Download PDF
Thromb Haemost 2013; 109(04): 606-613
DOI: 10.1160/TH12-10-0771
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI

Marjolein Raps
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
,
Frans M. Helmerhorst
2   Department of Reproductive Medicine, Leiden University Medical Center, Leiden, the Netherlands
,
Kathrin Fleischer
3   Department of Obstetrics and Gynaecology, University Medical Center St. Radboud, Nijmegen, the Netherlands
,
Anders E. A. Dahm
4   Department of Haematology, Oslo University Hospital, and University of Oslo, Oslo, Norway
,
Frits R. Rosendaal
1   Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
,
Jan Rosing
5   Department of Biochemistry, Maastricht University, Maastricht, the Netherlands
,
Pieter Reitsma
6   Department of Haemostasis and Thrombosis, Leiden University Medical Center, Leiden, the Netherlands
,
Per Morten Sandset
4   Department of Haematology, Oslo University Hospital, and University of Oslo, Oslo, Norway
,
Huib A. A. M. van Vliet
2   Department of Reproductive Medicine, Leiden University Medical Center, Leiden, the Netherlands
7   Department of Gynaecology Catharina Hospital, Eindhoven, the Netherlands
› Author Affiliations
Further Information

Publication History

Received: 24 October 2012

Accepted after major revision: 14 February 2012

Publication Date:
22 November 2017 (online)

    Permissions and Reprints

Summary

Use of combined oral contraceptives is associated with a three- to sixfold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.

Keywords

APC resistance - deep-vein thrombosis - oral contraceptives - protein C/S pathway - tissue factor pathway inhibitor (TFPI)
 

