Background: Background: We have reported previously that, compared with use of second generationn oral contraceptives, the use of third generation oral contraceptives iss associated with increased resistance to the anticoagulant action of activated proteinn C (APC). Owing to the cross-sectional design of that study, these observationss may have been subject to unknown bias or uncontrolled effects of thee menstrual cycle. We aimed to overcome these sources of bias by doing a cycle-controlledd randomised cross-over trial.

Methods: Methods: The response to APC in plasma was assessed in 33 women who receivedd two consecutive cycles of a second generation oral contraceptive (150pgg levonorgestrel and 30pg ethinylestradiol) or a third generation oral contraceptivee (150pg desogestrel and 30ug ethinylestradiol), and who switchedd preparations after two pill-free cycles. Normalised APC sensitivity ratio'ss were calculated by measurement of the effect of APC on thrombin generationn in the plasma of these women and in pooled plasma from 90 controls.

Findings: Findings: Of the 33 women, five were excluded. In the remaining 28 women, thee normalised APC sensitivity ratio increased during treatment with both preparations.. Compared with levonorgestrel, desogestrel-containing oral contraceptivee treatment caused a highly significant (p< 0.0001) additional increase inn normalised APC sensitivity ratio (0.51, 95% CI 0.37-0.66). Normalised APC sensitivityy ratios during oral contraceptive treatment correlated with the values beforee oral contraceptives use.

Interpretation: Interpretation: Oral contraceptive treatment diminishes the efficacy with whichh APC down-regulates in vitro thrombin formation. This phenomenon, designatedd as acquired APC resistance, is more pronounced in women using desogestrel-containingg oral contraceptives than in women using levonorgestrel-containingg preparations. Whether acquired APC resistance induced by orall contraceptives explains the increased risk of venous thromboembolism in orall contraceptives users remains to be established.