Rapid activation of haemostasis after hormonal emergency contraception

Summary

Hormonal emergency contraception (EC) is a well established contraceptive method, recommended to all women, although the effects on haemostais are not fully evaluated. The aim of this study was to evaluate whether exposure to EC has effects on well established cardiovascular risk factors, and also to examine whether differences exist between two EC treatments. In a prospective randomized cross over design 11 women used two different EC methods, one with estrogen and levonorgestrel (EE-EC) and one with levonorgestrel only (LNG-EC). Plasma concentrations of haemostatic factors (APC resistance, antithrombin, fibrinogen, prothrombin fragment 1+2, free protein S, factor VII and PAI-1), sex-hormone-binding globulin (SHBG), the apolipoprotein (apo)B/apoA1 ratio and C-reactive protein (CRP) were followed frequently during the following 48 h A rapid haemostatic activation was induced with both treatments, although more pronounced with EE-EC. Already two hours after EC, the plasma concentrations of haemostatic parameters and SHBG were significantly different from baseline concentrations. An ETP-based APC-resistance method showed increased APC resistance with EE-EC and decreased APC resistance with LNG-EC. The ApoB/ApoA1 ratio was affected in a favourable direction with EE-EC.CRP increased slightly regardless of treatment. Even a very short exposure to exogenous sex hormones causes prompt effects on hepatic protein synthesis and the coagulation system. This must be taken into consideration whenever exogenous steroid hormones are administered, especially to individuals with a genetic predisposition to thrombosis or transiently disturbed haemostasis.

Keywords

APC resistance - estrogen - levonorgestrel - SHBG

• References

• 1 Yuzpe AA, Lancee WJ. Ethinylestradiol and dl-norgestrel as postcoital contraceptive. Fertil Steril 1977; 28: 932-6.
• 2 Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception Task Force on Postovulatory Methods of Fertility Regulation. Lancet 1998; 352: 428-433.
• 3 Lake SR, Vernon SA. Emergency contraception and retinal vein thrombosis. Br J Ophthalmol 1999; 83: 628.
• 4 Vasilakis C, Jick SS, Jick H. The risk of venous thromboembolism in users of postcoital contraceptive pills. Contraception 1999; 59: 79-83.
• 5 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 VLeiden mutation: a randomized trial. Blood 2004; 103: 927-33.
• 6 van Rooijen M, Silveira A, Hamsten A. et al Sex hormone binding globulin – a surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 2004; 190: 332-7.
• 7 Koster T, Rosendaal FR, de Ronde H. et al Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
• 8 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.
• 9 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: 465-70.
• 10 Kaibara M, Watanabe T, Ooka F. et al Effect of high-dose progestogen on hemostatic properties of blood in patients with endometrial cancer. Clin Hemorheol Microcirc 2001; 24: 93-9.
• 11 Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999; 354: 1610-1.
• 12 Conard J, Plu-Bureau G, Bahi N. et al Progestogenonly contraception in women at high risk of venous thromboembolism. Contraception 2004; 70: 437-41.
• 13 Walldius G, Jungner I. The apoB/apoA-I ratio: a strong, new risk factor for cardiovascular disease and a target for lipid-lowering therapy--a review of the evidence. J Intern Med 2006; 259: 493-519.
• 14 Morrissey JH, Macik BG, Neuenschwander PF. et al Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-44.
• 15 Nicolaes GA, Thomassen MC, Tans G. et al Effect of activated protein C on thrombin generation and on the thrombin potential in normal and AP-resistant individuals. Blood Coagul Fibrinolysis 1997; 8: 28-38.
• 16 Kirk RE. Experimental design: Procedures for the behavioral sciences. Brooks/Cole Publishing Company Pacific Grove; USA: 1995
• 17 Littell RC, Milliken GA, Stroup WW. et al SAS System for Mixed Models. Cary, NC; SAS Institute Inc: 1996
• 18 Stege R, Carlstrom K, Collste L. et al Single drug polyestradiol phosphate therapy in prostatic cancer. Am J Clin Oncol 1988; 11 (Suppl. 02) S101-3.
• 19 Johansson E, Brache V, Alvarez F. et al Pharmacokinetic study of different dosing regimens of levonorgestrel for emergency contraception in healthy women. Human Reprod 2002; 17: 1472-6.
• 20 Silvestri A, Gebara O, Vitale C. et al Increased levels of C-reactive protein after oral hormone replacement therapy may not be related to an increased inflammatory response. Circulation 2003; 107: 3165-9.
• 21 van Rooijen M, Hansson LO, Frostegard J. et al Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response. J Thromb Haemost 2006; 4: 77-82.
• 22 Macintyre SS, Schultz D, Kushner I. Biosynthesis of C-reactive protein. Ann NY Acad Sci 1982; 389: 76-87.
• 23 Knopp RH, Broyles FE, Cheung M. et al Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel. Contraception 2001; 63: 1-11.
• 24 Webb A, Taberner D. Clotting factors after emergency contraception. Adv Contracept 1993; 9: 75-82.
• 25 Weenink GH, Ten Cate JW, Kahlé LH. et al "Morning after pill" and antithrombin III. Lancet 1981; 16: 1105
• 26 Kuhl H. Effects of progestogens on haemostasis. Maturitas 1996; 24: 1-19.
• 27 Tholstrup T, Miller GJ, Bysted A. et al Effect of individual dietary fatty acids on postprandial activation of blood coagulation factor VII and fibrinolysis in healthy young men. Am J Clin Nutr 2003; 77: 1125-32.
• 28 de Visser MC, van Hylckama Vlieg A, Tans G. et al Determinants of the APTT-and ETP-based APC sensitivity tests. J Thromb Haemost 2005; 3: 1488-94.
• 29 Rosing J, Tans G, Nicolaes GA. et al 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.
• 30 Curvers J, Thomassen MC, Nicholaes GA. et al Acquired APC resistance and oral contraceptives: differences between two functional tests. Br J Haematol 1999; 105: 88-94.
• 31 Curvers J, Thomassen MC, Rimmer J. et al Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Thromb Haemost 2002; 88: 5-11.
• 32 Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, el at. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects. Arch Intern Med 2000; 160: 49-52.
• 33 Vandenbroucke JP, Koster T, Briet E. et al Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.