A Randomized Cross-over Study on the Effects of Levonorgestrel- and Desogestrel-containing Oral Contraceptives on the Anticoagulant Pathways

Abstract

SummaryThe 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 cyclecontrolled 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 µg levonorgestrel/30 µg ethinylestradiol) or a third generation OC (150 µg desogestrel/30 µg ethinylestradiol) and who switched to the other OC after a two month wash out period. The anticoagulant parameters determined were: antithrombin (AT), α2-macroglobulin (α2-M), α1-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 αc2-M, α1-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 ETPbased (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.

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

“…oral contraceptives containing cyproterone acetate) had the lowest free protein S and TFPI free antigen levels. These results are consistent with other studies comparing the effect of different types of oral contraceptives on protein S. Several studies observed that desogestrel-containing combined pills decrease free and total protein S more than levonorgestrelcontaining combined pills [26][27][28]. Alhenc-Gelas et al found that users of cyproterone acetate containing oral contraceptives had lower protein S activity levels than users of oral contraceptives containing desogestrel [9].…”

Oral Contraceptives and the Risk of Venous Thrombosis

“…The molecular basis of acquired resistance to activated protein C during the use of oral contraceptives is unknown. Decreased levels of plasma protein S, the cofactor of activated protein C (the levels of which were significantly lower in users of desogestrel 82 ), only partially explain the resistance to activated protein C found in users of oral contraceptives.…”

Mechanistic View of Risk Factors for Venous Thromboembolism

“…Hormonal contraceptive use is associated with changes in the coagulation system at different levels. Crossover studies have demonstrated an increase in coagulation factors II, VII, VIII, and X in women using oral contraceptives, 61 a decrease of the levels of the natural anticoagulant protein S, 62 and a decrease of fibrinolytic activity, mainly through an increase of thrombin-activatable fibrinolysis inhibitor. 63 The use of oral contraceptive leads to increased resistance to the natural anticoagulant activity of activated protein C, which is partly explained by decreases of free protein S and free TF pathway inhibitor.…”