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Increased thrombin generation has emerged as a new surrogate marker of venous thromboembolism. Using calibrated automated thrombography, we tested the influence of the route of estrogen administration and progestogens on thrombin generation among postmenopausal women using hormone therapy.Baseline thrombin generation, together with clotting factors and inhibitors, was determined in plasma from 115 healthy postmenopausal women. Women were classified by the use of hormone therapy into three groups: nonusers (n = 38), users of oral estrogens (n = 38), and users of transdermal estrogens (n = 39).Oral estrogens dose dependently increased thrombin generation. Thrombin generation was increased among users of transdermal estrogens combined with progestins but was similar to nonusers among women using transdermal estrogens plus progesterone. Prothrombin was the main determinant of thrombin generation and explained a part of these differences. However, single clotting factors and inhibitors contributed little to the hormone-related changes in thrombin generation.Increased thrombin generation can be detected in women using hormone therapy, but this hypercoagulable phenotype depends both on the route of estrogen administration and the type of progestogens. These findings are consistent with current data on the risk of venous thromboembolism related to hormone therapy.