to the threshold concentration which induced a biphasic aggregation, all volunteers were genotyped for the PlA2 polymorphism, the Pro33 variant of GPIIIa. Platelets from subjects with the PlA2 polymorphism required higher TRAP concentrations to aggregate than those from subjects with no PlA2 allele (P=0.0012). However, they also required a higher ADP concentration to aggregate. In order to exclude any influence of GPIIIa polymorphism on TRAP-induced secretion, we studied the variability of platelet response to TRAP among the 77 individuals with no PlA2 allele, and found the same interdonor variability with the same distribution of threshold TRAP concentrations as for the 102 individuals. The results suggest that (i) platelet secretion in response to thrombin receptor activation could be a genetically controlled phenotype independent of the GPIIIa polymorphism; (ii) the PlA2 polymorphism is associated with platelet hypoaggregability.

Blood Platelets↗
PubMed1997

Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial.

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

Administration, Cutaneous↗
PubMed1997

Clinical features in 36 patients homozygous for the ARG 506-->GLN factor V mutation.

We analyzed the clinical features of 36 patients homozygous for the Arg 506 to Gln factor V mutation and found a circumstantial event at risk for thrombosis in 29 of the 31 patients with thrombosis. The most frequent predisposing factors were the post-partum period and the use of oral contraceptives in women, and surgery in both sexes. Venous thrombosis recurred in 48% of the patients. One patient had a myocardial infarction at age 33 years, and also had an antiphospholipid syndrome. Homozygous Gln 506 mutation leads to far less severe thrombotic complications than homozygous protein C and protein S deficiencies and does not seem to predispose patients to arterial thrombosis.

Adult↗
PubMed1997

Protein S deficiency.

The protein C (PC) pathway, with its cofactor protein S (PS), is an important natural antithrombotic mechanism. Patients with phenotypic PS deficiency may develop recurrent thrombosis during adulthood, with a probability of remaining free of thrombosis of about 50% at age 45. The molecular basis for hereditary PS deficiencies is highly heterogeneous, with a large spectrum of mutations that have various effects on the expression of the relevant allele.

Anticoagulants↗
PubMed1997

Protein C and protein S deficiencies.

The protein C (PC) pathway, with its cofactor protein S (PS), is an important natural antithrombotic mechanism. Both PC and PS deficiencies have been implicated in thrombophilia. The molecular basis for hereditary PC and PS deficiencies is highly heterogeneous, with a large spectrum of mutations that have various effects on the expression of the relevant allele. A small subset of patients who are homozygous or compound heterozygous for a PC gene mutation have severe thrombotic complications at birth, whereas onset occurs later in the other cases. Patients heterozygous for a PC or PS gene abnormality may develop recurrent thrombosis during adulthood, with a probability of remaining free of thrombosis of about 50% at age 45. A PC or PS gene defect is associated with the factor V Arg 506 to Gln mutation in 10% to 30% of symptomatic patients, suggesting that clinical expression is controlled by several genes in heterozygous patients.

Chromosome Mapping↗
PubMed1997

Purpura fulminans induced by disseminated intravascular coagulation following infection in 2 unrelated children with double heterozygosity for factor V Leiden and protein S deficiency.

Purpura fulminans is associated with homozygous protein C and homozygous protein S deficiency or may follow bacterial or viral infections. We present 2 children from 2 unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation. This report emphasizes the need for evaluation of hereditary defects in the inhibitory mechanisms of blood coagulation in patients with purpura fulminans at any age.

Child, Preschool↗
PubMed1996

Resistance to activated protein C: role in venous and arterial thrombosis.

Activated protein C resistance is the most prevalent cause of thrombophilia: it is found in 20 to 30% of patients with a deep venous thrombosis history. Activated protein C resistance is due to an arginine 506 to glutamine mutation in factor V. This mutation prevents normal inactivation of activated factor V by activated protein C. The estimated increase in relative risk of venous thrombosis is 5- to 10-fold in heterozygotes, and 50- to 100-fold in homozygotes. Activated protein C resistance does not seem to play a role in arterial thrombosis and in the occurrence of myocardial infarction.

Adult↗
PubMed1996

Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French Network on Molecular Abnormalities Responsible for Protein C and Protein S Deficiencies.

Circulating protein S (PS) is partly bound to C4b-binding protein, and only free PS can act as a cofactor for protein C (PC), a natural anticoagulant. Two types of PS deficiencies are commonly observed in patients with unexplained thrombosis, and they are characterized by having both a low total PS level and a low free PS level (type I) or by having only a low free PS level (type IIa). To elucidate the genetic mechanisms responsible for these two plasma phenotypes, we screened 118 symptomatic patients with type I or type IIa PS deficiency for a PS gene coding sequence variation. A total of 34 mutations, 17 of which were novel, were identified in 65 propositi (70% in type I and 44% in type IIa). In type I deficiency, 29 different mutations were distributed throughout the coding sequence. In type IIa deficiency, five different missense mutations were clustered in exons XII and XIII, with a Ser 460 to Pro mutation accounting for most cases (82%). This points to a role of the domain encoded by exons XII and XIII in the distribution between bound and free PS. The Ser 460 to Pro mutation was associated with the factor V Arg 506 to Gin mutation or a PC gene mutation in about half the patients, suggesting a cooperative effect on clinical expression.

