Download PDF
Semin Thromb Hemost 2020; 46(08): 872-886
DOI: 10.1055/s-0040-1714140
Review Article

Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk

Jonathan Douxfils
1   QUALIblood s.a., Namur, Belgium
2   Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, Faculty of Medicine, University of Namur, Namur, Belgium
,
Laure Morimont
1   QUALIblood s.a., Namur, Belgium
2   Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for Life Sciences, Faculty of Medicine, University of Namur, Namur, Belgium
,
Céline Bouvy
1   QUALIblood s.a., Namur, Belgium
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Combined oral contraceptives (COCs) induce several changes in the levels of coagulation factors. The levels of procoagulant factors are often increased, while levels of anticoagulant factors are decreased. Fibrinolysis is also affected, even if the effect seems to be more counterbalanced by opposite regulation of profibrinolytic and antifibrinolytic factors. These effects on hemostasis are more pronounced with third- or fourth-generation COC compared with second-generation COC. Venous thromboembolism (VTE) risk increases when multiple risk factors, including genetic and environmental, are present simultaneously. COC use causes changes in coagulation that modify the prothrombotic state induced by preexisting hemostatic alterations in a supra-additive manner. Therefore, testing appears to be of importance not only before implementing COC but also to monitor any potential thrombogenicity induced by COC therapy. Inherited genetic factors, such as factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C or protein S deficiencies, non-O blood group, as well as CYP2C9*2 and the rs4379368 mutations, have all been identified as genetic predictive risk factors of VTE in women. Nevertheless, the screening of these genetic biomarkers is not capable of assessing the phenotypic expression of the risk. This review will focus on the different options for screening the thrombogenic status in this population. Specific attention will be given to the endogenous thrombin potential-based activated protein C resistance, a test aiming at assessing the thrombogenicity induced by hormonal therapies and inherited or acquired thrombophilia.

Keywords

contraception - venous thromboembolism - predictive - blood - coagulation factors - activated protein C resistance


Publication History

Article published online:
20 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 2014; 12 (10) 1580-1590
    CrossrefPubMedGoogle Scholar
  • 2 Virchow RLK, Beneke R. Thrombose und Embolie (1846–1856): Leipzig: JA Barth; 1910
  • 3 Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost 2015; 114 (05) 885-889
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Hotoleanu C. Genetic risk factors in venous thromboembolism. Adv Exp Med Biol 2017; 906: 253-272
    Google Scholar
  • 5 Germain M, Chasman DI, de Haan H. et al; Cardiogenics Consortium. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet 2015; 96 (04) 532-542
    CrossrefPubMedGoogle Scholar
  • 6 de Visser MC, Poort SR, Vos HL, Rosendaal FR, Bertina RM. Factor X levels, polymorphisms in the promoter region of factor X, and the risk of venous thrombosis. Thromb Haemost 2001; 85 (06) 1011-1017
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms--the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994; 71 (06) 719-722
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342 (10) 696-701
    CrossrefPubMedGoogle Scholar
  • 9 van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95 (12) 3678-3682
    CrossrefPubMedGoogle Scholar
  • 10 Gallinaro L, Cattini MG, Sztukowska M. et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111 (07) 3540-3545
    CrossrefPubMedGoogle Scholar
  • 11 Jenkins PV, Rawley O, Smith OP, O'Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157 (06) 653-663
    CrossrefPubMedGoogle Scholar
  • 12 Kamphuisen PW, Rosendaal FR, Eikenboom JC, Bos R, Bertina RM. Factor V antigen levels and venous thrombosis: risk profile, interaction with factor V Leiden, and relation with factor VIII antigen levels. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1382-1386
