Download PDF
Thromb Haemost 2000; 84(01): 9-14
DOI: 10.1055/s-0037-1613959
Commentary
Schattauer GmbH

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
Joost C. M. Meijers   5
1   From the Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, the Netherlands
1   From the Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, the Netherlands
,
Saskia Middeldorp
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Winnie Tekelenburg
1   From the Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, the Netherlands
,
Abraham E. van den Ende
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Guido Tans
4   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
,
Martin H. Prins
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Jan Rosing
4   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
,
Harry R. Büller
3   Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
,
Bonno N. Bouma
1   From the Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, the Netherlands
1   From the Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, the Netherlands
› Author AffiliationsThis study was supported in part by a grant from the Dutch Thrombosis Foundation. JCMM and HRB are Established Investigators of the Netherlands Heart Foundation (grants D96.021 and D93.013).
The authors thank the volunteers for participating in this study. The recruitment of volunteers and the collection of the materials under GCP-rules was performed by the foundation SorgSaem, Amsterdam (Dr. A. van Enk).
Further Information

Publication History

Received 21 October 1999

Accepted after resubmission 11 April 2000

Publication Date:
10 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

The effect of oral contraceptives (OC) on fibrinolytic parameters was investigated in a cycle-controlled cross-over study in which 28 non-OC using women were randomly prescribed either a representative of the so-called second (30 µg ethinylestradiol, 150 µg levonorgestrel) or third generation OC (30 µg ethinylestradiol, 150 µg desogestrel) and who switched OC after a two month wash out period. During the use of OC, the levels of tissue-type plasminogen activator (tPA) activity, plasminogen, plasmin-α2-antiplasmin complexes and D-dimer significantly increased (by 30 to 80%), while the levels of plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity and tPA antigen significantly decreased (25 to 50%), suggesting an increase in endogenous fibrinolytic activity. These OC-induced changes were not different between the two contraceptive pills. TAFI (thrombin-activatable fibrinolysis inhibitor) levels increased on levonorgestrel, and even further increased on desogestrel. A clot lysis assay that probes both fibrinolytic activity and the efficacy of the coagulation system to generate thrombin necessary to down regulate fibrinolysis via TAFI showed no change of the clot lysis time during OC use. This finding suggests that the OC-induced increase in endogenous fibrinolytic activity is counteracted by an increased capacity of the coagulation system to down regulate fibrinolysis via TAFI. Indeed we observed that during OC use there was a significant increase of F1+2 generation during clot formation. When these assays were performed in the presence of an antibody against factor XI, we observed that the clot lysis time was significantly increased during OC use and that the increase in F1+2 generation during OC therapy was due to a factor XI-independent process, which was significantly higher on desogestrel than on levonorgestrel. These data indicate that the OC-induced inhibition of endogenous fibrinolysis takes place in a factor XI-independent way and is more pronounced on desogestrel than on levonorgestrel-containing OC.

Keywords

Oral contraceptives - fibrinolysis - TAFI - coagulation

5 Dr. J. C. M. Meijers, Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands


 

  • References

  • 1 Jordan WM. Pulmonary embolism. Lancet 1961; 02: 1146-7.
    PubMedSearch in Google Scholar
  • 2 Boyce J, Fawcett JW, Noall EWP. Coronary thrombosis and conovid. Lancet 1963; i: 111.
    PubMedSearch in Google Scholar
  • 3 Stadel BV. Oral contraceptives and cardiovascular disease. N Engl J Med 1981; 305: 612-8.
    CrossrefPubMedSearch in Google Scholar
  • 4 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; 1582-8.
    PubMedSearch in Google Scholar
  • 5 WHO. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995; 1575-82.
    PubMedSearch in Google Scholar
  • 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.
    CrossrefPubMedSearch in Google Scholar
  • 7 Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, Büller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deepvein thrombosis associated with oral contraceptives containing third-generation progestagen. Lancet 1995; 346: 1593-6.
    CrossrefPubMedSearch in Google Scholar
  • 8 Spitzer WO, Lewis MA, Heineman 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. British Med J 1996; 312: 83-8.
    CrossrefPubMedSearch in Google Scholar
  • 9 Herings RMC, Urquhart J, Leufkens HGM. Venous thromboembolism among new users of different oral contraceptives. Lancet 1999; 354: 127-8.
    CrossrefPubMedSearch in Google Scholar
  • 10 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.
    CrossrefPubMedSearch in Google Scholar
  • 11 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.
    CrossrefPubMedSearch in Google Scholar
  • 12 Newton JR. Classification and comparison of oral contraceptives containing new generation progestagens. Hum Reprod Update 1995; 01: 231-63.
    CrossrefPubMedSearch in Google Scholar
  • 13 Speroff L. Oral contraceptives and venous thromboembolism. Int J Gynaecol Obstet 1996; 54: 45-50.
    CrossrefPubMedSearch in Google Scholar
  • 14 Kluft C, Lansink M. Effects of oral contraceptives on haemostasis variables. Thromb Haemost 1997; 78: 315-26.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activatable fibrinolysis inhibitor. J Biol Chem 1995; 270: 14477-84.
    CrossrefPubMedSearch in Google Scholar
  • 16 Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995; 96: 2534-8.
    CrossrefPubMedSearch in Google Scholar
  • 17 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: 27176-81.
    CrossrefPubMedSearch in Google Scholar
  • 18 Mosnier LO, von dem Borne PAK, Meijers JCM, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost 1998; 80: 829-35.
    Thieme ConnectPubMedSearch in Google Scholar
  • 19 Von dem Borne PAK, Meijers JCM, Bouma BN. Feed-back activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-42.
    PubMedSearch in Google Scholar
  • 20 Von dem Borne PAK, Bajzar L, Meijers JCM, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997; 99: 2323-7.
    CrossrefPubMedSearch in Google Scholar
  • 21 Bouma BN, von dem Borne PAK, Meijers JCM. Factor XI and protection of the fibrin clot against lysis – A role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost 1998; 80: 24-7.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Braat EAM, Los P, Rijken DC. The inactivation of single-chain urokinasetype plasminogen activator by thrombin in a plasma milieu: effect of thrombomodulin. Blood Coag Fibrinol 1998; 09: 419-27.
    CrossrefPubMedSearch in Google Scholar
  • 23 Crook D, Godsland I. Safety evaluation of modern oral contraceptives. Effect on lipoprotein and carbohydrate metabolism. Contraception 1998; 57: 189-201.
    CrossrefPubMedSearch in Google Scholar
  • 24 Middeldorp S, Meijers JCM, van den Ende AE, van Enk A, Bouma BN, Tans G, Rosing 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Tans G, Curvers J, Middeldorp S, Thomassen MCLGD, Meijers JCM, Prins MH, Bouma BN, Büller HR, Rosing J. A randomized cross-over study on the effects of levonorgestrel- and desogestrel oral contreceptives on the anticoagulant pathways. Thromb Haemost 2000; 84: 15-21.
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Rosing J, Middeldorp S, Curvers J, Thomassen MCLGD, Nicolaes GAF, Meijers JCM, 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.
    CrossrefPubMedSearch in Google Scholar
  • 27 Bajzar L, Kalafatis M, Simioni P, Tracy PB. An antifibrinolytic mechanism describing the prothrombotic effect associated with factor VLeiden . J Biol Chem 1996; 271: 22949-52.
    CrossrefPubMedSearch in Google Scholar