Increased resistance to activated protein C in women taking third-generation oral contraceptives?

In a recently published paper in Blood,1 Kemmeren et al elegantly studied the effect of secondand third-generation oral contraceptives (OCs) on hemostatic variables that probe the activity of the protein C system. The authors showed that, because the progestagen poorly counteracted the effect of the estrogen component, desogestrel-containing OCs significantly increased activated protein C (APC) resistance, thus perhaps explaining the higher thrombotic risk associated with third-generation oral contraceptives. The design of this double-blind study is perfect. However, the intensity of the plasma anticoagulant response to activated protein C was determined by quantifying the effect of activated protein C on thrombin generation and was given only as the APC sensitivity ratio (APC-sr; the higher the values are, the lower the plasma anticoagulant response is), as described by Rosing et al,2 a choice that, for us, calls for some comments. The APC-sr parameter is obtained by calculating the P/N ratio. P is obtained, for a given patient’s plasma, by dividing the value of the endogenous thrombin potential (ETP) performed in the presence of a constant amount of purified activated protein C (ETPaPC) by the basal value of the ETP. N corresponds to P performed on a normal reference plasma. For a given patient’s plasma, the APC-sr parameter is finally the [(ETP-APC)/ETP] patient –[(ETP-APC)/ ETP]normal plasma ratio. The variations of the APC-sr parameter must be analyzed basically according to the variations of the various components of the formula and depend mainly on the variations of the (ETP-APC)patient and the ETPpatient components. No data in the paper by Kemmeren et al are given that would allow this cautious analytic interpretation to be performed. We thus studied the single paper from this team that used the same technical methodology but that also contained enough crude data to allow the analysis of the variations of the APC-sr parameter.2 Results are given in Table 1. As detailed, the values of the [(ETP-APC)/ETP]patient ratios obtained in women taking thirdgeneration oral contraceptives are obviously higher than those obtained in women taking second-generation oral contraceptives (nearly the same values as those found in factor VLeiden heterozygous carriers), quickly leading to the claim of a lower plasma response to activated protein C. However, the striking analytic facts are that the ETP-APC values are consistently higher in women taking third-generation OCs than in women taking secondgeneration OCs and that the values of the absolute differences calculated between ETP-APC and ETP values (Table 1, “ETP–ETPAPC”) are identical—midway between the one found in women not taking OCs and the one found in heterozygous factor VLeiden female carriers. Thus, women taking third-generation OCs are probably not less responsive to activated protein C than are women taking secondgeneration OCs but probably have only significantly higher basal values of the endogenous thrombin potential. Studies of the variations of the APC-sr parameter induce a bias of interpretation if they are not analyzed in relation to the variations of the parameter’s components. We imagine that the search for coagulation-related indicators, in hopes of understanding the higher prothrombotic risk in women taking third-generation OCs, is more likely to be informative if performed in order to understand what explains the effect of the progestagen desogestrel on the basal endogenous thrombin potential itself rather than in order to analyze the induced variations of sensitivity to activated protein C.