    CrossrefPubMedGoogle Scholar
  • 13 Rietveld IM, Lijfering WM, le Cessie S. et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019; 17 (01) 99-109
    CrossrefPubMedGoogle Scholar
  • 14 Speed V, Roberts LN, Patel JP, Arya R. Venous thromboembolism and women's health. Br J Haematol 2018; 183 (03) 346-363
    CrossrefPubMedGoogle Scholar
  • 15 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158 (06) 585-593
    CrossrefPubMedGoogle Scholar
  • 16 Vandenbroucke JP, Rosing J, Bloemenkamp KW. et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med 2001; 344 (20) 1527-1535
    CrossrefPubMedGoogle Scholar
  • 17 Christin-Maitre S. History of oral contraceptive drugs and their use worldwide. Best Pract Res Clin Endocrinol Metab 2013; 27 (01) 3-12
    CrossrefPubMedGoogle Scholar
  • 18 Mikkelsen EM, Riis AH, Wise LA, Hatch EE, Rothman KJ, Sørensen HT. Pre-gravid oral contraceptive use and time to pregnancy: a Danish prospective cohort study. Hum Reprod 2013; 28 (05) 1398-1405
    CrossrefPubMedGoogle Scholar
  • 19 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995; 346 (8990): 1575-1582
    CrossrefPubMedGoogle Scholar
  • 20 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995; 346 (8990): 1582-1588
    CrossrefPubMedGoogle Scholar
  • 21 European Medicines Agency. Guideline on Clinical investigation of Steroid Contraceptives in Women — EMEA/CPMP/EWP/519/98 Rev 1. 2005 Accessed April 25, 2018 at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003349.pdf
    Google Scholar
  • 22 Food and Drug Administration. Guidance for Industry - Labeling for Combined Oral Contraceptives. 2004 Accessed January 10, 2019 at: https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM133346.pdf
    Google Scholar
  • 23 Food and Drug Administration. Labeling for Combined Hormonal Contraceptives - Guidance for Industry. 2017 Accessed January 5, 2018 at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM590673.pdf
    Google Scholar
  • 24 Food and Drug Administration. Combined Hormonal Contraceptives (CHCs) and the Risk of Cardiovascular Disease Endpoints. 2011 Accessed December 26, 2019 at: https://www.fda.gov/media/82335/download
    Google Scholar
  • 25 European Medicines Agency. Assessment report cyproterone acetate/ethinylestradiol (2 mg/0.035 mg) containing medicinal products — Procedure number: EMEA/H/A-107i/1357.. 2013 Accessed January 13, 2020 at: https://www.ema.europa.eu/en/documents/referral/cyproterone/ethinylestradiol-containing-medicines-article-107i-procedure-prac-assessment-report_en.pdf
    Google Scholar
  • 26 European Medicines Agency. Assessment report for combined hormonal contraceptives containing medicinal products — Procedure number: EMEA/H/A-31/1356. 2014 Accessed January 13, 2020 at: https://www.ema.europa.eu/en/documents/referral/combined-hormonal-contraceptives-article-31-referral-prac-assessment-report_en.pdf
    Google Scholar
  • 27 Hugon-Rodin J, Horellou MH, Conard J, Gompel A, Plu-Bureau G. Type of combined contraceptives, factor V Leiden mutation and risk of venous thromboembolism. Thromb Haemost 2018; 118 (05) 922-928
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344 (8935): 1453-1457
    CrossrefPubMedGoogle Scholar
  • 29 Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost 2016; 115 (01) 25-30
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Hippisley-Cox J, Coupland C. Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. BMJ 2011; 343: d4656
    CrossrefPubMedGoogle Scholar
  • 31 Hippisley-Cox J, Coupland C, Brindle P. The performance of seven QPrediction risk scores in an independent external sample of patients from general practice: a validation study. BMJ Open 2014; 4 (08) e005809
    CrossrefPubMedGoogle Scholar
  • 32 Vernon E, Hiedemann B, Bowie BH. Economic evaluations of thrombophilia screening prior to prescribing combined oral contraceptives: a systematic and critical review. Appl Health Econ Health Policy 2017; 15 (05) 583-595
    CrossrefPubMedGoogle Scholar
  • 33 Haute Autorité de Santé. Recommandations en Santé Publique: Dépistage systématique de la thrombophilie avant une primo- prescription de contraception hormonale combinée. 2015 Accessed December 26, 2019 at: https://www.has-sante.fr/upload/docs/application/pdf/2014-09/synthese_et_recommandations_depistage_trombophilie_chc.pdf
