Effect over coagulation and fibrinolysis parameters of a prolonged release 24 + 4 daily use regime contraceptive formulation containing 2 mg dienogest/0.02 mg ethinylestradiol

Background A prolonged release combined oral contraceptive (COC) pill, containing 2 mg dienogest (DNG)/0.02 mg ethinylestradiol (EE) in a 24 + 4 daily dosing regimen has recently been approved in Europe.

To determine if this COC impacts coagulation and fibrinolytic factors in comparison to an immediate release COC containing 3 mg drospirenone (DRSP)/0.02 mg EE.

Forty-four patients received the novel product, and forty-seven the comparator (immediate release formulation) during nine complete cycles. Coagulation and fibrinolytic parameters were evaluated: activated protein C resistance ratio, Antithrombin III (AT III), C-reactive protein, Factor VII, Factor VIII, and D-Dimer.

Compared to baseline, at the end of the study both groups displayed significantly higher mean values for AT III: 1.06 mg/mL (standard deviation [SD], 95% CI, 0.98–1.15) for the DNG/EE formulation and 1.04 mg/mL (SD 95% CI, 0.96–1.12) for the comparator (p = 0.0006 and p = 0.0009, respectively). D-dimer showed a non-significant slight reduction in the DNG/EE group, from 276.62 ng/mL (SD, 95% CI, 228.92–334.26) before treatment to 243.98 ng/mL (SD, 95% CI, 192.45–309.31) ng/mL after treatment. Contrarily, the comparator displayed a non-significant rise in D-dimer values from 246.46 ng/mL (SD, 95% CI, 205.44–295.66) ng/mL to 275.30 ng/mL (SD, 95% CI 219.21–345.75; p = 0.4520). All other parameters showed no significant differences before and after the treatment for both groups.

The COC 2 mg DNG/0.02 mg EE was not associated with any meaningful changes in the analyzed coagulation and fibrinolytic parameters indicating that a prolonged release formulation does not impact on these factors. Clinical trial registry EudraCT: 2019-0018-77-97

Shortly after introducing the first combined oral contraceptives (COC) in the 1950s, the first cases of venous thromboembolism (VTE) associated with the use of COCs were registered [Citation1]. When using a COC, the estrogen compound is the primary cause of the thrombotic risk. Estrogens are also related to other adverse events such as weight gain, bleeding disorders, nausea, and bloating; hence, the estrogen dosage has been continuously reduced since the 1970s. Indeed, the reduced estrogen dosage has resulted in a lower incidence of VTE [Citation2–4]. Changes in the progestin compound of COCs were subsequently introduced to continue efforts at reducing risks. The first COCs contained progestins like lynestrenol and ethynodiol-diacetate, while in the 1970s, levonorgestrel (LNG) and the 1980s, progestins like gestodene and desogestrel were introduced as new compounds. Four studies published in 1995 and 1996 showed that women using COCs with gestodene or desogestrel displayed a two-fold higher VTE risk than women using COCs with LNG [Citation5–8]. Cyproterone acetate and drospirenone were introduced in 1988 and 2001, respectively. In several studies, an evaluation by the European Medicines Agency (EMA) and a Cochrane meta-analysis revealed that the risk of VTE in women using COC with cyproterone acetate or drospirenone is two-fold higher than with COCs containing LNG [Citation9,Citation10]. These studies further confirmed that the use of gestodene or desogestrel was associated with a higher VTE risk than LNG [Citation9,Citation10]. Historically, most available COCs use ethinylestradiol (EE) as an estrogenic compound; in particular, this molecule seems to trigger the occurrence of VTE in women. Progestins administered orally without any estrogen do not increase VTE risk. Combined with EE, progestins with partial androgenic activity, such as LNG, counteract the intense EE-induced stimulation of liver proteins by changing pro-coagulatory, anti-coagulatory, and fibrinolytic factors. EE leads to higher levels of fibrinogens, prothrombin, and coagulation factors VII, VIII, and X, and slightly lower levels of factor V. In contrast, non-androgenic or antiandrogenic progestins such as gestodene, desogestrel, cyproterone acetate, and drospirenone do have limited influence on the EE-induced effects and therefore increase VTE risk when used in combined pills [Citation11]. The changes in prothrombin levels, factor VII, and factor V, are more pronounced in combined pills using desogestrel as a progestin as compared to COCs