title: Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women.
abstract: Activated protein C (APC) resistance, determined with a thrombin-generation-based APC resistance test, may explain risk differences of venous thrombosis in users of second- and third-generation oral contraceptives (OC). To clinically validate this test, we analysed the Leiden thrombophilia case-control study (474 patients with a first episode of deep vein thrombosis and 474 age- and sex-matched control subjects). Data for men and women were analysed separately. As hormonal status in women is known to strongly influence the APC sensitivity ratio (APCsr), additional strata (OC use and menopausal state) were defined. The APCsr was higher in all patients than in control subjects. Odds ratios (OR), using the 90th percentile of all control subjects (APCsr > 4.5) as cut-off, were: 7.5 [95% confidence interval (CI) 1.6-33.8] for men, 3.0 (95% CI 1.0-8.8) for premenopausal women not using OC, 4.8 (95% CI 1.6-14.7) for premenopausal women using OC and 4.7 (95% CI 1.4-15.6) for postmenopausal women. After excluding the carriers of factor V Leiden, the OR became infinite for men (no control had an APCsr > 4.5), 1.4 (95% CI 0.2-8.2) for premenopausal women not using OC, 3.4 (95% CI 1.1-10.8) for premenopausal women using OC and 3.6 (95% CI 0.6-20.5) for postmenopausal women. A high APCsr, determined with the thrombin-generation-based APC resistance test, predicts venous thrombotic risk, in populations with and without factor V Leiden. In addition, acquired APC resistance resulting from OC use predicts an increased risk for venous thrombosis independent of factor V Leiden.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. g.tans@bioch.unimaas.nl
authors.forename: Guido
authors.initials: G
authors.lastname: Tans
authors.forename: Astrid
authors.initials: A
authors.lastname: van Hylckama Vlieg
authors.forename: M Christella L G D
authors.initials: MC
authors.lastname: Thomassen
authors.forename: Joyce
authors.initials: J
authors.lastname: Curvers
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Bertina
authors.forename: Jan
authors.initials: J
authors.lastname: Rosing
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
mesh_terms: D020016:Activated Protein C Resistance / Q000097:blood / Q000175:diagnosis*; D000328:Adult; D016022:Case-Control Studies; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects; D005165:Factor V / Q000032:analysis; D005260:Female; D006801:Humans; D008297:Male; D008593:Menopause / Q000097:blood; D008875:Middle Aged; D016017:Odds Ratio; D011237:Predictive Value of Tests; D018570:Risk Assessment; D013917:Thrombin / Q000096:biosynthesis*; D020246:Venous Thrombosis / Q000097:blood / Q000175:diagnosis*
chemical_list: D003278:Contraceptives, Oral, Hormonal; C095381:factor V Leiden; D005165:Factor V; D013917:Thrombin