    Google Scholar
  • 34 Hiedemann B, Vernon E, Bowie BH. Re-examining genetic screening and oral contraceptives: a patient-centered review. J Pers Med 2019; 9 (01) E4
    CrossrefPubMedGoogle Scholar
  • 35 Smith KJ, Monsef BS, Ragni MV. Should female relatives of factor V Leiden carriers be screened prior to oral contraceptive use? A cost-effectiveness analysis. Thromb Haemost 2008; 100 (03) 447-452
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 McDaid A, Logette E, Buchillier V. et al. Risk prediction of developing venous thrombosis in combined oral contraceptive users. PLoS One 2017; 12 (07) e0182041
    Google Scholar
  • 37 Sutherland CS, Ademi Z, Michaud J. et al. Economic evaluation of a novel genetic screening test for risk of venous thromboembolism compared with standard of care in women considering combined hormonal contraception in Switzerland. BMJ Open 2019; 9 (11) e031325
    CrossrefPubMedGoogle Scholar
  • 38 United Nations, Department of Economic and Social Affairs, Population Division (2019). Contraceptive Use by Method 2019: Data Booklet (ST/ESA/SER.A/435)
  • 39 Kahn SR, Comerota AJ, Cushman M. et al; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 2014; 130 (18) 1636-1661
    CrossrefPubMedGoogle Scholar
  • 40 Bonnar J. Coagulation effects of oral contraception. Am J Obstet Gynecol 1987; 157 (4 Pt 2): 1042-1048
    CrossrefPubMedGoogle Scholar
  • 41 Hunter DJ, Anderson AB, Haddon M. Changes in coagulation factors in postmenopausal women on ethinyl oestradiol. Br J Obstet Gynaecol 1979; 86 (06) 488-490
    CrossrefPubMedGoogle Scholar
  • 42 Harris GM, Stendt CL, Vollenhoven BJ, Gan TE, Tipping PG. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 1999; 60 (03) 175-180
    CrossrefPubMedGoogle Scholar
  • 43 Hoibraaten E, Os I, Seljeflot I, Andersen TO, Hofstad A, Sandset PM. The effects of hormone replacement therapy on hemostatic variables in women with angiographically verified coronary artery disease: results from the estrogen in women with atherosclerosis study. Thromb Res 2000; 98 (01) 19-27
    CrossrefPubMedGoogle Scholar
  • 44 Alhenc-Gelas M, Plu-Bureau G, Guillonneau S. et al. Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives. J Thromb Haemost 2004; 2 (09) 1594-1600
    CrossrefPubMedGoogle Scholar
  • 45 Farris M, Bastianelli C, Rosato E, Brosens I, Benagiano G. Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis. Expert Rev Clin Pharmacol 2017; 10 (10) 1129-1144
    CrossrefPubMedGoogle Scholar
  • 46 Grandi G, Napolitano A, Cagnacci A. Metabolic impact of combined hormonal contraceptives containing estradiol. Expert Opin Drug Metab Toxicol 2016; 12 (07) 779-787
    CrossrefPubMedGoogle Scholar
  • 47 Hugon-Rodin J, Alhenc-Gelas M, Hemker HC. et al. Sex hormone-binding globulin and thrombin generation in women using hormonal contraception. Biomarkers 2017; 22 (01) 81-85
    CrossrefPubMedGoogle Scholar
  • 48 Kemmeren JM, Algra A, Meijers JC, Bouma BN, Grobbee DE. Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation. Thromb Haemost 2002; 87 (02) 199-205
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Klipping C, Duijkers I, Parke S, Mellinger U, Serrani M, Junge W. Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel. Drugs R D 2011; 11 (02) 159-170
    CrossrefPubMedGoogle Scholar
  • 50 Kluft C, Endrikat J, Mulder SM, Gerlinger C, Heithecker R. A prospective study on the effects on hemostasis of two oral contraceptives containing drospirenone in combination with either 30 or 20 microg ethinyl estradiol and a reference containing desogestrel and 30 microg ethinyl estradiol. Contraception 2006; 73 (04) 336-343
    CrossrefPubMedGoogle Scholar
  • 51 Koenen RR, Christella M, Thomassen LG, Tans G, Rosing J, Hackeng TM. Effect of oral contraceptives on the anticoagulant activity of protein S in plasma. Thromb Haemost 2005; 93 (05) 853-859
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 Wiegratz I, Jung-Hoffmann C, Kuhl H. Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins. Contraception 1995; 51 (06) 341-346
