Hormone replacement therapy and hypercoagulability. Results from the Prospective Collaborative Danish Climacteric Study.

OBJECTIVE

To assess the influence of a variety of HRT regimens on the haemostatic balance using markers of fibrin turnover and inhibitors of coagulation.

DESIGN

An open randomised study allocating women to either a control group or five different HRT treatment groups.

SETTING

Gentofte Hospital, Hellerup, and Rigshospitalet, Copenhagen, Denmark.

POPULATION

One hundred and forty-nine postmenopausal women without previous venous thromboembolic disease.

METHODS

Prothrombin fragment 1+2 (F(1+2)), fibrin degradation products, antithrombin, protein C, total protein S and activated protein C-normalised ratio were measured at baseline and after 6 and 12 months of HRT in six groups of healthy postmenopausal women: (A). no HRT (reference group), (B). continuous oestradiol valerate (E(2)V) plus cyproterone acetate, (C). cyclic E(2)V plus cyproterone acetate, (D). continuous combined oestrogen (E(2)) plus norethindrone acetate, (E). E(2) combined with local delivery of levonorgestrel and (F). E(2)V plus medroxyprogesterone. HRT-induced changes in the concentration of inhibitors of coagulation and markers of fibrin turnover during 12 months of treatment.

RESULTS

Significant decreases of antithrombin and protein S were found in all treatment groups, of protein C in Groups C, D, E and F and of activated protein C-normalised ratio in Groups E and F. Fibrin degradation products increased after three months of treatment, whereas F(1+2) was persistently increased after three months in Group F. The cumulative response of antithrombin was significantly lower in Groups D, E and F than in the reference group. The cumulative response of protein S and activated protein C-normalised ratio was lower, whereas that of F(1+2) was significantly higher in Group F than in the reference group.

CONCLUSION

HRT reduces the inhibitory potential of coagulation significantly. The effect is related to the type of E(2)/progestin combination administered, but seems to be oestrogen-derived as the most pronounced effect is found with only quarterly progestin intake. Such procoagulant activity of HRT may well translate into clinical manifestations in thrombosis-prone individuals.