Use of combined oral contraceptives (OC) is associated with a significant r
isk of thrombosis. The mechanisms of this effect are not clearly defined. T
issue factor pathway inhibitor (TFPI) is a circulating anti-coagulant that
inhibits the earliest steps in activation of the extrinsic coagulation path
way, It plays a central role in control of coagulation but its contribution
to the thrombotic risk associated with OC has not been assessed, Plasma TF
PI antigen and activity, factor VIIa, prothrombin fragments 1&2, von Willeb
rand antigen, fibrinogen, and low density lipoprotein cholesterol were meas
ured by standard assays in women taking OC (aged 16 to 45 years, n = 40) an
d age-matched women not taking OC (controls, n = 40). Plasma TFPI antigen d
id 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% confi
dence 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. Plas
ma factor VIIa activity and prothrombin fragments 1&2 were also significant
ly increased in women using OC (both P < 0.001), indicating activation of t
he extrinsic coagulation pathway, These results demonstrate that normal cyc
lic variations in estrogen and/or progesterone do not significantly alter p
lasma TFPI levels. However, estrogens and/or progestogens in OC result in a
ctivation of the extrinsic coagulation pathway and significantly reduce pla
sma TFPI, its major circulating inhibitor. Reduced plasma TFPI levels may u
nderlie the thrombotic effects of OC. Am. J. Hematol. 60:175-180, 1999. (C)
1999 Wiley-Liss, Inc.