ANALYSIS OF THE F8 GENE IN INDIVIDUALS WITH HIGH PLASMA FACTOR VIII-CLEVELS AND ASSOCIATED VENOUS THROMBOSIS

High FVIII:C levels have previously been shown to be an independent ri sk factor for thrombosis with 4.8 times higher potential risk of throm bosis in individuals with FVIII:C levels greater than 1.5 u/ml. Recent ly, we found that raised FVIII:C levels are largely attributable to el evated FVIII:Ag levels. The determinants of FVIII:Ag levels are unclea r and might be partly genetic. The promoter of the F8 gene has recentl y been characterised we therefore investigated the promoter and the 3' terminus of the F8 gene for possible polymorphisms associated with ra ised FVIII:Ag levels in 62 selected individuals with a thrombotic tend ency. We confirm previous reports that raised FVIII:C levels are large ly attributable to an elevation in FVIII:Ag and this is also associate d with elevation of vWF; non-O blood group; relatively short APTT and relatively low APC ratio. We screened 1140bp of the proximal promoter including the protein binding sites identified by DNase I footprint an alysis by SSCP, however no polymorphisms were identified. Direct DNA s equence analysis of the region -542 to +165 failed to identify any seq uence polymorphisms. The recently described polymorphism in the polyad enylation cleavage site in the prothrombin gene associated with increa sed prothrombin activity prompted us to screen the region surrounding the 3' terminus of the F8 gene for polymorphisms but we found none.