using LNG. There are also changes in the protein C signal as the concentration and activity of protein C are slightly increased. This is compensated by higher levels of proteins acting as inhibitors of protein C (protein-C-inhibitor, 1-antitrypsin [1-antiprotease], and 2-macroglobulin). Levels of total and free protein S and its activity are decreased independently from the action of activated protein C (APC). This reduction is more pronounced in women using COCs with non-androgenic or antiandrogenic progestins than in those taking COCs with androgenic progestins. Of note, EE improves plasmatic fibrinolytic activity, reducing the concentration and activity of plasminogen-activation inhibitor (PAI) 1 and increasing tissue plasminogen activator as well as plasminogen levels. However, this is compensated by the rise in thrombin-activated fibrinolysis inhibitors [Citation12]. Overall, the hemostatic balance is shifted toward coagulation. Previous findings indicate that various COCs differently impact APC resistance and the concentration of sexual hormone-binding globulin (SHBG). Progestins and their modulating effects on EE-induced changes translate into different thrombotic event risks [Citation13,Citation14]. Nevertheless, despite the mentioned data, COCs are still widely used and accepted due to their high contraceptive efficacy. At the same time, they display an overall low profile of adverse events [Citation15]. Lowering the amount of EE from 0.03 mg to 0.02 mg in a dienogest containing COC and maintaining contraceptive efficacy is therefore a goal to reduce the risk of VTE induced by EE. In this sense, a prolonged-release formulation containing 0.02 mg EE and 2 mg dienogest (DNG) has been developed with these two hormones and a dosage that offers high contraceptive efficacy accompanied by a bleeding profile similar to that of a formulation containing 0.03 mg of EE, that avoids the high rate of unscheduled bleeding described under the use of other types of estrogens [Citation16]. The present study aimed to present the first data of the impact of this formulation on coagulation and fibrinolysis.

This document presents as a sub-analysis of a recently published European prospective, multicenter, comparative double-blind, double-dummy phase III trial in women who were seeking contraception to avoid pregnancy at one of the participating clinics [Citation16]. The duration of the trial was nine cycles of 28 days, with a follow-up visit scheduled 7–10 days after the last dose of the study drug. The trial protocol, trial information provided to participants and recruitment advertisements were approved by each centre’s Independent Ethics Committee and Institutional Review Board. The trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization (ICH) guidelines for Good Clinical Practice (GCP) and the relevant European Commission directives and laws of each country. All participants gave written informed consent prior to enrollment. Trial registration was at EudraCT: 2019-001877-97. The following hemostatic parameters were evaluated, before and after treatment: Antithrombin III (AT III), activated protein C (APC) resistance ratio, D-Dimer, and clotting factors VII and VIII, and C-reactive protein, in forty-four patients that received 2 mg DNG/0.02 mg EE (prolonged release) in a regime intake of 24 days followed by four placebos, and forty-seven patients the COC with 0.02 mg EE/3 mg DRSP (immediate release) as a comparative group with the same regimen continuously for nine complete cycles. These patients were a subgroup of 51 patients receiving the prolonged-release formulation with 2 mg DNG/0.02 mg EE and 51 patients receiving 3 mg DRSP/0.02 mg EE of the overall trial. Baseline characteristics of these participants are presented in . The initial patients’ data before and after were obtained for 28 cases for the 0.02 mg EE/2 mg DNG and 30 cases for the control group, respectively. The analysis was intended to show data of at least 30 patients per group. No sample size calculation was performed for these parameters. More details of the overall study can be found elsewhere [Citation16]. Data were evaluated after randomization before starting the intake and after nine months of treatment and are presented as mean ± standard deviations (SD), geometric means (SD, 95% confidence intervals [CI]), medians [minimum – maximum values], or frequencies n (%). Differences were compared using a 2-sample T-test.

