The effects of hormone replacement therapy on thrombin generation, fibrinolysis inhibition, and resistance to activated protein C: prospective cohort study and review of literature.
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 = -3.75 UI/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 consistent 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.
Douketis
J D
JD
Department of Medicine, McMaster University, Hamilton, Ontario, Canada. jdouket@fhs.mcmaster.ca
Gordon
M
M
Johnston
M
M
Julian
J A
JA
Adachi
J R
JR
Ginsberg
J S
JS
D020016:Activated Protein C Resistance / Q000097:blood*; D000284:Administration, Oral; D000990:Antithrombin III / Q000187:drug effects / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects*; D005500:Follow-Up Studies; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects / Q000378:metabolism; D010447:Peptide Hydrolases / Q000187:drug effects / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D017698:Postmenopause / Q000097:blood; D011446:Prospective Studies; D011516:Prothrombin / Q000187:drug effects / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis / Q000187:drug effects*; D013924:Thrombophlebitis / Q000139:chemically induced; D020246:Venous Thrombosis / Q000139:chemically induced
D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; C046193:antithrombin III-protease complex; C045879:prothrombin fragment 1.2; D000990:Antithrombin III; D011516:Prothrombin; D010447:Peptide Hydrolases; D013917:Thrombin