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-beta-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.