Final analysis was performed on those who completed the study, 44 for group DNG/EE, and 47 for the DRSP/EE group. The only significant difference between the beginning of the treatment and the end of treatment was found for AT III. At baseline, the geometric mean values for AT III were 0.88 mg/mL for the prolonged release formulation and 0.87 mg/mL for the comparator (SD, 95% confidence interval [CI], 0.83–0.94) and (SD, 95% CI, 0.81–0.92). Compared to baseline, at the end of the study both groups displayed significantly higher geometric mean for AT III: 1.06 mg/mL (SD, 95% CI, 0.98–1.15) for the DNG/EE formulation and 1.04 mg/mL SD (95% CI, 0.96–1.12) for the comparator (p = 0.0006 and p = 0.0009, respectively). There were no intergroup differences between the two groups regarding the geometric mean ratios, before or after treatment. When looking over the APC resistance ratio, no significant change from baseline to end of treatment was observed for both arms. The geometric mean value in the DNG/EE formulation was 2.61 (SD, 95% CI, 2.33–2.93) before treatment and 2.50 (SD, 95% CI, 2.15–2.90) after nine months (p = 0.6212). Similar results were observed in the comparator group: a geometric mean value of 2.82 (SD, 95% CI, 2.57–3.10) before treatment and a geometric mean of 2.83 (SD, 95% CI, 2.50–3.21) after treatment (p = 0.9629). D-dimer, the following important marker, very often used as a surrogate marker for evaluating the risk of VTE, also showed no change in either group before or after treatment. In the DNG/EE group, the values were 276.62 ng/mL (SD, 95% CI, 228.92–334.26) before treatment, with a slight reduction to 243.98 ng/mL (SD, 95% CI, 192.45–309.31) after nine months. The comparator group displayed a slight rise in the values from 246.46 ng/mL (95% CI, 205.44–295.66) to 275.30 ng/mL (SD, 95% CI, 219.21–345.75). This difference was not statistically significant (p = 0.4520). For all the other three analyzed factors, no significant differences could be observed before and after the 9-month treatment for both groups. Also, the in-between comparative geometric mean values were also not significantly different. depicts all the analyzed values.

It is currently well established that the estrogens in combined hormonal contraceptives are responsible for the elevated risk of thromboembolic events. Epidemiological studies have shown that the progestin component and estrogens may also be involved in the etiology of venous and arterial diseases. This reflects the influence of progestins on the synthesis, release, and activation of pro-and anticoagulatory and fibrinolytic factors on the function of platelets and endothelium and possibly on smooth muscle cells [Citation17]. In 2014, the EMA published data on the VTE risk of different COCs, with an update released in 2018. Combined contraceptives with LNG, norethisterone, and norgestimate have a risk of 5–7 VTE cases/10,000 women/year, and in combination with dienogest, a risk of 8–11, while COCs with the progestins such as desogestrel, gestodene, or drospirenone have a risk of 9–12 VTE cases/10,000 women/year. Non-COC users display a risk of 2 VTE cases/10,000 women/year [Citation18]. Based on the data, the use of COCs leads to a two to four-fold increase in risk for VTE [Citation18,Citation19]. This increase depends on the dosage and type of used estrogen. Estradiol and estradiol valerate are assumed to have a lower impact on liver proteins than EE as they are metabolized more rapidly [Citation20]. Hence, estrogenic compounds generally change the dynamic hemostatic balance and are responsible for the increased cardiovascular risk when using COCs [Citation20]. In contrast, progestins (except for progestins with partial glucocorticoid activity such as medroxyprogesterone-acetate and norethisterone) do not increase the risk of VTE [Citation21,Citation22]. The use of COCs results in an acceleration of coagulation and fibrinolysis, as demonstrated by several authors [Citation17,Citation23,Citation24], by an increase of various markers of haemostasis and fibrin turnover. This is induced by the marked action of EE on hepatic and vascular function, as also documented by the rise of sex hormone binding globulin (SHBG) in an EE dose related manner. Progestins with pronounced androgenic properties, e.g. LNG, may counteract the estrogen-induced changes in the hepatic synthesis of hematological factors, unlike other progestogens with anti-androgenic properties or with neutral androgenic properties may not. Based on