DNA Mutational Analysis↗
PubMed1996

Homozygous variant of antithrombin with lack of affinity for heparin: management of severe thrombotic complications associated with intrauterine fetal demise.

Patients with homozygous heparin-binding-site (HBS) qualitative antithrombin deficiencies are at significant risk of venous and arterial thrombosis. We report on the eighth case of homozygous HBS deficiency, and the fourth case concerning the Arg 47-Cys mutation. The proposita is a 25 year old, without known thrombotic antecedent, despite an oral contraceptive therapy for 7 years. After 25 weeks of a first pregnancy, she presented an intrauterine fetal demise complicated with deep vein thrombosis and pulmonary embolism. Heparin therapy was inefficient (no clinical nor angiographic improvement, no biological hypocoagulability). Heparin cofactor activity was < 10%, antigen concentration was normal. The crossed immunoelectrophoresis of patient's plasma, with and without heparin, showed a typical profile of qualitative HBS antithrombin deficiency. The molecular analysis revealed an homozygous Arg 4-Cys mutation. Antithrombotic therapy was achieved with continuous infusion of antithrombin concentrates (80 IU/kg/day) and unfractionated heparin (500 IU/kg/day) during 12 days, leading to clinical improvement, and followed by treatment with vitamin K antagonists. This observation emphasizes the risk of intrauterine fetal demise and the inefficiency of heparin therapy without antithrombin infusion in type II HBS homozygous deficiency. The management of a future pregnancy will probably require repeated infusions of antithrombin.

Adult↗
PubMed1996

Molecular basis for protein C hereditary deficiency.

The clinical presentation of hereditary protein C deficiency is highly variable. Homozygosity and compound heterozygosity have been linked to severe thrombotic complications early in the life. Heterozygous patients have a moderate form of the disease with deep venous thrombosis during adulthood. In the French population, we found 53 different mutations in 90 families. The amount of the protein C produced by the mutant allele as well as the genetic status partly account for the variable clinical expression. Other gene may also be involved: Arg 506 to Gln factor V mutation shows a frequency of 10 to 20% in symptomatic protein C deficient patients. Some protein C gene mutations are associated with a non functional circulating protein; most of them are located in the GLA domain and in the serine protease domain. The biochemical characterization of a few of theses variants has shown the important role of some amino acids on the activation and the mechanism of action of protein C.

Alleles↗
PubMed1996

Five novel mutations of the protein S active gene (PROS 1) in 8 Norman families.

To further elucidate the molecular basis for hereditary thrombophilia, we screened the protein S active gene in 11 families with type I deficiency, using a strategy based on denaturing gradient gel electrophoresis (DGGE) of all the coding sequences. Fragments with an abnormal DGGE pattern were sequenced, and 5 novel mutations were identified in 8 families. The mutations were a 7-nucleotide deletion in exon II, a 4-nucleotide deletion in exon III, a T insertion in exon VII, a C to T transition transforming Leu 259 into Pro and a T to C transition transforming Cys 625 into Arg in 4 families. These mutations were the only sequence variations found in the propositus' gene exons and co-segregated with the plasma phenotype. A total of 28 members of these 8 families were heterozygous for one of the 5 mutations. Twenty-four (58,5%) of the 41 deficient subjects over 18 years of age had clinical thrombophilia, whereas the 13 subjects under 18 were asymptomatic. Of the 28 subjects, 6 (21,5%) were also found to bear the factor V Arg 506 Gln mutation.

Adolescent↗
PubMed1996

[Exploration of hemostasis in current practice].

The exploration of coagulation in biological practice implies simple routine tests. A normal bleeding time associated with a normal platelet count allows to exclude any primary haemostasis abnormality. A prolonged bleeding time is most frequently the result of a thrombocytopenia, the etiology of which remains to be determined. A prolonged bleeding time is also observed in von Willebrand disease and in thrombopathia. Such diagnosis requires appropriate investigation. The exploration of the coagulation cascade includes prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen level. A congenital or acquired deficiency in one or more coagulation factors should be distinguished from a lupus anticoagulant or from the occurrence of an antibody against a coagulation factor. Indeed, a prolonged APTT is not always related to a bleeding risk. Only the identification of the coagulation abnormality can predict the bleeding or thrombotic risk during surgery. In each case, an appropriate preventive therapy should be prescribed.

Blood Coagulation Disorders↗
PubMed1996

[Activated protein C resistance: role in venous and arterial thrombosis].

Activated protein C resistance is the most prevalent cause of thrombophilia: it is found in 20% to 30% of patients with a history of deep venous thrombosis history. Activated protein C resistance is due to an arginine 506 to glutamine mutation in factor V. This mutation prevents normal inactivation of activated factor V by activated protein C. The estimated increase in relative risk of venous thrombosis is 5 to 10 fold in heterozygotes, and 50- to 100- fold in homozygotes. Activated protein C resistance does not seem to play a role in arterial thrombosis or in the occurrence of myocardial infarction.

Blood Coagulation Disorders↗