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

Citation
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
Citations number
28
Categorie Soggetti
Hematology,"Cardiovascular & Hematology Research
Journal title
BRITISH JOURNAL OF HAEMATOLOGY
ISSN journal
00071048 → ACNP
Volume
115
Issue
2
Year of publication
2001
Pages
415 - 420
Database
ISI
SICI code
0007-1048(200111)115:2<415:HRTAAR>2.0.ZU;2-8
Abstract
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.