  • References

  • 1 Vandenbroucke JP, Rosing J, Bloemenkamp KWM. et al. Oral contraceptives and the risk of venous thrombosis. N Eng J Med 2001; 344: 1527-1534.
    CrossrefPubMedGoogle Scholar
  • 2 Rosendaal FR, Van Hylckama Vlieg A, Tanis BC. et al. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003; 1: 1371-1380.
    CrossrefPubMedGoogle Scholar
  • 3 Van Hylckama Vlieg A, Helmerhorst FM. et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. Br Med J 2009; 339: b2921.
    CrossrefPubMedGoogle Scholar
  • 4 Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. Br Med J 2009; 339: b2890.
    CrossrefPubMedGoogle Scholar
  • 5 Tans G, Curvers J, Middeldorp S. et al. A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost 2000; 84: 15-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 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.
    CrossrefPubMedGoogle Scholar
  • 7 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.
    CrossrefPubMedGoogle Scholar
  • 8 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: 1350-1356.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Parkin L, Sharples K, Hernandez RK. et al. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. Br Med J 2011; 342: d2139.
    CrossrefPubMedGoogle Scholar
  • 10 Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. Br Med J 2011; 342: 2151.
    CrossrefPubMedGoogle Scholar
  • 11 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.
    CrossrefPubMedGoogle Scholar
  • 12 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: 346-351.
    CrossrefPubMedGoogle Scholar
  • 13 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: 1488-1494.
    CrossrefPubMedGoogle Scholar
  • 14 Hoibraaten E, Mowinckel MC, De Ronde H. et al. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial. Br J Haematol 2001; 115: 415-420.
    CrossrefPubMedGoogle Scholar
  • 15 Bajaj MS, Kuppuswamy MN, Manepalli AN. et al. Transcriptional expression of tissue factor pathway inhibitor, thrombomodulin and von Willebrand factor in normal human tissues. Thromb Haemost 1999; 82: 1047-1052.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Broze Jr. GJ. Tissue factor pathway inhibitor. Thromb Haemost 1995; 74: 90-93.
    PubMedGoogle Scholar
  • 17 Hackeng TM, Maurissen LF, Castoldi E. et al. Regulation of TFPI function by protein S. J Thromb Haemost 2009; 7 (Suppl. 01) 165-168.
    CrossrefPubMedGoogle Scholar
  • 18 Bertina RM. Molecular risk factors for thrombosis. Thromb Haemost 1999; 82: 601-609.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Hackeng TM, Rosing J. Protein S as cofactor for TFPI. Arterioscler Thromb Vasc Biol 2009; 29: 2015-2020.
    CrossrefPubMedGoogle Scholar
  • 20 Castoldi E, Simioni P, Tormene D. et al. Hereditary and acquired protein S deficiencies are associated with low TFPI levels in plasma. J Thromb Haemost 2010; 08: 294-300.
    CrossrefPubMedGoogle Scholar
  • 21 Dahm AE, Sandset PM, Rosendaal FR. The association between protein S levels and anticoagulant activity of tissue factor pathway inhibitor type 1. J Thromb Haemost 2008; 06: 393-395.
    CrossrefPubMedGoogle Scholar
  • 22 Hackeng TM, Sere KM, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci USA 2006; 103: 3106-3111.
    CrossrefPubMedGoogle Scholar
  • 23 Dielis AW, Castoldi E, Spronk HM. et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008; 06: 125-131.
    PubMedGoogle Scholar
  • 24 Van Vliet HA, Tchaikovski SN, Rosendaal FR. et al. The effect of the levonorges-trelreleasing intrauterine system on the resistance to activated protein C (APC). Thromb Haemost 2009; 101: 691-695.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Van Vliet HA, Winkel TA, Noort I, Rosing J, Rosendaal FR. Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate. J Thromb Haemost 2004; 02: 2060-2062.
    CrossrefPubMedGoogle Scholar
  • 26 Van Vliet HA, Rodrigues SP, Snieders MN. et al. Sensitivity to activated protein C during the menstrual cycle in women with and without factor VLeiden. Thromb Res 2008; 121: 757-761.
    CrossrefPubMedGoogle Scholar
  • 27 Fleischer K, Van Vliet HA, Rosendaal FR. et al. Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: a cross-over study. Thromb Res 2009; 123: 429-435.
    CrossrefPubMedGoogle Scholar
  • 28 WHO. Medical eligibility criteria for contraceptive use. 4th ed. Geneva: WHO; 2009. Available at: www.who.int/reproductivehealth/publications/family_planning/9789241563888/en/index.html.2011
    Google Scholar
  • 29 Van Vliet HA, Winkel TA, Noort I, Rosing J, Rosendaal FR. Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate. J Thromb Haemost 2004; 02: 2060-2062.
    CrossrefPubMedGoogle Scholar
  • 30 Giri TK, Hillarp A, Hardig Y, Zoller B, Dahlback B. A new direct, fast and quantitative enzyme-linked ligandsorbent assay for measurement of free protein S antigen. Thromb Haemost 1998; 79: 767-772.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 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: 4387-4392.
    CrossrefPubMedGoogle Scholar
  • 32 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: 233-238.
    CrossrefPubMedGoogle Scholar
  • 33 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; 02: 2060-2062.
    CrossrefPubMedGoogle Scholar
  • 34 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: 992-997.
    CrossrefPubMedGoogle Scholar
  • 35 Van Hylckama Vlieg A, Helmerhorst FM. et al. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol 2010; 30: 2297-2300.
    CrossrefPubMedGoogle Scholar
  • 36 Lidegaard O, Nielsen LH, Skovlund CW. et al. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10. Br Med J 2012; 344: e2990.
    CrossrefPubMedGoogle Scholar
  • 37 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; 02: 1594-1600.
    CrossrefPubMedGoogle Scholar
  • 38 Koenen RR, Christella M, Thomassen LG. et al. Effect of oral contraceptives on the anticoagulant activity of protein S in plasma. Thromb Haemost 2005; 93: 853-859.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 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 trial. Blood 2004; 103: 927-933.
    PubMedGoogle Scholar
  • 40 The effects of seven monophasic oral contraceptive regimens on hemostatic variables: conclusions from a large randomized multicenter study. Contraception. 2003; 67: 173-185.
    PubMed
  • 41 Kluft C, Endrikat J, Mulder SM. et al. 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: 336-343.
    CrossrefPubMedGoogle Scholar
  • 42 Johnson JV, Lowell J, Badger GJ. et al. Effects of oral and transdermal hormonal contraception on vascular risk markers: a randomized controlled trial. Obstet Gynecol 2008; 111: 278-284.
    CrossrefPubMedGoogle Scholar
  • 43 Jensen JT, Burke AE, Barnhart KT. et al. Effects of switching from oral to trans-dermal or transvaginal contraception on markers of thrombosis. Contraception 2008; 78: 451-458.
    CrossrefPubMedGoogle Scholar
  • 44 Lidegaard O, Nielsen LH, Skovlund CW. et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. Br Med J 2011; 343: pd6423.
    CrossrefPubMedGoogle Scholar
  • 45 Carlsson S, Dahlback B. Dependence on vitamin K-dependent protein S for eukaryotic cell secretion of the beta-chain of C4b–binding protein. J Biol Chem 2010; 285: 32038-32046.
    CrossrefPubMedGoogle Scholar