Activated protein c sensitivity ratio based on the endogenous thrombin potential is not a risk factor for pregnancy-associated venous thromboembolism

Women who use oral contraceptives (OC) become acquired APC resistant, measured by the effect of APC on the endogenous thrombin potential (ETP). This phenomenon is more pronounced in women using third-generation OC than in women using secondgeneration OC. Whether acquired APC resistance induced by OC contributes to an increased risk of venous thromboembolism (VTE) remains to be established. The aim of our study was to examine whether acquired APC resistance determined with an ETP-based normalized APC sensitivity ratio (nAPCsr) is a risk determinant for VTE in women with pregnancyassociated thromboembolism. We measured the activities of antithrombin, protein C, protein S, and performed a genetic analysis of FV mutation (G1691A, FVL), methylenetetrahydrofolate reductase mutation (MTHFR C677T), and prothrombin mutation (G20210A) in 64 women with VTE during pregnancy and the puerperium and in 114 normal women. Normalized ETP-based APC sensitivity ratios were determined as described by Rosing et al. A significantly (p <0.05) higher nAPCsr was present in normal women using hormones, in younger women (<45 yrs), and in women with carrier status of FVL. Further analysis was restricted to FVL negative individuals. Neither the analysis with continuous nAPCsr nor the analysis using cut-off values for nAPCsr showed a significant difference between patients and normal women. However, although not significant, the odds ratio for an increased nAPCsr in women with a history of thromboembolism and without actual hormone use was 1.6 (7/40 vs. 7/59, p=0.43) using the 90% percentile cut-off and approximately 3 (6/40 vs. 3/59, p= 0.152) using the 95% percentile. In normal women without FVL a significant (p< 0.05) negative correlation of nAPCsr with age (r= -0.39), antithrombin activity (r= -0.38), protein S activity (r= -0,26), and a significant positive correlation with hormone intake (r= 0.36) was present. In conclusion, nAPCsr is influenced by several coagulation parameters which are modified by the use of OC. Consequently, a multivariate analysis did not show a significant association of nAPCsr to venous thromboembolism. The clinical relevance of acquired APC resistance determined by nAPCsr is unclear. Our study demonstrates that nAPCsr is not a risk factor for pregnancy-associated venous thromboembolism.