    CrossrefPubMedGoogle Scholar
  • 53 Kluft C, Zimmerman Y, Mawet M. et al. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception 2017; 95 (02) 140-147
    CrossrefPubMedGoogle Scholar
  • 54 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 (01) 233-238
    CrossrefPubMedGoogle Scholar
  • 55 Winkler UH. Effects on hemostatic variables of desogestrel- and gestodene-containing oral contraceptives in comparison with levonorgestrel-containing oral contraceptives: a review. Am J Obstet Gynecol 1998; 179 (3 Pt 2): S51-61
    CrossrefPubMedGoogle Scholar
  • 56 Winkler UH, Howie H, Bühler K, Korver T, Geurts TB, Coelingh Bennink HJ. A randomized controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75 microgram desogestrel or 30 microgram levonorgestrel. Contraception 1998; 57 (06) 385-392
    CrossrefPubMedGoogle Scholar
  • 57 Lindqvist PG, Rosing J, Malmquist A, Hillarp A. Etonogestrel implant use is not related to hypercoagulable changes in anticoagulant system. J Thromb Haemost 2003; 1 (03) 601-602
    CrossrefPubMedGoogle Scholar
  • 58 Oral Contraceptive and Hemostasis Study Group. The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study. Contraception 2003; 67 (03) 173-185
    CrossrefPubMedGoogle Scholar
  • 59 van Vliet HA, Frolich M, Christella M. et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod 2005; 20 (02) 563-568
    CrossrefPubMedGoogle Scholar
  • 60 van Vliet HA, Bertina RM, Dahm AE. et al. Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor. J Thromb Haemost 2008; 6 (02) 346-351
    CrossrefPubMedGoogle Scholar
  • 61 Raps M, Curvers J, Helmerhorst FM. et al. Thyroid function, activated protein C resistance and the risk of venous thrombosis in users of hormonal contraceptives. Thromb Res 2014; 133 (04) 640-644
    CrossrefPubMedGoogle Scholar
  • 62 Rühl H, Schröder L, Müller J. et al. Impact of hormone-associated resistance to activated protein C on the thrombotic potential of oral contraceptives: a prospective observational study. PLoS One 2014; 9 (08) e105007
    CrossrefPubMedGoogle Scholar
  • 63 Lete I, Chabbert-Buffet N, Jamin C. et al. Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: a literature review. Eur J Contracept Reprod Health Care 2015; 20 (05) 329-343
    CrossrefPubMedGoogle Scholar
  • 64 Tchaikovski SN, Thomassen MC, Costa SD, Bremme K, Rosing J. Changes in haemostatic parameters during the menstrual cycle and subsequent use of drospirenone-containing oral contraceptives. Thromb Res 2014; 134 (05) 1032-1037
    CrossrefPubMedGoogle Scholar
  • 65 Zia A, Callaghan MU, Callaghan JH. et al. Hypercoagulability in adolescent girls on oral contraceptives-global coagulation profile and estrogen receptor polymorphisms. Am J Hematol 2015; 90 (08) 725-731
    CrossrefPubMedGoogle Scholar
  • 66 Westhoff CL, Eisenberger A, Tang R, Cremers S, Grossman LV, Pike MC. Clotting factor changes during the first cycle of oral contraceptive use. Contraception 2016; 93 (01) 70-76
    CrossrefPubMedGoogle Scholar
  • 67 Mohamed ABO, Kelchtermans H, Konings J. et al. The effects of oral contraceptive usage on thrombin generation and activated protein C resistance in Saudi women, with a possible impact of the body mass index. PLoS One 2018; 13 (10) e0206376
    CrossrefPubMedGoogle Scholar
  • 68 Adam A, Albert A, Boulanger J, Genot D, Demoulin A, Damas J. Influence of oral contraceptives and pregnancy on constituents of the kallikrein-kininogen system in plasma. Clin Chem 1985; 31 (09) 1533-1536
    CrossrefPubMedGoogle Scholar
  • 69 Ågren UM, Anttila M, Mäenpää-Liukko K. et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on haemostasis, lipids and carbohydrate metabolism. Eur J Contracept Reprod Health Care 2011; 16 (06) 444-457
    CrossrefPubMedGoogle Scholar
  • 70 Aldrighi JM, De Campos LS, Eluf Gebara OC, Petta CA, Bahamondes L. Effect of a combined oral contraceptive containing 20 microg ethinyl estradiol and 75 microg gestodene on hemostatic parameters. Gynecol Endocrinol 2006; 22 (01) 1-4
    CrossrefPubMedGoogle Scholar
  • 71 Archer DF, Mammen EF, Grubb GS. The effects of a low-dose monophasic preparation of levonorgestrel and ethinyl estradiol on coagulation and other hemostatic factors. Am J Obstet Gynecol 1999; 181 (5 Pt 2): 63-66
