PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects

Abstract

Impaired fibrinolysis as a result of increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma is a common finding in patients with deep vein thrombosis (DVT). A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to influence the levels of PAI-1. The 4G allele was found to be associated with higher plasma PAI-1 activity (act), but contradictory results on the incidence of the 4G allele in DVT patients have been reported. The aim of this study was to analyse whether the PAI-1 promoter 4G/5G genotype increases the risk of venous thrombosis in subjects with thrombophilic defects, and to determine the distribution of the PAI-1 4G/5G genotype and its relation to plasma PAI-1 levels in 190 unrelated patients with DVT in comparison with a control group of 152 healthy subjects. No differences between the 4G/5G allele distribution in the DVT group (0.43/0.57) and in the control group (0.42/0.58) were observed. However, the presence of the 4G allele significantly increased the risk of thrombosis in patients with other thrombophilic defects. Significantly higher PAI-1 levels were observed in DVT patients than in the controls. Our results also showed significant differences in the plasma levels of PAI-1 antigen (ag) and PAI-1 act among the 4G/5G genotypes in DVT patients. A multivariate analysis revealed that, in the DVT group, PAI-1 ag levels were influenced by the 4G allele dosage, triglyceride levels and body mass index (BMI). The influence of the 4G allele dosage on PAI-1 levels was independent of the triglyceride levels and BMI. In the control group, no significant correlation between PAI-1 levels and 4G allele dosage was observed. In conclusion, the PAI-1 promoter polymorphism was found to have an influence on PAI-1 levels in DVT patients and on the risk of venous thrombosis in subjects with other genetic thrombophilic defects.

Mutations and Polymorphisms in Genes Affecting Hemostasis Proteins and Homocysteine Metabolism in Children with Arterial Ischemic Stroke

“…Furthermore, the role of a common polymorphism in the factor XIII A subunit (FXIII Val34Leu), which affects cross-linked fibrin structure, as well as of a polymorphism in the promoter of the plasminogen activator inhibitor-1 gene (PAI-1 4G), which results in an increased plasma PAI-1 concentrations in individuals homozygous for 4G allele, are controversial [13,14,15,16,17]. The HPA-1a/1b polymorphism of human platelet antigen 1 (HPA-1), localized on platelet glycoprotein GPIIIa, has also been identified as an inherited risk factor for atherothrombosis, enhancing platelet activation [18, 19].…”

Analysis of thrombophilic genetic mutations in patients with Sheehan`s syndrome: is thrombophilia responsible for the pathogenesis of Sheehan`s syndrome?

“…Among 4G/4G, 5G/ 5G and 4G/5G genotypes, the highest PAI-1 activity value was observed in 4G/4G, but this genotype was not found to be a major risk factor for venous thromboembolism by itself [8]. Besides, the presence of the 4G allele significantly increased the risk of thrombosis in patients with other thrombophilic defects [33]. The frequency of the 4G/ 4G was found in 8 homozygote patients (20%), 4G/5G in 24 heterozygote patients (60%) and 5G/5G in 8 normal patients (20%).…”

Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension

“…4G/5G allele distribution is similar in patients with thrombosis and healthy subjects. On the other hand, the 4G allele is not an independent risk factor for thrombosis [46]. When 4G/4G allele compared with other two alleles, the 4G/4G genotype was significantly higher in our study group.…”