E. Hoibraaten et al., Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial, BR J HAEM, 115(2), 2001, pp. 415-420
Recent studies suggest that low-dose oral contraceptives may cause acquired
resistance to activated protein C (APC). The aims of this study were to de
termine whether hormone replacement therapy (HRT) may also induce acquired
APC resistance and to study the effects of APC resistance on the risk of re
current thrombosis. The patients comprised 140 females with at least one pr
evious venous thromboembolism (VTE), who were randomized to receive continu
ous treatment with 2 mg 17-beta -oestradiol and 1 mg norethisterone acetate
(n = 71) or placebo (n = 69). Normalized APC sensitivity ratios (nAPCsr) w
ere calculated by measurement of the effect of APC on thrombin generation i
n 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 f
emales 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 mut
ation [mean change 1.10 (0.71-1.49), n = 12], but remained unchanged on pla
cebo (n = 59). The baseline nAPCsr as well as the increase in nAPCsr associ
ated with HRT use was not higher in the five women who subsequently develop
ed recurrent VTE. Free protein S and free TFPI were both important paramete
rs for the acquired APC resistant phenotype. We conclude that HRT diminishe
s 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 o
f VTE associated with use of HRT.