A Randomized Cross-over Study on the Effects of Levonorgestrel- and Desogestrel-containing Oral Contraceptives on the Anticoagulant Pathways

Summary

The use of oral contraceptives (OC) causes disturbances of the procoagulant, anticoagulant and fibrinolytic pathways of blood coagulation which may contribute to the increased risk of venous thrombosis associated with OC therapy. Here we report the results of a cyclecontrolled randomized cross-over study, in which we determined the effects of so-called second and third generation OC’s on a number of anticoagulant parameters. In this study, 28 non-OC using women were randomly prescribed either a second generation (150 µg levonorgestrel/30 µg ethinylestradiol) or a third generation OC (150 µg desogestrel/30 µg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), α₂-macroglobulin (α₂-M), α₁-antitrypsin, protein C inhibitor (PCI), protein C, total and free protein S and activated protein C sensitivity ratios (APC-sr) measured with two functional APC resistance tests which quantify the effect of APC on either the activated partial thromboplastin time (aPTT) or on the endogenous thrombin potential (ETP). During the use of desogestrel-containing OC the plasma levels of αc₂-M, α₁-antitrypsin, PCI and protein C significantly increased, whereas AT and protein S significantly decreased. Similar trends were observed with levonorgestrel-containing OC, although on this kind of OC the changes in AT, PCI and protein S (which was even slightly increased) did not reach significance. Compared with levonorgestrel, desogestrel-containing OC caused a significant decrease of total (p <0.005) as well as free protein S (p <0.0001) and more pronounced APC resistance in both the aPTT (p = 0.02) and ETPbased (p <0.0001) APC resistance tests. These observations indicate that the activity of the anticoagulant pathways in plasma from users of desogestrel-containing OC is more extensively impaired than in plasma from users of levonorgestrel-containing OC.

Keywords

Oral contraceptives - haemostasis - thrombosis

⁴ Present address: Dr. J. C. M. Meijers, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

