Review ArticleMechanisms of Estrogen-Induced Venous Thromboembolism
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.
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