Impaired Procoagulant-anticoagulant Balance during Hormone Replacement Therapy?

Abstract

SummaryIn this randomised, placebo-controlled 12-week study, sixty healthy postmenopausal women received either placebo (N = 16) or daily 2 mg micronised oestradiol, either unopposed (N = 16, E2 group) or combined with a progestagen for 14 days of each cycle (N = 28, E2+P group).As compared to placebo, plasma levels of AT III were reduced only in the E2 group (∼28%), plasma levels of protein C decreased only in the E2+P group (∼4%) and plasma levels of protein S decreased in both the E2 and E2+P group (∼21%). In both the E2 and E2+P groups, the plasma levels of factor VII (antigen and activity) showed a borderline significant increase (∼10%), whereas no significant change was observed in active factor VII. Plasma levels of tissue-type plasminogen activator (∼22%), urokinase plasminogen activator (∼25%) and plasminogen activator inhibitor type-1 (∼43%) decreased in the E2 and E2+P groups, whereas those of plasminogen increased (∼12%). Treatment was associated with an increase in levels of prothrombin fragment 1+2 (∼31%), but levels of thrombin-antithrombin III complexes, and of plasmin-α2-antiplasmin complexes and total fibrin(ogen) degradation products did not change significantly.Short-term E2 and E2+P treatment is associated with a shift in the procoagulant-anticoagulant balance towards a procoagulant state. A substantial proportion of women do not have a net increase in fibrinolytic activity. These data may be relevant in explaining the increased risk of venous thromboembolism associated with ERT and HRT, and possibly also in explaining the negative results of the Heart and Estrogen/progestin Replacement Study.

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

“…Protein S is present in plasma in two forms, as approximately 60% is bound to C4b-binding protein, while the remaining part circulates in free form. Apparently, HRT does not alter the concentration of free protein S in plasma 9,13,15,21,22 , while the total protein S concentration is reduced 11,13,22 . However, HRT reduces the concentration of C4b-binding protein 23 , and this can explain why HRT reduces the total concentration of protein S. Free protein S is an important co-factor in the activated protein C-induced degradation of factor Va, while bound protein S does not possess this function.…”

Postmenopausal Hormone Therapy and Risk of Idiopathic Venous Thromboembolism

“…34 Moreover, several trials have failed to show any changes in levels of hemostatic parameters between progestogen subgroups. [35][36][37][38] Nevertheless, recent data suggested that trimegestone, a norpregnane derivative, had a stronger effect on fibrinolysis inhibition as compared to dydrogesterone. 39 Thus, whether or not progestogens have differential effects on hemostasis requires further investigation.…”

Hormone Therapy and Venous Thromboembolism Among Postmenopausal Women

“…With regard to the norpregnane derivatives, one randomized trial failed to show any changes in hemostatic variables among women receiving oral estrogen combined with nomegestrol acetate. 33 Among women recruited from the Project Aging Women, van Baal et al 34 and Post et al 35 have studied the effect of trimegestone (a norpregnane derivative), dydrogesterone, or both combined with oral estrogen therapy on hemostatic variables. Deleterious effects of oral estrogen therapy on coagulation without significant differences between all progestogen subgroups were found.…”