Review Article
Mechanisms of Estrogen-Induced Venous Thromboembolism

https://doi.org/10.1016/j.thromres.2010.01.045Get rights and content

Abstract

The use of oral contraceptives (OC) is a well established risk factor for venous thrombosis. It has been known for many years that almost all haemostatic parameters i.e. plasma levels of coagulation factors, anticoagulant proteins and proteins involved in the fibrinolytic pathway change during OC use. The discovery of several risk factors of venous thrombosis in the 1990s shed new light on the association between the effects of OC on the haemostatic system and the increased risk of venous thrombosis. In this review, we summarize the current knowledge on the effects of different kinds of hormonal contraceptives (OC, transdermal contraceptives, vaginal ring and levonorgestrel-releasing intrauterine device) on haemostatic variables and the relationship between the changes of these variables and the risk of venous thrombosis.

Section snippets

Oral contraceptives and venous thrombosis

The first case reports describing venous thromboembolic events in women using OC, including fatal cases, appeared shortly after the introduction of the pill, in the early 1960s [3], [4]. The earliest OC preparations contained the progestogen norethynodrel, which was accidentally contaminated with the estrogen compound mestranol. Following the reduction of the mestranol contamination women experienced one of the most frequent side effects of progestogen-only preparations, breakthrough bleeding.

Total estrogenicity of contraceptives

Due to the observed differences in the risk of VT induced by OC containing the same dose of estrogen but different progestogen compounds, the prothrombotic effect of the pill was considered to be not strictly dependent on the dose of estrogen but rather on the “total estrogenicity” of the formulation [16]. The “total estrogenicity” rises with increasing dose of estrogen but decreases with increasing anti-estrogenic activity of progestogen compound. It was suggested that third generation

Risk factors of VT

Despite intensive research, the underlying mechanisms of the OC-induced VT remained obscure for a long time. It appeared that OC use causes changes in plasma levels of almost all proteins involved in coagulation and fibrinolysis [20], [21], [22], [23], [24]. These changes are relatively modest and may have synergistic as well as opposing effects. The implications of these changes for the development of VT were not fully appreciated which was amongst others due to the fact that for a long time

OC-induced changes in coagulation

The advances in thrombosis research enabled a better interpretation of the relations between the multiple effects of OC on the haemostatic parameters and the risk of VT. The changes in the procoagulant, anticoagulant and fibrinolytic pathways that occur during OC use and the differences between the effects of second and third generation OC are summarized in Table 1. A well-designed randomized cycle-controlled cross-over study [20], [21], [22] demonstrated that OC increased the plasma levels of

OC use and APC resistance

An interesting phenomenon related to the protein C system was observed in OC users: they were shown to be more resistant to the anticoagulant effect of APC than non-users. Acquired APC resistance during the pill use was demonstrated by measuring the effect of APC on the activated partial thromboplastin time (aPTT) [46] and on thrombin generation [47]. However, the differences in sensitivity to APC between non-pill users and users of different OC formulations, determined with the aPTT-based

Role of protein S and TFPI in the development of APC resistance

The sensitivity of plasma for APC is influenced by the plasma levels of several coagulation factors and anticoagulant proteins. Prothrombin, protein S and TFPI are considered to be the major determinants of the thrombin generation-based APC resistance test [34], [51]. The plasma levels of these proteins are affected by OC use [17], [21], [35], which might account for increased APC resistance. Yet, prothrombin is also one of the major determinants of other global coagulation tests, such as the

Non-oral hormonal contraceptives

Since the majority of the proteins involved in the haemostasis are synthesized in the liver, the prothrombotic effect of OC was for a long time thought to relate to the first-pass effect of estrogens and progestogens through the liver [59]. Therefore, preparations lacking this first-pass effect were expected to be a safer option of hormonal contraception. Consequently, combined hormonal contraceptives with non-oral ways of administration, i.e. the hormone-releasing transdermal patch and the

Progestogen-only contraceptives

In contrast to combined hormonal contraceptives, only few studies have been published on the effect of progestogen-only contraceptives on coagulation. Case-control studies on the risk of thrombosis in women using progestogen-only pills or injectables suggest that there is little or no increase of the risk of VT [67], [68], [69], although these studies were limited by the small number of participating women using these types of contraceptives. Furthermore, Kemmeren et al., demonstrated favorable

