Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives
Authors: Geoffrey M. Harris, Caroline L. Stendt, Beverley J. Vollenhoven, T. Eng Gan, Peter G. Tipping
Journal: American Journal of Hematology (1999)

Use of combined oral contraceptives (OC) is associated with a significant risk of thrombosis. The mechanisms of this effect are not clearly defined. Tissue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that inhibits the earliest steps in activation of the extrinsic coagulation pathway. It plays a central role in control of coagulation but its contribution to the thrombotic risk associated with OC has not been assessed. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in women taking OC (aged 16 to 45 years, n = 40) and age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OC had a 25% reduction in plasma TFPI antigen (median 51.0 ng/ml; 95% confidence intervals [CI] 37.5 to 85.5; control 68.0 ng/ml, CI 61.0 to 95.0; P < 0.001) and a 29% reduction in TFPI activity (78.5 U/ml, CI 57.5 to 107.5; control 111.0 U/ml, CI 79.5 to 171.0; P < 0.001) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1&2 were also significantly increased in women using OC (both P < 0.001), indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progestogens in OC result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may underlie the thrombotic effects of OC.This article reports the findings of a study that determined whether use of oral contraceptive (OC) is associated with significant changes in plasma tissue factor pathway inhibitor (TFPI), which may contribute to thrombotic risk. Plasma TFPI antigen and activity, factor VIIa, prothrombin fragments 1 and 2, von Willebrand antigen, fibrinogen, and low density lipoprotein cholesterol were measured by standard assays in 40 women aged 16-45 taking OCs and 40 age-matched women not taking OCs. Results revealed that the plasma TFPI antigen did not vary significantly across the menstrual cycle in controls. Women on OCs had a 25% reduction in plasma TFPI antigen (median, 51.0 ng/ml; 95% confidence interval (CI), 37.5-85.5; controls, 68.0 ng/ml; CI, 61.0-95.0) and a 29% reduction in TFPI activity (78.5 U/ml; CI, 57.5-107.5; controls, 111.0 U/ml; CI, 79.5-171.0) compared to controls. Plasma factor VIIa activity and prothrombin fragments 1 and 2 were also significantly increased in women using OCs, indicating activation of the extrinsic coagulation pathway. These results demonstrate that normal cyclic variations in estrogen and/or progesterone do not significantly alter plasma TFPI levels. However, estrogens and/or progesterone in OCs result in activation of the extrinsic coagulation pathway and significantly reduce plasma TFPI, its major circulation inhibitor. In conclusion, reduced plasma TFPI levels may underlie the thrombotic effects of OCs.