Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII

Abstract

Oral combined hormone replacement therapy (HRT) with oestradiol and norethisterone increases plasma levels of prothrombin fragment 1+2 (F1+2), indicating an increase in thrombin generation, but the mechanisms underlying this increase are uncertain. The aim of this randomized, placebo-controlled study was to determine whether an increase in factor VII, a factor that combines with tissue factor to activate the extrinsic pathway, or a decrease in tissue factor pathway inhibitor (TFPI), an inhibitor of extrinsic pathway activation, may contribute to increases in thrombin generation occurring with HRT. Healthy postmenopausal women aged 50-75 years received placebo (n=19) or oral combined HRT (n=18) and had blood collected for measurement of factor VII coagulation activity (VIIc), activated factor VII (VIIa) and TFPI at baseline and at 6 weeks. Baseline characteristics were similar in the two groups, including age, body mass index and cholesterol levels. As reported previously, HRT increased the F1+2 concentration by 20%. Placebo had no effect on VIIc, VIIa or TFPI, but 6 weeks of combined HRT decreased VIIc [from 1.11+/-0.06 (mean+/-S.E.M.) to 1.03+/-0.06 i.u./ml; P<0.03], VIIa [from 43.9; 10.8-198.3 (median; range) to 35.0; 6.3-66.8 m-units/ml; P<0.03] and TFPI [from 81.3+/-6.5 to 60.4+/-5.5 ng/ml; P<0.0001]. The decrease in TPFI with HRT was not correlated with the elevation in F1+2 levels. In conclusion, the increase in thrombin generation seen with HRT is not due to an effect on factor VII; in addition, while a contribution from the decrease in TFPI is possible, increased thrombin generation is not directly related to the decrease in TFPI.

Risk of venous thromboembolic disease in postmenopausal women taking oral or transdermal hormone replacement therapy

“…A decrease in the level of TFPI, which lowers the inhibition of the extrinsic pathway, results in downstream activation of coagulation and an increase in thrombin generation (Peverill et al, 2001;Bladbjerg et al, 2003). The observed lower TFPI levels in all studies may contribute to increased coronary heart disease (CHD) risk associated with HRT, mainly in subgroups of women with atherosclerosis and with an increased risk of intimal TF expression (Bladbjerg et al, 2003).…”

“…* Fibrinogen equivalent units using estrogen replacement for only three months. Peverill et al (2001) found that six weeks of estradiol and norethisterone resulted in a 26% decrease in TFPI antigen levels. Bladbjerg et al (2003) have observed that after 5-6 years of HRT/ERT, plasma concentration of TFPI in postmenopausal women was significantly reduced.…”

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

“…15,16 Plasma TFPI antigen and activity are also altered by estrogen, decreasing 15-20% in women using oral contraceptives or estrogen replacement therapy. [17][18][19][20] Approximately 10% of circulating TFPI is concentrated within quiescent platelets 9,10 and is entirely TFPIα. 10,21 TFPIα is secreted from activated platelets, 21 with a portion also localizing to the activated platelet surface.…”

Hormonal Therapies and Venous Thrombosis

“…*Address correspondence to this author at the Thrombosis Center, Istituto Clinico Humanitas, Rozzano (MI), Italy; E-mail: lidia.rota@humanitas.it Prothrombotic effects of HRT are related to several actions. Low doses of oestradiol are associated with less activation of coagulation, including TFPI and APC Resistance, and inflammatory markers if compared with regular dose: low dose and conventional dose formulations had similar effects on C reactive protein [11,12]; however also the increase synthesis of clotting factors as to the decreased synthesis of clotting inhibitors as to an acquired form of activated protein C resistance are involved in the hypercoagulable state of women ongoing HRT [1]. As confirm of this trend to hypercoagulable state, markers of thrombin generation are frequently increased in women taking HRT: increased levels of prothrombin fragments 1+2, TAT complexes and D-dimer have been found in several studies [13].…”