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Cited by 203Blood Coagulation and Thrombosis MechanismsVenous Thromboembolism Diagnosis and ManagementReproductive Health and Contraception

A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways

Tans, Guido, Curvers, Joyce, Middeldorp, Saskia, Thomassen, M. Christella, Prins, Martin, Bouma, Bonno, Büller, Harry, Meijers, Joost +1 more·2000·Thrombosis and Haemostasis
DOI 10.1055/s-0037-1613960
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Abstract

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 cycle-controlled 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 microg levonorgestrel/30 microg ethinylestradiol) or a third generation OC (150 microg desogestrel/30 microg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), alpha2-macroglobulin (alpha2-M), alpha1-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 alpha2-M, alpha1-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 ETP-based (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.

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  • Human studies clearly indicate that estrogen treatment results in a prothrombotic state.

    “Human studies clearly indicate that estrogen treatment results in a prothrombotic state.”

    From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [63]

  • Combined oral contraceptives increase plasma levels of factors II, VII, VIII, X, and fibrinogen, and decrease factor V levels.

    “A randomized cross over study among women showed that combined oral contraceptives affect the coagulation cascade by increasing plasma levels of factors II, VII, VIII, X, and fibrinogen, and by decreasing factor V levels [62, 63].”

    From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [63]

  • CHC use causes a pronounced decrease in total and free Protein S antigen, more significantly with third-generation progesterone-containing CHCs.

    “Simultaneously, a pronounced decrease in levels of Protein S antigen (total and free) has been noted with CHC use, more significantly with use of 3rd generation progesterone containing CHCs[63, 65, 66] and in post-menopausal women [64].”

    From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [63]

  • CHC use decreases plasma levels of tissue factor pathway inhibitor and antithrombin.

    “Studies of the anticoagulant pathway show a decrease in plasma levels of naturally occurring inhibitors of hemostasis such as tissue factor pathway inhibitor and antithrombin with CHC use [63, 64].”

    From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [63]

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Authors
Tans, G., Curvers, J., Middeldorp, S., Thomassen, M. C., Prins, M., Bouma, B., Büller, H., Meijers, J., & Rosing, J.
Affiliations
  • Maastricht University (NL)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University Medical Center Utrecht (NL)
Corresponding author
Rosing, Jan
ORCID
Venue
Thrombosis and Haemostasis
Publisher
Georg Thieme Verlag KG
Published
2000
Volume
84
Issue
07
Pages
15-21
ISSN
  • 0340-6245 (ISSN-L)
  • 2567-689X
DOI
10.1055/s-0037-1613960
OpenAlex
W1834120352
Cited by
203
References
43
Citations by year
2026: 1 · 2025: 3 · 2024: 9 · 2023: 10 · 2022: 1 · 2021: 5 · 2020: 8 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 12 · 2013: 10 · 2012: 11
FWCI
8.51
Type
journal article
Language
en
Open access
closed
Locations
  • Thrombosis and Haemostasis (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Dutch Thrombosis Foundation (TSN)
  • Dutch Organization for Scientific Research (NWO) (900-526192)
  • Netherlands Heart Foundation (HRB (D93.013) and JCMM (D96.021))
  • Dr. A. van Enk, Institute Sorg Saem, Amsterdam
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
Keywords
oral contraceptives, levonorgestrel, desogestrel, anticoagulant pathway, protein S, antithrombin III, protein C, activated protein C resistance, alpha2-macroglobulin, alpha-1-antitrypsin, protein C inhibitor, venous thrombosis risk, coagulation, endogenous thrombin potential, activated partial thromboplastin time
MeSH terms
Adolescent, Adult, alpha-Macroglobulins, alpha 1-Antitrypsin, Antithrombins, Blood Coagulation, Blood Proteins, Contraceptives, Oral, Combined, Contraceptives, Oral, Hormonal, Ethinyl Estradiol, Female, Humans, Netherlands, Partial Thromboplastin Time, Protein C, Thrombin, Biomarkers, Levonorgestrel, Desogestrel, Protein S, Protein C Inhibitor, Cross-Over Studies, Thrombophilia, Activated Protein C Resistance

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