The Effects of Hormone Replacement Therapy on Thrombin Generation, Fibrinolysis Inhibition, and Resistance to Activated Protein C: Prospective Cohort Study and Review of the Literature

Abstract

Recent studies have found that hormone replacement therapy (HRT) is associated with a two- to fourfold increased risk of venous thromboembolism, but the thrombogenic mechanism of HRT remains unclear. To investigate whether HRT use induces a procoagulant state, we undertook a prospective cohort study in postmenopausal women to investigate the effects of 3 months of treatment with oral HRT (conjugated equine estrogen 0.625 mg daily and medroxyprogesterone 2.5 mg daily) on markers of thrombin generation (prothrombin fragment 1+2, thrombin–antithrombin complexes), fibrinolytic potential (plasminogen activator inhibitor-1 (PAI-1) activity), and activated protein C (APC) resistance. In addition, we reviewed the literature for studies investigating the effects of HRT on markers of thrombin generation and fibrinolytic potential. In 12 patients who received HRT for a mean of 3.8 months, there was no significant effect of HRT on levels of F1+2, thrombin–antithrombin complexes, or the APC ratio. HRT use had the greatest effect on PAI-1 activity (mean difference=−3.76 IU/mL; 95% confidence interval: −8.9, 1.1) compared to other coagulation parameters, but this did not attain statistical significance p=0.12 . In the literature review, the effects of HRT on markers of thrombin generation were inconsistent across studies. There was a consistent pattern of increased fibrinolytic potential with HRT use associated with one marker (PAI-1), but not with another marker (tissue plasminogen activator antigen). We conclude that there is a lack of consistence evidence that the increased risk of venous thromboembolism associated with HRT use is due to a procoagulant state related to increased thrombin generation, decreased fibrinolytic potential, or acquired APC resistance.