The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism - Results from a randomized, double-blind, clinical trial
E. Hoibraaten et al., The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism - Results from a randomized, double-blind, clinical trial, THROMB HAEM, 85(5), 2001, pp. 775-781
In a recent randomized, double-blind, placebo-controlled trial of women wit
h a history of venous thromboembolism (VTE), we found that hormone replacem
ent therapy (HRT) was associated with an early excess risk of recurrent thr
ombosis. The aims of the present study were to characterize the effects of
HRT on coagulation in these women to elucidate the mechanism(s) by which HR
T increases the risk of thrombosis. The study comprised 140 women who were
randomized to receive continuous treatment for 24 months with once daily 2
mg 17-beta -estradiol plus 1 mg norethisterone acetate (n = 71) or placebo
(n = 69). HRT caused significant increases in prothrombin fragments 1+2, th
rombin-antithrombin complex. and D-Dimer after 3 months, but these changes
were less pronounced on prolonged treatment. The increases in markers of ac
tivated coagulation was higher in those women who subsequently developed re
current thrombosis, but was similar in carriers and non-carriers of the fac
tor V Leiden mutation. HRT had no effects on fibrinogen and factor VIII. Ac
tivated factor VII, but not factor VII antigen, decreased significantly on
HRT as compared with placebo. The coagulation inhibitors antithrombin, prot
ein C, and TFPI. but not protein S, ail showed significant sustained decrea
ses in the HRT group as compared with placebo. Antithrombin and protein C d
ecreased by 8-12% on HRT, whereas TFPI activity decreased by 12-17% and TFP
I free antigen by 29-30%. In multivariate analysis, only TFPI activity was
a significant predictor for the increased activation of coagulation. We con
clude that HRT was associated with early activation of coagulation, which c
orroborates the finding of an early risk of recurrent VTE. This activation
may in part be explained by reduction in circulating anticoagulants.