Summary. Recent studies suggest that low-dose oral contraceptives may cause acquired resistance to activated protein C (APC). The aims of this study were to determine whether hormone replacement therapy (HRT) may also induce acquired APC resistance and to study the effects of APC resistance on the risk of recurrent thrombosis. The patients comprised 140 females with at least one previous venous thromboembolism (VTE), who were randomized to receive continuous treatment with 2 mg 17-b-oestradiol and 1 mg norethisterone acetate (n 71) or placebo (n 69). Normalized APC sensitivity ratios (nAPCsr) were calculated by measurement of the effect of APC on thrombin generation in plasma collected at baseline and after 3 months of treatment. Of the 140 women, 121 had plasma samples collected both at baseline and after 3 months.The nAPCsr increased significantly (P , 0´001) on HRT (n 62), both in females not carrying the factor V Leiden mutation [mean change 0´57 (95% CI 0´45±0´70), n 50] and in females heterozygous for the factor V Leiden mutation [mean change 1´10 (0´71±1´49), n 12], but remained unchanged on placebo (n 59). The baseline nAPCsr as well as the increase in nAPCsr associated with HRT use was not higher in the five women who subsequently developed recurrent VTE. Free protein S and free TFPI were both important parameters for the acquired APC resistant phenotype. We conclude that HRT diminishes the efficacy by which APC downregulates in-vitro thrombin formation in a similar fashion to that observed with low-dose oral contraceptives, but the increase in nAPCsr alone is not sufficient to explain the increased risk of VTE associated with use of HRT.

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Postmenopausal hormone therapy is associated with marked reduction in tissue factor pathway inhibitor (TFPI) levels, and low TFPI levels have been associated with increased risk of venous thrombosis. Polymorphisms in the TFPI gene may affect the expression of TFPI. We aimed to investigate the influences of such polymorphisms on plasma TFPI levels and to investigate the effect of hormone therapy. Four single nucleotide polymorphisms in the TFPI gene (the -287T/C and the -399C/T polymorphisms in the 5' upstream region, and the intron 7 -33T/C and the exon 9 874G/A polymorphisms) were studied with regard to frequency, phenotype, and their influence on hormone therapy in postmenopausal women with a history of venous thrombosis (n = 138), in healthy postmenopausal women (n = 202), and in normal controls (n = 212). The frequencies of the -287C and the -33C variants were nonsignificantly lower in cases than in controls, and the polymorphisms were associated with slightly higher levels of free TFPI antigen (-287C; P = 0.076) and higher TFPI activity (-33C; P < 0.001). The -399T variant showed equal distribution in cases and controls, but was associated with lower levels of TFPI activity (P = 0.036). Conventional-dose hormone therapy induced significant reductions in TFPI levels irrespective of genotypes. In healthy women treated with low-dose hormone therapy, the reduction in TFPI levels was less pronounced with the -287C variant (P = 0.054). Our study indicates that polymorphisms in the TFPI gene may be of importance for plasma TFPI levels and for the effects of hormone therapy.