Combined Oral Contraceptives-induced coagulopathies - Evaluation of the prothrombotic state using a global coagulation assay

Promoters

Prof. Jonathan DOUXFILS, UNamur, Pharmacy department / QUALIblood (industrial promoter)

Prof. Jean-Michel DOGNE, UNamur, Pharmacy department (academic promoter)

Jury

• Prof. Jonathan Douxfils, UNamur / QUALIblood (industrial promoter)
• Prof. Jean-Michel Dogné, UNamur (academic promoter)
• Prof. François Mullier, CHU UCL Namur
• Prof. Bernard Masereel, UNamur
• Prof. Philippe Hainaut, Cliniques universitaires Saint-Luc
• Prof. Ulysse Gaspard, ULiège
• Prof. Jean-Michel Foidart, ULiège / Estetra srl
• Prof. Jean-François Arnal, Université de Toulouse

Summary

Twenty-two thousand cases of thrombosis occur each year in Europe following the use of birth control pills containing an oestrogen derivative and a progestin (and qualified as combined oral contraceptives (COCs)). One of the major challenges for healthcare professionals is to identify women at risk. To this end, several guidelines offer support in tailoring contraception, according to the patient’s profile. However, these strategies rely on epidemiological data and do not allow for an accurate assessment of the risk of venous thromboembolism (VTE) at the individual level.

Recent data has confirmed activated protein C (APC) resistance, a dysregulation of haemostasis, as an independent VTE risk factor. Although several methods for APC resistance (APCR) detection have been developed, the endogenous thrombin potential (ETP)-based APCR assay has proven to be the most suitable for the assessment of COC-induced changes on the coagulation system. Besides, this test is required by the European Medicines Agency as part of the haematological assessment of the thrombogenic profile of new COC preparations. In addition, as the result is presented as a normalized APC sensitivity ratio (nAPCsr) ranging from 0 to 10, result interpretation is very easy: the higher the nAPCsr, the higher the resistance to APC.

The objective of this thesis is to demonstrate the analytical performances of the ETP-based APCR assay as well as its interest in the routine care setting to aspire to the title of biomarker to characterize the VTE risk of women on contraception. 

Although this test was developed more than 20 years ago, it has been underused because the lack of standardization led to an unacceptable variability, hampering the proper evaluation of APCR induced by hormonal therapies in different studies. The first step undeniably consisted in validating the methodology, according to regulatory requirements in terms of analytical performances. To ensure the good reproducibility of the test, we transferred the methodology in two external laboratories to verify that similar results were obtained regardless of the laboratory. Finally, considering its screening potential, the next phase consisted in implementing the ETP-based APCR assay on an automated platform. Indeed, making it available in clinical routine would make the test accessible to prescribers and patients.

In a second step, to illustrate the VTE risk prediction capacities of the nAPCsr, we created exploratory prediction models by combining both the level of APCR (expressed as nAPCsr) for specific COC preparations with their respective VTE relative risk extracted from published epidemiological studies. VTE risk estimated by the models for different birth control pills were similar to those reported in population-based phase IV trials. Actually, these population-based phase IV trials are undertaken following the marketing of a new COC to assess its long-term safety and to identify unusual side effects. In definitive, these models could serve for regulatory purpose since they could permit to avoid waiting almost a decade before positioning on the potential risk of VTE of a particular COC (currently set only at the end of population-based phase IV trials). It may also save time and money for the pharmaceutical companies and the regulators and may facilitate the uptake of innovative compounds for the clinicians by providing reassuring data on the risk of VTE with hormonal therapies.

Lastly, in 2021, a new COC containing 15 mg of estetrol and 3 mg of drospirenone was marketed. The haemostasis profile investigated during the phase II clinical trial revealed a moderate effect of this preparation on the nAPCsr. In agreement with the pharmaceutical company which produces it, we further explored data originating from the ETP-based APCR assay. Thanks to these investigations, we could confirm the lower impact of this new COC on the global coagulation process compared to the most commonly used birth control pills (containing ethinylestradiol as oestrogen derivative).

As a perspective, we are convinced that the nAPCsr has the potential to become a safety biomarker to assess the VTE risk in women on COCs and a surrogate endpoint allowing an in-silico evaluation of the VTE risk profile of new COC preparations before population-based phase IV trials are completed. Starting the procedure of biomarker qualification by the European Medicine Agency will represent the next step. Future research should also focus on the extended use of the nAPCsr. We have already demonstrated that it could be useful in other hormone-induced coagulopathies, such as during pregnancy and in the postpartum period or due to the intake of menopausal replacement therapies or tamoxifen therapy in breast cancer patients. Last but not least, as mentioned in the last ISTH SSC communication, the scope of this test goes beyond hormone-induced prothrombotic states and might be relevant in other pathologies such as haematological cancer and antiphospholipid syndrome.