Conclusions

In conclusion, decreased plasma levels of protein S and TFPI, which are both considered to be the major risk factors of VT, are likely responsible for the increased APC resistance during hormonal contraception and may explain the elevated risk of VT in OC users. Epidemiological studies and laboratory data indicate that the risk of VT during the use of hormonal contraceptives increases in the following order: progestogen-only OC and levonorgestrel-releasing intrauterine device < second

Conflict of interest

There are no conflicts of interest for this paper.

References (77)

  • T. Koster et al.

    Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study

    Lancet

    (1993)
  • H. Jick et al.

    Venous thromboembolic disease and ABO blood type. A cooperative study

    Lancet

    (1969)
  • G. Grunbacher et al.

    The fibrinogen gamma (FGG) 10034C>T polymorphism is associated with venous thrombosis

    Thromb Res

    (2007)
  • L.C. Gennari et al.

    Endogenous or exogenous coagulation factor level and the response to activated protein C

    Thromb Res

    (2006)
  • M.C. de Visser

    van Hylckama Vlieg A, Tans G, et al: Determinants of the APTT- and ETP-based APC sensitivity tests

    J Thromb Haemost

    (2005)
  • M.C. de Visser et al.

    A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis

    Blood

    (1999)
  • A. van Hylckama Vlieg et al.

    High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly

    J Thromb Haemost

    (2003)
  • A. Dahm et al.

    Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis

    Blood

    (2003)
  • F.R. Rosendaal

    Venous thrombosis: a multicausal disease

    Lancet

    (1999)
  • J.P. Vandenbroucke et al.

    Third-generation oral contraceptive and deep venous thrombosis: from epidemiologic controversy to new insight in coagulation

    Am J Obstet Gynecol

    (1997)
  • A.W. Dielis et al.

    Coagulation factors and the protein C system as determinants of thrombin generation in a normal population

    J Thromb Haemost

    (2008)
  • H.A. van Vliet et al.

    Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor

    J Thromb Haemost

    (2008)
  • A.E. Dahm et al.

    The association between protein S levels and anticoagulant activity of tissue factor pathway inhibitor type 1

    J Thromb Haemost

    (2008)
  • S.N. Tchaikovski et al.

    Pregnancy-associated changes in the hemostatic system in wild-type and factor V Leiden mice

    J Thromb Haemost

    (2009)
  • J. Rosing et al.

    Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C

    J Biol Chem

    (1995)
  • T.M. Hackeng et al.

    Regulation of TFPI function by protein S

    J Thromb Haemost

    (2009)
  • M. Humpel et al.

    Investigations of pharmacokinetics of levonorgestrel to specific consideration of a possible first-pass effect in women

    Contraception

    (1978)
  • S.S. Jick et al.

    Risk of nonfatal venous thromboembolism with oral contraceptives containing norgestimate or desogestrel compared with oral contraceptives containing levonorgestrel

    Contraception

    (2006)
  • C. Kluft et al.

    Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables

    Contraception

    (2008)
  • K. Fleischer 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)
  • M.W. van den Heuvel et al.

    Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive

    Contraception

    (2005)
  • C. Vasilakis et al.

    del Mar Melero-Montes M: Risk of idiopathic venous thromboembolism in users of progestagens alone

    Lancet

    (1999)
  • I.D. Walker

    Factor V Leiden: should all women be screened prior to commencing the contraceptive pill?

    Blood Rev

    (1999)
  • J. Rosing et al.

    Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study

    Lancet

    (1999)
  • M. Alhenc-Gelas et al.

    Impact of progestagens on activated protein C (APC) resistance among users of oral contraceptives

    J Thromb Haemost

    (2004)
  • WHO scientific group meeting on cardiovascular disease and steroid hormone contraceptives. Wkly Epidemiol Rec 1997,...
  • E.T. Tyler

    Oral contraception and venous thrombosis

    Jama

    (1963)
  • Connell EB: Contraception in the prepill era. Contraception 1999,...
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