the increasing knowledge of the effects of EE on the hemostatic system, it became evident that EE is the triggering factor for the risk of VTE in combined contraceptives. Therefore, efforts have been made to develop new estrogenic compounds with lower pro-coagulatory effects on the hemostatic system. In 2009 and 2011, the estrogens estradiol-valerate (E2V), and 17ß-estradiol (17ß-E2) were marketed [Citation25,Citation26]. E2V was combined with dienogest, as this progestin is known for its strong potency on endometrial activity (high uterotropic index). It was intended to lower spotting and breakthrough bleedings while potentially inhibiting ovulation [Citation27]. Several studies have been published comparing the effects on hemostatic markers of COCs with EE/LNG and/or COCs with E2V/dienogest. A cross-over study that enrolled 29 women and a randomized study with 58 women showed that changes in hemostatic parameters (including Factor VI and VIII, antithrombin, C-reactive protein, APC-resistance, PAI-1 activity, D-dimer as well as fibrinogen levels) were more pronounced in women using COCs with EE/LNG compared to women using COCs with E2V/dienogest. However, these changes were not statistically different; all were within the reference values [Citation27,Citation28]. 17ß-E2 was marketed with nomegestrol acetate (NOMAC) [Citation26]. Two double-blind, randomized trials were performed in France and Finland. The findings showed that the combination of 17ß-E2/NOMAC has less impact on blood coagulation, fibrinolysis, and hemostatic markers than COCs with EE/LNG [Citation29,Citation30]. Therefore, 17ß-E2/NOMAC might have a lower risk profile for VTE than EE/LNG. However, studies with VTE as primary endpoints are still needed to confirm this. As shown before by Schindler et al. [Citation17], desogestrel or LNG used as a progestogen only pill (POP) do not affect the hemostatic system, and they have shown an overall potentially favorable effect on haemostasis. Hemostatic markers are not the only parameters that influence the occurrence of thrombotic events, but they represent a critical component that influences this clinical event. For any 10 IU/dL increment of factor VIII, the risk for a single or recurrent episode of venous thrombosis increases by 10% and 24%, respectively [Citation31]. Platelet count was also performed in our study. No drug-induced immune thrombocytopenia (ITP) case was observed in both treatment groups, suggesting that the observed increase of ITP reported by Garbe et al. [Citation32] in combined DRSP/EE users was due to the estrogen effect. Recently, a study has been published evaluating the effects of a new contraceptive with the combination of estetrol (E4) and DRSP. After six treatment cycles, the changes in haemostasis parameters were slightly less pronounced or comparable to the changes induced by EE/LNG. Compared to EE/DRSP, the changes were similar but more pronounced. The findings support the hypothesis that the estrogen compound of COC is responsible for the differences in haemostasis parameters. E4 did influence the haemostasis parameters and, therefore, the hemostatic balance [Citation33]. The prolonged-release formation containing 2 mg DNG/0.02 mg EE in a 24 + 4 regime over nine months reduced Cmax and prolonged the Tmax of the product in about two hours in comparison to an immediate release formulation and did not affect the investigated hemostatic parameters. Hence, with this formulation the exposure of EE is not only reduced significantly without compromising the bleeding profile at the same time due to the prolonged release formulation. Therefore, this novel COC can be considered neutral regarding potential changes in blood coagulation as there is no effect on the liver-dependent coagulation factor. The only significant difference between the beginning of the treatment and the end of treatment was found for ATIII. Especially the fact that neither the APC resistance ratio nor the D-dimer showed no difference is promising data, even knowing that the examined group of patients may have been too small. Interestingly, this prolonged release product has a more positive balance when compared to the immediate release formulation of 2 mg DNG/0.03 mg EE. Indeed, for the 0.03 mg EE formulation factor VII showed a significant increase from 109.2% to 130.7%. The prolonged release formulation did not have such a negative impact. Also, for the immediate release formulation, C-reactive protein showed a rise from 93.3% to 102.8%, and an increase