    CrossrefPubMedGoogle Scholar
  • 72 Basdevant A, Conard J, Pelissier C. et al. Hemostatic and metabolic effects of lowering the ethinyl-estradiol dose from 30 mcg to 20 mcg in oral contraceptives containing desogestrel. Contraception 1993; 48 (03) 193-204
    CrossrefPubMedGoogle Scholar
  • 73 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 (02) 153-165
    CrossrefPubMedGoogle Scholar
  • 74 Endrikat J, Klipping C, Gerlinger C. et al. A double-blind comparative study of the effects of a 23-day oral contraceptive regimen with 20 microg ethinyl estradiol and 75 microg gestodene and a 21-day regimen with 30 microg ethinyl estradiol and 75 microg gestodene on hemostatic variables, lipids, and carbohydrate metabolism. Contraception 2001; 64 (04) 235-241
    CrossrefPubMedGoogle Scholar
  • 75 Fruzzetti F, Genazzani AR, Ricci C, De Negri F, Bersi C, Carmassi F. A 12-month clinical investigation with a 24-day regimen containing 15 microg ethinylestradiol plus 60 microg gestodene with respect to hemostasis and cycle control. Contraception 2001; 63 (06) 303-307
    CrossrefPubMedGoogle Scholar
  • 76 Gaussem P, Alhenc-Gelas M, Thomas JL. et al. Haemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol. A double-blind, randomised study. Thromb Haemost 2011; 105 (03) 560-567
    Article in Thieme ConnectPubMedGoogle Scholar
  • 77 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 (03) 402-404
    Article in Thieme ConnectPubMedGoogle Scholar
  • 78 Hoem N-O, Johannesen S, Hauge G, Rud AC, Sandem S, Briseid K. Contact activation factors in plasma from women using oral contraceptives--increased levels of factor XII, kinin-free high molecular weight kininogen and acetone-activated kallikrein. Thromb Res 1991; 64 (04) 427-434
    CrossrefPubMedGoogle Scholar
  • 79 Jespersen J, Endrikat J, Düsterberg B. et al. A 1-year study to compare the hemostatic effects of oral contraceptive containing 20 microg of ethinylestradiol and 100 microg of levonorgestrel with 30 microg of ethinylestradiol and 100 microg of levonorgestrel. Contraception 2005; 72 (02) 98-104
    CrossrefPubMedGoogle Scholar
  • 80 Jespersen J, Kluft C. Increased euglobulin fibrinolytic potential in women on oral contraceptives low in oestrogen--levels of extrinsic and intrinsic plasminogen activators, prekallikrein, factor XII, and C1-inactivator. Thromb Haemost 1985; 54 (02) 454-459
    Article in Thieme ConnectPubMedGoogle Scholar
  • 81 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 (1 Pt 2): 396-403
    CrossrefPubMedGoogle Scholar
  • 82 Junge W, Mellinger U, Parke S, Serrani M. Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive: a randomized, open-label, single-centre study. Clin Drug Investig 2011; 31 (08) 573-584
    CrossrefPubMedGoogle Scholar
  • 83 Klipping C, Marr J. Effects of two combined oral contraceptives containing ethinyl estradiol 20 microg combined with either drospirenone or desogestrel on lipids, hemostatic parameters and carbohydrate metabolism. Contraception 2005; 71 (06) 409-416
    CrossrefPubMedGoogle Scholar
  • 84 Meade TW, Haines AP, North WRS, Chakrabarti R, Howarth DJ, Stirling Y. Haemostatic, lipid, and blood-pressure profiles of women on oral contraceptives containing 50 microgram or 30 microgram oestrogen. Lancet 1977; 2 (8045): 948-951
    CrossrefPubMedGoogle Scholar
  • 85 Meijers JC, Middeldorp S, Tekelenburg W. et al. Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent down regulation of fibrinolysis: a randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost 2000; 84 (01) 9-14
    Article in Thieme ConnectPubMedGoogle Scholar
  • 86 Melis GB, Fruzzetti F, Nicoletti I. et al. A comparative study on the effects of a monophasic pill containing desogestrel plus 20 micrograms ethinylestradiol, a triphasic combination containing levonorgestrel and a monophasic combination containing gestodene on coagulatory factors. Contraception 1991; 43 (01) 23-31
    CrossrefPubMedGoogle Scholar
  • 87 Nicolaes GA, Thomassen MC, 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; 8 (01) 28-38
    CrossrefPubMedGoogle Scholar
