Combined Estrogen and Progesterone Therapy and Thrombotic Risk

Evidence for Increased Thrombotic Risk

The combination of estrogen and progesterone in hormone therapy significantly increases the risk of blood clots (thromboembolism) by approximately 2-3 fold compared to non-users 1, 2
Meta-analysis of 12 studies demonstrated that hormone replacement therapy (HRT) was associated with a more than doubled risk of venous thromboembolism (RR 2.14; 95% CI 1.64-2.81) 1, 2
The Women's Health Initiative (WHI) study confirmed this finding, showing a two-fold increased rate of venous thromboembolic disease (RH 2.11; 95% CI 1.26-3.55) in women taking combined estrogen-progestin therapy 3

Estrogen, with or without progestin, affects multiple hemostatic pathways in a prothrombotic direction, including increasing factor VII activity, D-dimer, and prothrombin F1.2, and decreasing anti-thrombin III, tissue factor pathway inhibitor, and tissue plasminogen activator 6, 7

The American College of Rheumatology strongly recommends against combined estrogen-progestin contraceptives in women with positive antiphospholipid antibodies due to further increased thrombosis risk 8
Prothrombotic genetic variants significantly increase thrombosis risk with hormone therapy, including Factor V Leiden carriers and prothrombin 20210A variant 6, 7

The U.S. Preventive Services Task Force concluded there is good evidence that HRT increases the risk for venous thromboembolism 3, 1
The risk of thrombosis should be carefully weighed against potential benefits of hormone therapy for each individual 1