for D-dimer from 25.8 µg/L to 98.0 µg/L. AT III decreased from 105.3% to 95.7% in the immediate release formulation whilst it increased under the use of the prolonged release formulation. These differences were all statistically significant (with the exception for AT III under the immediate release formulation). No such changes have been observed under the treatment with the 2 mg DNG/0.02 mg EE formulation showing again the neutrality of the innovative formulation in comparison to the 2 mg DNG/0.03 mg EE formulation [Citation34]. Regarding the limitations of this study one can mention the number of investigated patients which was a sub-group set of the original trial (n = 44 for prolonged release and n = 47 for the immediate release formulation). Also, the fact that hemostatic parameters are only possible indicators for the clinical occurrence of thromboembolic events under the use of COCs. Why only AT III showed a difference remains unclear. Nevertheless, the rise in this value can be considered positive as no negative impact is expected due to this change in coagulation and fibrinolysis. The clinical risk of additional thromboembolic events can only be elucidated in large clinical trials and/or post-authorization safety studies especially statistically powered for these events. In conclusion, the COC with 2 mg DNG/0.02 mg EE was not associated with any meaningful changes in the analyzed hemostatic parameters indicating that a prolonged release formulation does not impact on these factors. Authors’ contributions PAR made substantial contributions to the conception of the original trial protocol. Kristina Biskupska-Bodova and Tamas Nyirady were investigators (original data acquisition). PAR, AA, CE analyzed and interpreted the data of this sub-analysis and drafted the content of the present manuscript. All authors revised multiple versions of the manuscript and approved the final version for publication. Acknowledgments Authors thank all participants, investigators and support staff at each trial centre. The authors wish to thank SCOPE International for the management and statistical analysis of the trial. Disclosure statement The authors are employees of Exeltis, member of Insud Pharma. Data availability statement The data underlying this article will be shared upon reasonable request to the corresponding author. Additional information Funding

- Jordan WM, Anand JK. Pulmonary embolism. Lancet. 1961;278(7212):1146–1147. doi: 10.1016/S0140-6736(61)91061-3. - Vessey M, Mant D, Smith A, et al. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J (Clin Res Ed). 1986;292(6519):526–526. doi: 10.1136/bmj.292.6519.526. - Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, et al. The risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen is enhanced by factor V Leiden mutation. Lancet. 1995;346(8990):1593–1596. doi: 10.1016/s0140-6736(95)91929-5. - Gerstman BB, Piper JM, Tomita DK, et al. Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol. 1991;133(1):32–37. doi: 10.1093/oxfordjournals.aje.a115799. - Thorogood M, Mann J, Murphy M, et al. Risk factors for fatal venous thromboembolism in young women: a case-control study. Int J Epidemiol. 1992;21(1):48–52. doi: 10.1093/ije/21.1.48. - Vandenbroucke JP, Koster T, Briët E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344(8935):1453–1457. doi: 10.1016/s0140-6736(94)90286-0. - Effect of different progestagens in low estrogen oral contraceptives on venous thromboembolic disease. World Health Organization collaborative study of cardiovascular disease and steroid hormone contraception. Lancet. 1995;346(8990):1582–1588. - Farmer RD, Lawrenson RA, Thompson CR, et al. Population-based study of the risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997;349(9045):83–88. doi: 10.1016/s0140-6736(96)07496-x. - European Medicines Agency. Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks – CHMP endorses PRAC recommendation. EMA/35464/2014. Available from: https://www.ema.europa.eu/en/documents/referral/benefits-combined-hormonal-contraceptives-chcs-continue-outweigh-risks_en.pdf(open in a new window). - Stegeman BH, de Bastos M, Rosendaal FR, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ. 2013;347(sep12 1):f5298–f5298. doi: 10.1136/bmj.f5298. - Wiegratz I, Kuhl H. Metabolic and clinical effects of progestogens. Eur J Contracept Reprod Health Care. 2006;11(3):153–161. doi: 10.1080/13625180600772741. - Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res. 2010;126(1):5–11. doi: 10.1016/j.thromres.2010.01.045. - Raps M, Helmerhorst F, Fleischer K, et al. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost. 2012;10(6):992–997. doi: 10.1111/j.1538-7836.2012.04720.x. - van Vliet HA, Frolich M, Christella M, et al. Association between sex hormone-binding globulin levels and activated protein C resistance in explaining the risk of thrombosis in users of oral contraceptives containing different progestogens. Hum Reprod. 2005;20(2):563–568. doi: 10.1093/humrep/deh612. - Regidor PA, Schindler AE. Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestins: dienogest and drospirenone. Oncotarget. 2017;8(47):83334–83342. doi: 10.18632/oncotarget.19833. - Biskupska-Bodova K, Sójka-Kupny J, Nyirády T, et al. A randomised double-blind trial to determine the bleeding profile of the prolonged-release contraceptive dienogest 2 mg/ethinylestradiol 0.02 mg versus an immediate-release formulation of drospirenone 3 mg/ethinylestradiol 0.02 mg. Eur J Contracept Reprod Health Care. 2024: 16;1–10. doi: 10.1080/13625187.2024.2398433. - Schindler AE. Differential effects of progestins on hemostasis. Maturitas. 2003;46 Suppl 1(Suppl 1):S31–S37. doi: 10.1016/j.maturitas.2003.09.016. - PRAC referral assessment report. Procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data. Combined hormonal contraceptives containing medicinal products INN: chlormadinone, desogestrel, dienogest, drospirenone, etonogestrel, gestodene, nomegestrol, norelgestromin or norgestimate. Procedure number: EMEA/H/A-31/1356; 2013. - WHO medical eligibility criteria for contraceptive use. 5th ed.; 2015. World Health Organisation - Khialani D, Rosendaal F, Vlieg AvH Hormonal contraceptives and the risk of venous thrombosis. Semin Thromb Hemost. 2020;46(8):865–871. doi: 10.1055/s-0040-1715793. - Lidegaard Ø, Løkkegaard E, Jensen A, et al. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24):2257–2266. doi: 10.1056/NEJMoa1111840. - Lidegaard Ø, Nielsen LH, Wessel Skovlund C, et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and estrogen doses: Danish Cohort Study, 2001-9. BMJ. 2011;343(oct25 4):d6423–d6423. doi: 10.1136/bmj.d6423. - Kuhl H. Effects of progestogens on hemostasis. Maturitas. 1996;24(1–2):1–19. doi: 10.1016/0378-5122(96)00994-2. - Winkler UH. Hormone replacement therapy and hemostasis: principles of a complex interaction. Maturitas. 1996;24(3):131–145. doi: 10.1016/s0378-5122(96)82003-2. - Kiley JW, Shulman LP. Estradiol valerate and dienogest: a new approach to oral contraception. Int J Womens Health. 2011;3:281–286. doi: 10.2147/IJWH.S22645. - Burke A. Nomegestrol acetate-17b-estradiol for oral contraception. Patient Prefer Adherence. 2013;7:607–619. doi: 10.2147/PPA.S39371. - Parke S, Junge W, Mellinger U, et al. Comparative effects of a four-phasic regimen of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel on hemostatic parameters. Hum Reprod. 2008;23(1):i78–i79. doi: 10.1093/humrep/den1049. - Parke S, Nauhm G, Mellinger U, et al. Metabolic effects of a new four-phasic oral contraceptive containing estradiol valerate and dienogest. Obstet Gynecol. 2008;111(Suppl 4):S3–S12. doi: 10.1097/AOG.0b013e3181636fe9. - Ågren UM, Anttila M, Mäenpää-Liukko K, et al. Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol compared with one containing levonorgestrel and ethinylestradiol on hemostasis, lipids, and carbohydrate metabolism. Eur J Contracept Reprod Health Care. 2011;16(6):444–457. doi: 10.3109/13625187.2011.604450. - Gaussem P, Alhenc-Gelas M, Thomas JL, et al. Hemostatic effects of a new combined oral contraceptive, nomegestrol acetate/17β-estradiol, compared with those of levonorgestrel/ethinyl estradiol. A double-blind, randomized study. Thromb Haemost. 2011;105(3):560–567. doi: 10.1160/TH10-05-0327. - Kraaijenhagen R, In ‘t Anker P, Koopman M, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost. 2000;83(01):5–9. doi: 10.1055/s-0037-1613747. - Garbe E, Andersohn F, Bronder E, et al. Drug-induced immune thrombocytopenia: results from the Berlin Case-Control Surveillance Study. Eur J Clin Pharmacol. 2012;68(5):821–832. doi: 10.1007/s00228-011-1184-3. - Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6):396–402. doi: 10.1016/j.contraception.2020.08.015. - Spona J, Feichtinger W, Kindermann C, et al. Double-blind, randomized, placebo controlled study on the effects of the monophasic oral contraceptive containing 30 micrograms ethinyl estradiol and 2.00 mg dienogest on the hemostatic system. Contraception. 1997;56(2):67–75. doi: 10.1016/s0010-7824(97)00094-2.