  • 88 Norris LA, Bonnar J. The effect of oestrogen dose and progestogen type on haemostatic changes in women taking low dose oral contraceptives. Br J Obstet Gynaecol 1996; 103 (03) 261-267
    CrossrefPubMedGoogle Scholar
  • 89 Oral Contraceptive and Hemostasis Study Group. An open label, randomized study to evaluate the effects of seven monophasic oral contraceptive regimens on hemostatic variables. Outline of the protocol. Contraception 1999; 59 (06) 345-355
    CrossrefPubMedGoogle Scholar
  • 90 Oslakovic S, Zadro R. Comparison of the impact of four generations of progestins on hemostatic variables. Clin Appl Thromb Hemost 2014; 20 (04) 448-455
    CrossrefPubMedGoogle Scholar
  • 91 Peters K, Gordon N, Ricciotti N, Hsieh J, Howard B, Weiss H. Hemostatic effects of two desogestrel-containing combined oral contraceptive regimens: a multinational, multicenter, randomized, open-label study. Clin Exp Obstet Gynecol 2016; 43 (03) 334-340
    CrossrefPubMedGoogle Scholar
  • 92 Quehenberger P, Kapiotis S, Pärtan C. et al. Studies on oral contraceptive-induced changes in blood coagulation and fibrinolysis and the estrogen effect on endothelial cells. Ann Hematol 1993; 67 (01) 33-36
    CrossrefPubMedGoogle Scholar
  • 93 Raps M, Helmerhorst FM, Fleischer K. et al. The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI. Thromb Haemost 2013; 109 (04) 606-613
    Article in Thieme ConnectPubMedGoogle Scholar
  • 94 Raps M, Rosendaal F, Ballieux B. et al. Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial. J Thromb Haemost 2013; 11 (05) 855-861
    CrossrefPubMedGoogle Scholar
  • 95 Task Force on Oral Contraceptive. A multicentre study of coagulation and haemostatic variables during oral contraception: variations with four formulations. Task Force on Oral Contraceptives--WHO Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland. Br J Obstet Gynaecol 1991; 98 (11) 1117-1128
    CrossrefPubMedGoogle Scholar
  • 96 Winkler U, Schindler A, Endrikat J, Dusterberg B. A comparative study of the effects of the hemostatic system of two monophasic gestodene oral contraceptives containing 20 micrograms and 30 micrograms ethinylestradiol. Contraception 1996; 53 (02) 75-84
    CrossrefPubMedGoogle Scholar
  • 97 Ferreira AC, Montes MB, Franceschini SA, Toloi MR. Effects of two oral contraceptives, containing 30 or 20 microg of ethinyl estradiol in combination with gestodene, on blood coagulation and fibrinolysis in Brazilian women. Int J Fertil Womens Med 2001; 46 (05) 265-270
    PubMedGoogle Scholar
  • 98 Raps M, Helmerhorst F, Fleischer K. et al. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; 10 (06) 992-997
    CrossrefPubMedGoogle Scholar
  • 99 Tchaikovski SN, van Vliet HA, Thomassen MC. et al. Effect of oral contraceptives on thrombin generation measured via calibrated automated thrombography. Thromb Haemost 2007; 98 (06) 1350-1356
    Article in Thieme ConnectPubMedGoogle Scholar
  • 100 Bastianelli C, Farris M, Rosato E, Brosens I, Benagiano G. Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism. Expert Rev Clin Pharmacol 2017; 10 (03) 315-326
    PubMedGoogle Scholar
  • 101 Blanco-Molina MA, Lozano M, Cano A, Cristobal I, Pallardo LP, Lete I. Progestin-only contraception and venous thromboembolism. Thromb Res 2012; 129 (05) e257-e262
    CrossrefPubMedGoogle Scholar
  • 102 Conard J, Plu-Bureau G, Bahi N, Horellou MH, Pelissier C, Thalabard JC. Progestogen-only contraception in women at high risk of venous thromboembolism. Contraception 2004; 70 (06) 437-441
    CrossrefPubMedGoogle Scholar
  • 103 Holmegard HN, Nordestgaard BG, Schnohr P, Tybjaerg-Hansen A, Benn M. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost 2014; 12 (03) 297-305
    CrossrefPubMedGoogle Scholar
  • 104 Leck I, Thomson JM, Bocaz JA. et al. A multicentre study of coagulation and haemostatic variables during oral contraception: variations with geographical location and ethnicity. Task Force on Oral Contraceptives--WHO Special Programme of Research, Development and Research Training in Human Reproduction. Int J Epidemiol 1991; 20 (04) 913-920
    CrossrefPubMedGoogle Scholar
