To cite this article: Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Ballieux B, van Vliet H. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; 10: 992-7.Summary. Background: It takes many years to obtain reliable values for the risk of venous thrombosis of hormonal contraceptive users from clinical data. Measurement of activated protein C (APC) resistance via thrombin generation is a validated test for determining the thrombogenicity of hormonal contraceptives. Sex hormone-binding globulin (SHBG) might serve as a marker for the risk of venous thrombosis, and can be easily and rapidly measured in routine laboratories. Objective: To determine whether SHBG is a useful marker for the thrombotic risk of hormonal contraceptive users by comparing plasma SHBG levels with normalized APC sensitivity ratio (nAPCsr) values and thrombosis risks reported in the recent literature. Methods: We conducted an observational study in 262 users of different contraceptives, and measured nAPCsr and SHBG levels. Results: Users of contraceptives with a higher risk of causing venous thrombosis, i.e. combined hormonal contraceptives containing desogestrel, cyproterone acetate or drospirenone, and the transdermal patch, had higher SHBG levels than users of combined hormonal contraceptives containing levonorgestrel, which carry a lower thrombosis risk. Users of the patch had the highest SHBG levels, with a mean difference of 246 nmol L )1 (95% confidence interval 179-349) from that in users of levonorgestrel-containing combined hormonal contraceptives. SHBG levels were positively associated with both the nAPCsr and the risks of venous thrombosis reported in the recent literature. Conclusion: SHBG is a useful marker with which to estimate the thrombotic safety of a preparation.
To cite this article: Raps M, Rosendaal F, Ballieux B, Rosing J, Thomassen S, Helmerhorst F, van Vliet H. Resistance to APC and SHBG levels during use of a four-phasic oral contraceptive containing dienogest and estradiol valerate: a randomized controlled trial. J Thromb Haemost 2013; 11: 855-61.Summary. Background: The use of combined oral contraceptives is associated with a 3-to 6-fold increased risk of venous thrombosis. This increased risk depends on the estrogen dose as well as the progestogen type of combined oral contraceptives. Thrombin generation-based activated protein C resistance (APC resistance) and sex hormone-binding globulin (SHBG) levels predict the thrombotic risk of a combined hormonal contraceptive. Recently, a four-phasic oral contraceptive containing dienogest (DNG) and estradiol valerate (E2V) has been marketed. The aim of this study was to evaluate the thrombotic risk of the DNG/E2V oral contraceptive by comparing APC resistance by measuring normalized APC sensitivity ratios (nAPCsr) and SHBG levels in users of oral contraceptives containing dienogest and estradiol valerate (DNG/E2V) and oral contraceptives containing levonorgestrel and ethinyl estradiol (LNG/EE). Methods: We conducted a single-center, randomized, open label, parallel-group study in 74 women using DNG/E2V or LNG/ EE, and measured nAPCsr and SHBG levels in every phase of the regimen of DNG/E2V. Results: During the pill cycle SHBG levels did not differ between DNG/E2V users and LNG/EE users. nAPCsr levels were overall slightly lower in DNG/E2V users than in LNG/EE users, mean difference À0.44 (95% CI, À1.04 to 0.17) for day 2, À0.20 (95% CI, À0.76 to 0.37) for day 7, À0.27 (95% CI, À0.81 to 0.28) for day 24 and À0.34 (95% CI, À0.91 to 0.24) for day 26. Conclusion: No statistical significant differences in nAPCsr and SHBG levels were found between users of the oral contraceptive containing DNG/E2V and LNG/EE, suggesting a comparable thrombotic risk Keywords: activated protein C resistance, natural estrogen, oral contraceptives, sex hormone binding globulin, thrombotic risk. IntroductionUse of combined oral contraceptives is associated with a 3-to 6-fold increased risk of venous thrombosis. This increased risk depends on the estrogen dose as well as the progestogen-type of combined oral contraceptives [1]. Socalled 'high-dose' combined oral contraceptives containing 50 lg or more ethinyl estradiol (EE) are associated with a 2-fold higher risk of thrombosis than 'low-dose' combined oral contraceptives containing 20-30 lg EE [2,3]. Furthermore, combined oral contraceptives containing the progestogens gestodene (GTD), desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP) increase the risk of venous thrombosis by a factor two compared with combined oral contraceptives containing levonorgestrel (LNG) [1][2][3][4][5][6][7][8][9][10].The differences in the risk of venous thrombosis can at least partially be explained by the different effects of various combined oral contraceptives on the resistance to activated protein...
To cite this article: Raps M, Helmerhorst FM, Fleischer K, van Hylckama VA, Stegeman BH, Thomassen S, Rosendaal FR, Rosing J, Ballieux BEPB, van Vliet HAAM. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives: reply to a rebuttal. 2013; 11: 396-7. Kluft et al. question the design of our recent study regarding sex hormone-binding globulin (SHBG) as a marker for the risk of venous thrombosis during use of hormonal contraceptives [1]. They state that when measured only in women 'on-treatment', SHBG showed a very weak association with normalized activated protein C sensitivity ratios (nAPCsr) determined with the thrombin generation-based APC resistance test. Hence, in their opinion SHBG is not a surrogate marker for venous thrombosis. They claim this statement is supported by a recent publication of Stegeman et al. [2]. J Thromb HaemostIn our study [1] of 262 participants, 232 women were users of different hormonal contraceptives, of whom we only included on-treatment data. In addition, a group of 13 nonusers with a regular ovulatory menstrual cycle and 17 users of the non-hormonal copper-releasing IUD were included. Kluft et al. state that the difference in correlation is due to inclusion of pre-treatment data. With pre-treatment data, they likely indicate these 13 non-users and 17 users of the copper-releasing IUD. They are correct that no correlation between SHBG and nAPCsr was found in non-users of hormonal contraceptives [2]; therefore it would have been better to exclude the group of non-users and non-hormonal contraceptive users from the correlation analysis. We re-analyzed our data without the 30 non-hormonal contraceptive users (non-users and users of the copper-releasing IUD) and found similar results: r 2 = 0.468; equation, log 10 (SHBG) = 1.515 + (0.163 9 nAPCsr) (Fig.
Use of combined oral contraceptives is associated with a three- to six-fold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.
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