Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second‐ and third‐generation oral contraceptives

Abstract

Summary.Epidemiological studies have shown that women who use third-generation oral contraceptives (OC) containing desogestrel, gestodene or norgestimate have a higher risk of venous thrombosis than women who use second-generation OC containing levonorgestrel. It is also known that a mutation in factor V (factor V Leiden ), which results in resistance to activated protein C (APC) and which is the most common cause of hereditary thrombophilia, potentiates the prothrombotic effect of OC.Effects of APC on thrombin generation in the plasma of women using OC were compared to the response to APC in non-OC users and in individuals that were heterozygous or homozygous for factor V Leiden . The response towards APC was evaluated on basis of the ratio (APC-sr) of the time integrals of thrombin formation determined in the presence and absence of APC.Compared with women not using OC, women who used OC exhibited a significantly decreased sensitivity to APC (P < 0 . 001), independent of the kind of OC used. Women who used third-generation monophasic OC were significantly less sensitive to APC than women using second-generation OC (P < 0 . 001) and had APC-sr that did not significantly differ from heterozygous female carriers of factor V Leiden who did not use OC. Women who were heterozygous for factor V Leiden and used OC had APC-sr in the range of homozygous carriers of factor V Leiden . Two women who started OC therapy had significantly elevated APC-sr within 3 d.Acquired APC resistance may explain the epidemiological observation of increased risk for venous thrombosis in OC users, especially in women using third-generation OC.

Acquired APC resistance and oral contraceptives: differences between two functional tests

“…Table I summarizes the data together with the results for men and women, separately. In both tests women appeared slightly more resistant to APC than men, confirming earlier reports (De Stefano et al, 1996;Henkens et al, 1995;Koster et al, 1993;Rosing et al, 1997), but only in the ETP-based assay did the gender difference reach statistical significance (P < 0·05, Table I). Fig 2 and Table II summarize the effects of OC use on nAPCsr obtained in both tests for plasmas of normal healthy women who do not carry the factor V Leiden mutation and of women heterozygous for the factor V Leiden mutation.…”

“…Acquired APC resistance particularly occurs in plasma of women who use oral contraceptives (Henkens et al, 1995;Olivieri et al, 1995;Rosing et al, 1997) or who are pregnant (Meinardi et al, 1997) and is particularly observed in a functional test in which the ability of APC to down-regulate coagulation is quantitated by measuring its effect on thrombin generation initiated in plasma via the extrinsic pathway .…”

“…However, screening methods that are based on measurement of the effect of APC on the aPTT of undiluted plasma do not fully discriminate between carriers and non-carriers of the factor V Leiden mutation (Engel et al, 1996;Rosen & Sturk, 1997;. In particular, women who are using oral contraceptives (Henkens et al, 1995;Olivieri et al, 1995;Rosing et al, 1997) or who are pregnant (Meinardi et al, 1997) appear to be less sensitive to the anticoagulant action of APC and hence are considered to have acquired APC resistance.…”

Hypercoagulability in adolescent girls on oral contraceptives‐global coagulation profile and estrogen receptor polymorphisms

“…Second, although OCP use causes overall hypercoagulability, a well-known fact, our study shows that the variable effects of OCPs on the PS system are likely to be the main determinant for differences in hypercoagulability. The increased risk of VTE with third generation progesterone containing OCPs as compared to first or second generation progesterone is thought to be explained by a differential effect of progesterone on activated PC resistance [32] and is a well known phenomenon. Our study subjects were on the same OCP preparation, containing a second-generation progesterone norgestimate, yet developed variable thrombomodulin resistance.…”

Calibrating Thrombin Generation in Different Samples: Less Effort with a Less Efficient Substrate

“…Fluorescence based applications have now the widest distribution because these techniques have advantages over the absorption based approaches as the signal in the latter is disturbed by turbidity caused by coagulation events. It is now possible to perform measurements for the characterization of hereditary or acquired coagulation disturbances as well as for investigations into the influence of various medicines that affect the coagulation process beyond the time of clotting [9][10][11][12][13][14][15][16][17][18][19]. Hemker et al have reviewed further literature on such applications [20].…”