A COMMON 4G ALLELE IN THE PROMOTER OF THE PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1) GENE AS A RISK FACTOR FOR PULMONARY-EMBOLISM AND ARTERIAL THROMBOSIS IN HEREDITARY PROTEIN-S DEFICIENCY

Reduced fibrinolytic capacity due to increased plasminogen activator i nhibitor-1 (PAI-1) activity in plasma is a common finding in patients with coronary heart disease or venous thromboembolism, although its cl inical significance is debated. Recently, a dimorphism in the PAI-1 pr omoter (4G-5G) has been reported and homozygosity for the 4G allele is associated with increased transcription and higher PAI-1 levels. Homo zygous 4G genotype has been suggested to be a risk factor for myocardi al infarction. In the present study, the 4G-5G dimorphism was determin ed in 349 individuals from 21 thrombophilic families with hereditary p rotein S deficiency and in 140 unrelated healthy controls. Among the 1 43 protein S deficient individuals, there was no relationship between deep or superficial venous thrombosis and the PAI-1 dimorphism. Howeve r, 26% (12/46) of individuals having protein S deficiency combined wit h homozygosity for the 4G allele had suffered pulmonary embolism as co mpared to 7% (7/97) of protein S deficient individuals carrying at lea st one 5G allele (p = 0.0019). In protein S deficient individuals, art erial thrombosis was found to be associated with smoking and 4G homozy gosity. No association was found between the PAI-1 dimorphism and arte rial or venous thromboembolism in family members without protein S def iciency. In conclusion, the PAI-1 genotype affects the phenotypic expr ession of thrombophilia in protein S deficient individuals.