Recently, discussions focused on the question whether acquired activated (APC) resistance is a clue to the observed association between venous thromboembolism (VTE) risk and oral contraceptive (OC) use, especially with the so-called third-generation OC. The objective of our study was to check the validity of acquired APC resistance regarding VTE risk in a case-control study. Sixty-seven women with confirmed VTE diagnosis (n = 67) were consecutively ascertained in primary health care settings, interviewed and blood samples taken (at the earliest 6 months after VTE). Cases were age-matched to 290 population controls. Acquired APC resistance was measured as normalized APC ratio (APCRN). The effect of APC on tissue factor initiated thrombin generation was measured in plasma using alpha 2-macroglobulin attached thrombin activity as an endpoint. Higher risk (odds) ratio with 95% CI) of VTE for carriers of heterozygote Factor V Leiden mutation was confirmed [OR = 2.72 (CI:1.51-4.92)]. However, there is no association between VTE and the level of APCRN OR 0.65 (CI:0.35-1.22). We conclude that acquired APC resistance, measured with a tissue factor initiated test, is unlikely to have a direct association to the clinical outcome of venous thromboembolism.
PIP: The observed association between venous thromboembolism (VTE) risk and third-generation oral contraceptive (OC) use may reflect an OC-related activated protein C (APC) resistance. The validity of this hypothesis was assessed in a case-control study of 67 reproductive age women (mean age, 34.2 years) from southeast Germany diagnosed with VTE in 1995-97 and 290 age-matched population controls. The normalized APC ratio was measured as the effect of APC on tissue factor-initiated thrombin generation in plasma using alpha 2-macroglobulin attached thrombin activity as an end point. To minimize the influence of acute phase proteins, blood was drawn at least 6 months after VTE. The risk of VTE was significantly increased in carriers of heterozygote Factor V Leiden (odds ratio (OR), 2.72; 95% confidence interval (CI), 1.51-4.92). There was no association between VTE and the normalized APC ratio (OR, 0.65; 95% CI, 0.35-1.22). In women who were not current OC users and did not have the Factor V Leiden mutation, there was no association between the normalized APC ratio and VTE risk. Thus, Factor V Leiden mutation and OC use may be mild confounders of the association between the normalized APC ratio assay for acquired APC resistance and VTE risk. Overall, these findings suggest that acquired APC resistance does not have a direct association with the clinical outcome of VTE. However, this lack of association should be confirmed in a cohort study capable of taking time-dependent influences into account.