Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial

Br J Haematol. 2001 Nov;115(2):415-20. doi: 10.1046/j.1365-2141.2001.03111.x.


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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Activated Protein C Resistance / chemically induced*
  • Activated Protein C Resistance / genetics
  • Aged
  • Double-Blind Method
  • Drug Combinations
  • Estradiol / adverse effects
  • Estrogen Replacement Therapy / adverse effects*
  • Factor V / genetics
  • Female
  • Follow-Up Studies
  • Heterozygote
  • Humans
  • Middle Aged
  • Mutation
  • Norethindrone / adverse effects
  • Norethindrone / analogs & derivatives*
  • Norethindrone Acetate
  • Recurrence
  • Thromboembolism / chemically induced
  • Thromboembolism / genetics


  • Drug Combinations
  • factor V Leiden
  • Estradiol
  • Factor V
  • Norethindrone Acetate
  • Norethindrone