title: 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.
authors: Centre for Heart and Chest Research, Department of Medicine, Monash Medical Centre and Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia. roger.peverill@med.monash.edu.au
authors: R E
authors: RE
authors: Peverill
authors: H J
authors: HJ
authors: Teede
authors: J J
authors: JJ
authors: Smolich
authors: E
authors: E
authors: Malan
authors: D
authors: D
authors: Kotsopoulos
authors: P G
authors: PG
authors: Tipping
authors: B P
authors: BP
authors: McGrath
mesh_terms: D000367:Age Factors; D000368:Aged; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000502:physiology*; D015914:Estrogen Replacement Therapy / Q000379:methods*; D005167:Factor VII / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009640:Norethindrone / Q000494:pharmacology; D016011:Normal Distribution; D045167:Progesterone Congeners / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D045167:Progesterone Congeners; D004958:Estradiol; D005167:Factor VII; D013925:Thromboplastin; D013917:Thrombin; D009640:Norethindrone