  • 105 Lindberg UB, Crona N, Stigendal L, Teger-Nilsson AC, Silfverstolpe G. A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters. Thromb Haemost 1989; 61 (01) 65-69
    Article in Thieme ConnectPubMedGoogle Scholar
  • 106 Oliver MF. Thrombosis and oestrogens. Lancet 1967; 2 (7514): 510-511
    CrossrefPubMedGoogle Scholar
  • 107 Vikan T, Schirmer H, Njølstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol 2009; 161 (03) 435-442
    CrossrefPubMedGoogle Scholar
  • 108 de Bastos M, Stegeman BH, Rosendaal FR. et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014; (03) CD010813
    PubMedGoogle Scholar
  • 109 Fruzzetti F, Cagnacci A. Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives?. Open Access J Contracept 2018; 9: 75-79
    Google Scholar
  • 110 Book of Abstracts: The 15th Congress of the European Society of Contraception and Reproductive Health. Eur J Contracept Reprod Health Care 2018; 23 (sup1): 1-143
    CrossrefPubMedGoogle Scholar
  • 111 Foidart JM, Lobo R, Rosing J. et al. Estetrol (E4) is a unique native estrogen that does not modify coagulation markers in postmenopausal women and maintains sensitivity to activated protein C (APC) [abstract]. 30th Annual Meeting of The North America Menopause Society September 25–28, 2019, Chicago, IL. Menopause 2019;26(12): 1445–1481
    Google Scholar
  • 112 Bagot CN, Marsh MS, Whitehead M. et al. The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost 2010; 8 (08) 1736-1744
    CrossrefPubMedGoogle Scholar
  • 113 Mashchak CA, Lobo RA, Dozono-Takano R. et al. Comparison of pharmacodynamic properties of various estrogen formulations. Am J Obstet Gynecol 1982; 144 (05) 511-518
    CrossrefPubMedGoogle Scholar
  • 114 Stumpf PG. Pharmacokinetics of estrogen. Obstet Gynecol 1990; 75 (04) 9S-14 S, discussion 15S–17S
    CrossrefPubMedGoogle Scholar
  • 115 Visser M, Coelingh Bennink HJ. Clinical applications for estetrol. J Steroid Biochem Mol Biol 2009; 114 (1-2): 85-89
    CrossrefPubMedGoogle Scholar
  • 116 Ariëns RA, de Lange M, Snieder H, Boothby M, Spector TD, Grant PJ. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet 2002; 359 (9307): 667-671
    CrossrefPubMedGoogle Scholar
  • 117 Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc Biol 2009; 29 (03) 332-336
    CrossrefPubMedGoogle Scholar
  • 118 Cushman M, Larson JC, Rosendaal FR. et al. Biomarkers, menopausal hormone therapy and risk of venous thrombosis: the Women's Health Initiative. Res Pract Thromb Haemost 2018; 2 (02) 310-319
    CrossrefPubMedGoogle Scholar
  • 119 Riley RS, Gilbert AR, Dalton JB, Pai S, McPherson RA. Widely used types and clinical applications of D-dimer assay. Lab Med 2016; 47 (02) 90-102
    CrossrefPubMedGoogle Scholar
  • 120 Thachil J, Lippi G, Favaloro EJ. D-dimer testing: laboratory aspects and current issues. Methods Mol Biol 2017; 1646: 91-104
    Google Scholar
  • 121 Martinelli I, De Stefano V, Mannucci PM. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11 (03) 140-156
    CrossrefPubMedGoogle Scholar
  • 122 Tsantes AE, Nikolopoulos GK, Bagos PG. et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost 2007; 97 (06) 907-913
    Article in Thieme ConnectPubMedGoogle Scholar
  • 123 van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis. Blood 2000; 95 (09) 2855-2859
    CrossrefPubMedGoogle Scholar
  • 124 Garand M, Lin JH, Zagorac B, Koschinsky ML, Boffa MB. Regulation of the gene encoding human thrombin-activatable fibrinolysis inhibitor by estrogen and progesterone. Blood Coagul Fibrinolysis 2013; 24 (04) 393-404
    CrossrefPubMedGoogle Scholar
  • 125 Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998; 273 (42) 27176-27181
    CrossrefPubMedGoogle Scholar
  • 126 Schneider M, Brufatto N, Neill E, Nesheim M. Activated thrombin-activatable fibrinolysis inhibitor reduces the ability of high molecular weight fibrin degradation products to protect plasmin from antiplasmin. J Biol Chem 2004; 279 (14) 13340-13345
    CrossrefPubMedGoogle Scholar
  • 127 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342 (8886-8887): 1503-1506
    CrossrefPubMedGoogle Scholar
  • 128 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330 (08) 517-522
    CrossrefPubMedGoogle Scholar