• References

• 1 Speroff L. Oral contraceptives and venous thromboembolism. Int J Gynaecol Obstet 1996; 54: 45-50.
• 2 Newton JR. Classification and comparison of oral contraceptives containing new generation progestagens. Hum Reprod Update 1995; 01: 231-63.
• 3 Kluft C, Lansink M. Effects of oral contraceptives on haemostasis variables. Thromb Haemost 1997; 78: 315-26.
• 4 Winkler UH. Effects on hemostatic variables of desogestrel-and gestodenecontaining oral contraceptives in comparison with levonorgestrel-containing oral contraceptives: A review. Am J Obstet Gynecol 1998; 179: S51-S61.
• 5 WHO. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 346: 1582-8.
• 6 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-93.
• 7 Spitzer WO, Lewis MA, Heinemann LA, Thorogood M, MacRae KD. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women. BMJ 1996; 312: 83-8.
• 8 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing thirdgeneration progestagen. Lancet 1995; 346: 1593-6.
• 9 Lewis MA, Heinemann LA, MacRae KD, Bruppacher R, Spitzer WO. The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. The Transnational Research Group on Oral Contraceptives and the Health of Young Women. Contraception 1996; 54: 5-13.
• 10 Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet 1997; 349: 83-8.
• 11 Herings RMC, Urquhart J, Leufkens HGM. Venous thromboembolism among new users of different oral contraceptives. Lancet 1999; 354: 127-8.
• 12 Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost 1999; 82: 601-9.
• 13 de Visser MCH, 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: 1271-6.
• 14 Rodeghiero F, Tosetto A. Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999; 130: 643-50.
• 15 Rosing J, Tans G, Nicolaes GAF, Thomassen MCLGD, van Oerle R, van der Ploeg PMEN, Heijnen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: Different sensitivities to activated protein C in women using second-and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-8.
• 16 de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72: 880-6.
• 17 Rosing J, Middeldorp S, Curvers J, Thomassen MCLGD, Nicolaes GAF, Meijers J, Bouma BN, Büller HR, Prins MH, Tans G. Acquired APC resistance and oral contraceptives: A randomised cross-over study of two low dose oral contraceptives. Lancet 1999; 354: 2036-40.
• 18 Nicolaes GAF, Thomassen MCLGD, van Oerle R, Hamulyak K, Hemker HC, Tans G, Rosing J. A prothrombinase-based assay for detection of resistance to activated protein C. Thromb Haemost 1996; 76 (03) 404-10.
• 19 Nicolaes GAF, Thomassen MCLGD, Tans G, Rosing J, Hemker HC. Effect of activated protein C on thrombin generation and on the thrombin potential in plasma of normal and APC-resistant individuals. Blood Coagul Fibrinolysis 1997; 08: 28-38.
• 20 Böttcher CJF, van Gent CM, Pries C. A Rapid and Sensitive Sub-micro Phosphorus Determination. Anal Chim Acta 1961; 24: 203-7.
• 21 Elisen MG, Maseland MH, Church FC, Bouma BN, Meijers JC. Role of the A⁺ helix in heparin binding to protein C inhibitor. Thromb Haemost 1996; 75: 760-6.
• 22 Sala N, Owen WG, Collen D. A functional assay of protein C in human plasma. Blood 1984; 63: 671-5.
• 23 Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten Cate JW, Mertens K, van Mourik JA. Association of idiopathic venous thromboembolism with single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-6.
• 24 Pocock SJ. Clinical trials, a practical approach. Chichester: John Wiley & Sons; 1983
• 25 Curvers J, Thomassen MCLGD, Nicolaes GAF, van Oerle R, Hamulyak K, Hemker HC, Tans G, Rosing J. Acquired APC resistance and oral contraceptives: Differences between two functional tests. Br J Haematol 1999; 105: 88-94.
• 26 Heeb MJ, Griffin JH. Physiologic inhibition of human activated protein C by alpha 1-antitrypsin. J Biol Chem 1988; 263: 11613-6.
• 27 Heeb MJ, Gruber A, Griffin JH. Identification of divalent metal iondependent inhibition of activated protein C by alpha 2-macroglobulin and alpha 2-antiplasmin in blood and comparisons to inhibition of factor Xa, thrombin, and plasmin. J Biol Chem 1991; 266: 17606-12.
• 28 Espana F, Gruber A, Heeb MJ, Hanson SR, Harker LA, Griffin JH. In vivo and in vitro complexes of activated protein C with two inhibitors in baboons. Blood 1991; 77: 1754-60.
• 29 Jespersen J, Petersen KR, Skouby SO. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. Am J Obstet Gynecol 1990; 163: 396-403.
• 30 Basdevant A, Conard J, Pelissier C, Guyene TT, Lapousterle C, Mayer M, Guy BGrand, Degrelle H. Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel. Contraception 1993; 48: 193-204.
• 31 Granata A, Sobbrio GA, D’Arrigo F, Barillari M, De Luca P, Egitto M, Granese D, Pulle C, Trimarchi F. Changes in the plasma levels of proteins C and S in young women on low-dose oestrogen oral contraceptives. Clin Exp Obstet Gynecol 1991; 18: 9-12.
• 32 Cachrimanidou AC, Hellberg D, Nilsson S, von Schoulz B, Crona N, Siegbahn A. Hemostasis profile and lipid metabolism with long-interval use of a desogestrel-containing oral contraceptive. Contraception 1994; 50: 153-65.
• 33 Petersen KR, Sidelmann J, Skouby SO, Jespersen J. Effects of monophasic low-dose oral contraceptives on fibrin formation and resolution in young women. Am J Obstet Gynecol 1993; 168: 32-8.
• 34 Winkler UH, Holscher T, Schulte H, Zierleyn JP, Collet W, Schindler AE. Ethinylestradiol 20 versus 30 micrograms combined with 150 micrograms desogestrel: a large comparative study of the effects of two low-dose oral contraceptives on the hemostatic system. Gynecol Endocrinol 1996; 10: 265-71.
• 35 Malm J, Laurell M, Dahlback B. Changes in the plasma levels of vitamin Kdependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception. Br J Haematol 1988; 68: 437-43.
• 36 Jespersen J, Nielsen MT. Levels of protein S during the normal menstrual cycle and in women on oral contraceptives low in estrogen. Gynecol Obstet Invest 1989; 28: 82-6.
• 37 Olivieri O, Friso S, Manzato F, Guella A, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russo C, Corrocher R. Resistance to activated protein C in healthy women taking oral contraceptives. Br J Haematol 1995; 91: 465-70.
• 38 Olivieri O, Friso S, Manzato F, Grazioli S, Bernardi F, Lunghi B, Girelli D, Azzini M, Brocco G, Russo C, Corrocher R. Resistance to activated protein C, associated with oral contraceptives use effect of formulations, duration of assumption, and doses of oestro-progestins. Contraception 1996; 54 (03) 149-52.
• 39 Henkens CM, Bom VJ, Seinen AJ, van der Meer J. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1995; 73: 402-4.
• 40 Schramm W, Heinemann LAJ. Oral contraceptives and venous thromboembolism: Acquired APC resistance?. Br J Haematol 1997; 98: 491-2.
• 41 Rotteveel RC, Roozendaal KJ, Eijsman L, Hemker HC. The influence of oral contraceptives on the time-integral of thrombin generation (thrombin potential). Thromb Haemost 1993; 70: 959-62.
• 42 Middeldorp S, Meijers JCM, van den Ende AE, van Enk A, Bouma BN, Tans G, Rosing J, Prins MH, Büller HR. Effects on coagulation of levonorgestrel and desogestrel containing low dose oral contraceptives – a crossover study. Thromb Haemost 2000; 84: 4-8.
• 43 Zöller B, Berntsdotter A, Garcia de PFrutos, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-23.
• 44 Freyburger G, Javorschi S, Labrouche S, Bernard P. Proposal for objective evaluation of the performance of various functional APC-resistance tests in genotyped patients. Thomb Haemost 1997; 78 (05) 1360-5.