Third-generation oral contraceptives (OC) have been associated with an increased risk of venous thrombosis compared with second-generation OC. To find an explanation for this increased risk, the effect of a second- and third-generation OC and of the progestagens used in these pills on several fibrinolytic parameters was studied in the absence or presence of the factor V Leiden mutation. In a single-center, double-blind trial, 51 women without and 35 women with the factor V Leiden mutation were randomized to either a second-generation (30 μg ethinylestradiol/150 μg levonorgestrel) or a third-generation (30 μg ethinylestradiol/150 μg desogestrel) oral contraceptive. After two menstrual cycles of use and a wash-out period of two cycles, the participants received the corresponding progestagen-only preparation containing 150 μg levonorgestrel or 150 μg desogestrel. D-Dimers, thrombin-activatable fibrinolysis inhibitor (TAFI) and the clot lysis time in the absence (LYSmin) or the presence (LYSplus) of a blocking anti-factor XI antibody were determined in plasmas of the participating women, and the mean difference in changes between the OC were calculated. Both combined OC induced increased plasma levels of D-dimers and TAFI, and induced a prolongation of LYSplus, whereas LYSmin hardly changed. Virtually no changes in fibrinolytic parameters were observed for the progestagen-only preparations. No differential effects between levonorgestrel- and desogestrel-containing OC were found in women without factor V Leiden. Women with the mutation on levonorgestrel-containing OC showed an increased LYSplus compared with desogestrel containing OC (3.9; 95% confidence interval, 0.1–7.7). When using progestagen-only preparations, no differential effect on the fibrinolytic parameters were found, except for non-carriers on levonorgestrel who showed a reduced LYSmin compared with non-carriers on desogestrel (−4.0; 95% confidence interval, −7.8 to −0.2). In conclusion, the effect of oral contraceptives on fibrinolytic parameters is largely independent of the type of progestagen. The increased fibrinolytic activity during OC use appears to be induced by the estrogen component and may be counteracted by increased TAFI activation. This may result in an enhanced downregulation of fibrinolysis.
J.C.M.M. is an established investigator of the Netherlands Heart Foundation (grant D96.021). J. M. Kemmeren, A. Algra and D. E. Grobbee are with the Julius Center for General Practice and Patient Oriented Research, A. Algra is also with the Department of Neurology, and J. C. M. Meijers and B. N. Bouma are with the Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands; and J. C. M. Meijers is also with the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
(Received 6 September 2001;
revised 6 February 2002; accepted 8 February 2002)
Sponsorship: This project was supported by grant 98.001 from the Dutch Thrombosis Foundation.
Address correspondence to Dr A Algra, Julius Center for General Practice and Patient Oriented Research, University Medical Center Utrecht, Room D.01.335, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel: (+31) 30 2509350; fax: (+31) 30 2505480; e-mail: A.Algra@neuro.azu.nl