The effect of the levonorgestrel-releasing intrauterine system on the resistance to activated protein C (APC)

Summary

Exogenously administered estrogens and progestogens as during combined oral contraceptive use increase the risk of venous thrombosis. The thrombin generation-based APC resistance assay is a global coagulation test that enables quantification of the net prothrombotic effect of combined oral contraceptives and that predicts the risk of thrombosis. The thrombotic risk of the levonorgestrel-releasing intrauterine system is unknown. It was the objective of this study to evaluate the thrombotic risk by comparing the APC resistance before and after insertion of a levonorgestrel-releasing or a copper-containing intrauterine device. We measured normalized APC-sensitivity ratios (nAPCsr) before and three months after insertion of the levonorgestrelintrauterine system in 56 women and the copper-intrauterine device in 18 women. In women without hormonal contraceptive use or a pregnancy in the three months before collection of the baseline samples, nAPCsr were lower three months after insertion of the levonorgestrel-intrauterine system than at baseline (difference –0.29; 95% CI –0.04 to –0.53) and hardly changed after insertion of the copper-intrauterine device (difference -0.11; 95% CI –1.03 to 0.82). In women who switched from a combined oral contraceptive to the levonorgestrel-system the difference was more pronounced (-1.48; 95% CI –0.85 to –2.11). In this study we observed that the levonorgestrel-intrauterine system decreases the resistance to APC which indicates that the levonorgestrel-intrauterine system does not have a prothrombotic effect.

Keywords

Intrauterine device - activated protein C resistance - venous thrombosis - hemostasis

• References

• 1 Vandenbroucke JP, Rosing J, Bloemenkamp KW. et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344: 1527-1535.
• 2 Rosendaal FR, Van Hylckama Vlieg A, Tanis BC. et al. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003; 1: 1371-1380.
• 3 Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. Br Med J 2001; 323: 131-134.
• 4 Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 2001; 358: 1427-1429.
• 5 Mirena website. Available at: http://www.mirenaus.com. Accessed August 7, 2008.
• 6 Shulman LP, Nelson AL, Darney PD. Recent developments in hormone delivery systems. Am J Obstet Gynecol 2004; 190: S39-S48.
• 7 Jensen JT. Contraceptive and therapeutic effects of the levonorgestrel intrauterine system: an overview. Obstet Gynecol Surv 2005; 60: 604-612.
• 8 Electronic Medicines Compendium. Available at: http://emc.medicines.org.uk. Accessed August 7, 2008.
• 9 Vasilakis C, Jick H, Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999; 354: 1610-1611.
• 10 Heinemann LA, Assmann A, DoMinh T. et al. Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Eur J Contracept Reprod Health Care 1999; 4: 67-73.
• 11 Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives.. Results of an international, multicenter, case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Contraception 1998; 57: 315-324.
• 12 WHO.. Medical eligibility criteria for contraceptive use. Available at: http://www.who.int/reproductivehealth/publications/mec/summary.html. Accessed at August 7, 2008.
• 13 Rosing J, Middeldorp S, Curvers J. et al. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-2040.
• 14 van Vliet HA, Winkel TA, Noort I. et al. Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate. J Thromb Haemost 2004; 2: 2060-2062.
• 15 Alhenc-Gelas M, Plu-Bureau Guillonneau S. et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost 2004; 2: 1594-1600.
• 16 Tans G, van Hylckama Vlieg A, Thomassen MC. et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-470.
• 17 Tchaikovski S, van Vliet HAAM, Thomassen CLGD. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography (CAT). Thromb Haemost 2007; 98: 1350-1356.
• 18 Nicolaes GA, Thomassen MC, van Oerle R. et al. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996; 76: 404-410.
• 19 de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-1276.
• 20 Kemmeren JM, Algra A, Meijers JC. et al. Effect of second- and third generation oral contraceptives on the protein C system in the absence or presence of the factor V Leiden mutation: a randomized controlled trial. Blood 2004; 103: 927-33.
• 21 Lindqvist PG, Rosing J, Malmquist A. et al. Etonogestrel implant use is not related to hypercoagulable changes in anticoagulant system. J Thromb Haemost 2003; 1: 601-602.
• 22 Curvers J, Thomassen MC, Rimmer J. et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost 2002; 88: 5-11.