  • 129 Middeldorp S, Meijers JC, van den Ende AE. et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000; 84 (01) 4-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 130 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 (9195): 2036-2040
    CrossrefPubMedGoogle Scholar
  • 131 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993; 90 (03) 1004-1008
    CrossrefPubMedGoogle Scholar
  • 132 Kadauke S, Khor B, Van Cott EM. Activated protein C resistance testing for factor V Leiden. Am J Hematol 2014; 89 (12) 1147-1150
    CrossrefPubMedGoogle Scholar
  • 133 Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina RM, Sandset PM. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101 (11) 4387-4392
    CrossrefPubMedGoogle Scholar
  • 134 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 (07) 1488-1494
    CrossrefPubMedGoogle Scholar
  • 135 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 (01) 5-11
    Article in Thieme ConnectPubMedGoogle Scholar
  • 136 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 (03) 465-470
    CrossrefPubMedGoogle Scholar
  • 137 Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010; 126 (01) 5-11
    CrossrefPubMedGoogle Scholar
  • 138 Nappi RE, Paoletti AM, Volpe A. et al. Multinational, multicentre, randomised, open-label study evaluating the impact of a 91-day extended regimen combined oral contraceptive, compared with two 28-day traditional combined oral contraceptives, on haemostatic parameters in healthy women. Eur J Contracept Reprod Health Care 2014; 19 (04) 285-294
    CrossrefPubMedGoogle Scholar
  • 139 Douxfils J, Morimont L, Delvigne AS. et al. Validation and standardization of the ETP-based activated protein C resistance test for the clinical investigation of steroid contraceptives in women: an unmet clinical and regulatory need. Clin Chem Lab Med 2020; 58 (02) 294-305
    CrossrefPubMedGoogle Scholar
  • 140 Lavigne-Lissalde G, Sanchez C, Castelli C. et al. Prothrombin G20210A carriers the genetic mutation and a history of venous thrombosis contributes to thrombin generation independently of factor II plasma levels. J Thromb Haemost 2010; 8 (05) 942-949
    CrossrefPubMedGoogle Scholar
  • 141 Marco A, Brocal C, Martirena F, Lucas J, Marco P. Clinical and biological factors that contribute to thrombin generation in prothrombin G20210A carriers: a case-control study in a single Thrombophilia Center. Thromb Res 2012; 129 (05) e266-e268
    CrossrefPubMedGoogle Scholar
  • 142 Szlam F, Sreeram G, Solomon C, Levy JH, Molinaro RJ, Tanaka KA. Elevated factor VIII enhances thrombin generation in the presence of factor VIII-deficiency, factor XI-deficiency or fondaparinux. Thromb Res 2011; 127 (02) 135-140
    CrossrefPubMedGoogle Scholar
  • 143 Duchemin J, Pan-Petesch B, Arnaud B, Blouch MT, Abgrall JF. Influence of coagulation factors and tissue factor concentration on the thrombin generation test in plasma. Thromb Haemost 2008; 99 (04) 767-773
    Article in Thieme ConnectPubMedGoogle Scholar
  • 144 Morimont L, Bouvy C, Delvigne AS, Dogné J-M, Douxfils J. Proof of concept of a new scale for the harmonization and the standardization of the ETP-based APC resistance. J Thromb Haemost 2020; 18 (04) 895-904
    CrossrefPubMedGoogle Scholar
  • 145 Evrard J, Morimont L, Siriez R, Dogné J-M, Douxfils J. PB1224 | Assessment of the APC resistance measured by thrombin generation and clot waveform analysis: a pilot study — special issue: abstracts of the XXVII Congress of the International Society on Thrombosis and Haemostasis, July 6–10, 2019. Res Pract Thromb Haemost 2019; 3 (Suppl. 01) 1-891
    PubMedGoogle Scholar
  • 146 Dhont M. History of oral contraception. Eur J Contracept Reprod Health Care 2010; 15 (Suppl. 02) S12-S18
    CrossrefPubMedGoogle Scholar
  • 147 Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus 2011; 9 (02) 120-138
    Google Scholar
  • 148 van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2016; 14 (07) 1393-1403
    CrossrefPubMedGoogle Scholar
  • 149 Hannaford PC. Epidemiology of the contraceptive pill and venous thromboembolism. Thromb Res 2011; 127 (Suppl. 03) S30-S34
    CrossrefPubMedGoogle Scholar