Biomarkers, menopausal hormone therapy and risk of venous thrombosis: The Women's Health Initiative

Essentials•Venous thrombosis is the most common vascular complication of menopausal hormone use.•We studied biomarkers to predict thrombosis with hormones in the Women's Health Initiative.•Lower proteins C and S, and higher D‐dimer were related to thrombosis risk.•The 25% of women with high D‐dimer had a six‐times greater risk of thrombosis with hormones. Essentials Venous thrombosis is the most common vascular complication of menopausal hormone use. We studied biomarkers to predict thrombosis with hormones in the Women's Health Initiative. Lower proteins C and S, and higher D‐dimer were related to thrombosis risk. The 25% of women with high D‐dimer had a six‐times greater risk of thrombosis with hormones. Oral menopausal hormone therapy causes venous thrombosis but whether biomarkers of thrombosis risk can identify women at risk is unknown. We completed a nested case control study in the two Women's Health Initiative hormone trials; 27 347 women aged 50‐79 were randomized to hormone therapy (conjugated equine estrogen with or without medroxyprogesterone acetate) or placebo. With 4 years follow‐up, biomarkers were measured using stored baseline samples prior to starting treatment, and one‐year later, in 215 women who developed thrombosis and 867 controls. Overall, lower protein C and free protein S, and higher D‐dimer, prothrombin fragment 1.2 and plasmin‐antiplasmin complex were associated with risk of future thrombosis with odds ratios ranging from 1.9 to 3.2. Compared to women with normal biomarkers assigned to placebo, the risk of thrombosis with hormone therapy was increased among women with abnormal biomarkers, especially elevated D‐dimer, elevated plasmin‐antiplasmin, and low free protein S; the largest association was for D‐dimer: odds ratio 6.0 (95% CI 3.6‐9.8). Differences in associations by hormone use were not significant on the multiplicative scale. Considering a multi‐marker score of eight biomarkers, women with three or more abnormal biomarkers had 15.5‐fold increased odds of VT (95% CI 6.8‐35.1). One‐year changes in biomarkers were not robustly associated with subsequent thrombosis risk. Abnormal levels of biomarkers of thrombosis risk identified women at increased risk of future venous thrombosis with oral menopausal hormone therapy. Findings support the potential for clinical use of D‐dimer testing in advance of hormone therapy prescription.