Effects on Coagulation of Levonorgestrel- and Desogestrel-containing Low Dose Oral Contraceptives: a Cross-over Study

Abstract

SummaryCombined oral contraceptives (OC) are known to increase the risk of venous thromboembolism. The aim of this randomized, cycle-controlled, cross-over study in 28 healthy volunteers was to assess potential differences between the effects of an OC containing 150 µg levonorgestrel (as representative of the so-called second generation OC) and an OC containing 150 µg desogestrel (as representative of the third generation OC) in combination with 30 µg ethinylestradiol on several coagulation factors and markers of thrombin formation. All participants used each OC for two cycles, and were switched to the other OC after a washout period of two menstrual cycles. The plasma concentrations of factors II, VII, X, and fibrinogen significantly increased during use of both the levonorgestrel- and desogestrel-containing OC’s. The plasma concentrations of factor VIII increased, and of factor V decreased, changes which only reached statistical significance during the use of the desogestrel-containing OC. During exposure to the desogestrel-containing OC, as compared with the levonorgestrel-containing OC, both factor VII and factor II showed a greater increase (FVII: 32% and 12% respectively; p <0.0001; FII: 16% and 12% respectively; p = 0.048), whereas factor V showed a greater decrease (–11% and –3% respectively; p = 0.010). Only one of the markers for ongoing coagulation (prothrombin fragment 1+2) showed a significant increase during OC use, whereas concentrations of thrombin-antithrombin complexes and soluble fibrin remained unchanged. For these markers, there was no difference between the tested OC’s. We conclude that there are differences between the effects of levonorgestrel and desogestrel-containing OC’s on some coagulation factors. Whether these changes provide a biological explanation for the reported differences in venous thromboembolic risk is as yet unclear. The real challenge now becomes to define a pattern of changes in the various systems which, if affected simultaneously, may tip the hemostatic balance towards a prethrombotic state and may lead to overt clinical venous thromboembolism.

Aortic thrombus with contraceptive vaginal ring use

“…5 In general, secondgeneration COCs carry a higher risk of thrombotic stroke but lower risk of VTE compared to third-generation COCs. Desogestrel is known to cause pronounced resistance to protein C and reduce circulating levels of protein S. 1,7 Desogestrel has also been shown to increase plasma levels of Factors II, VII, VIII, and X, while decreasing Factor V. 8 These qualities are often mimicked by antiphospholipid syndrome, which is differentiated from other hypercoagulable states by its propensity to cause both arterial and venous thromboemboli. 9 The most common serious side effect of COCs is VTE.…”

Cerebral Venous Thrombosis With Topical Estrogen-Progesterone Use in a Young Heterosexual Male

“…The data in human studies examining the effect of hormonal therapy on platelet number, activation, and aggregation are not precise. Another suggested mechanism is working on the coagulation cascade by increasing plasma levels of factors II, VII, VIII, X, and fibrinogen and decreasing factor V levels 8…”

Sclerotherapy of lower limb veins: Indications, contraindications and treatment strategies to prevent complications – A consensus document of the International Union of Phlebology-2023

“…235 They increase plasma procoagulant factor levels including fibrinogen, prothrombin and coagulation factors VII, VIII and X while decreasing the plasma antithrombin level, the major inhibitor of several activated coagulation factors, and the concentration and activity of tissue factor inhibitor. 236–238 In addition, the OCP induces resistance to the anticoagulant effect of activated protein C (APC), and APC resistance (APCR) is directly correlated with an increased risk of VTE. 235…”

“…235 They increase plasma procoagulant factor levels including fibrinogen, prothrombin and coagulation factors VII, VIII and X while decreasing the plasma antithrombin level, the major inhibitor of several activated coagulation factors, and the concentration and activity of tissue factor inhibitor. [236][237][238] In addition, the OCP induces resistance to the anticoagulant effect of activated protein C (APC), and APC resistance (APCR) is directly correlated with an increased risk of VTE. 235 Other oestrogen-releasing contraceptive preparations such as the transdermal patch or vaginal ring bypass the first-pass metabolism in the liver where the coagulation proteins are synthesised, yet still pose a thrombogenic risk.…”