Didembourg, Marie

Dogne, Jean-Michel

Douxfils, Jonathan

Foidart, Jean-Michel

Morimont, Laure

English

Repository of the University of Namur

Correlation Between Activated Protein C Resistance And The Relative Risk Of Venous Thromboembolism In Women Using Hormonal Therapy

RESEARCH OUTPUTS / RÉSULTATS DE RECHERCHEAuthor(s) - Auteur(s) :Publication date - Date de publication :Permanent link - Permalien :Rights / License - Licence de droit d’auteur :Bibliothèque Universitaire Moretus PlantinInstitutional Repository - Research PortalDépôt Institutionnel - Portail de la Rechercheresearchportal.unamur.beUniversity of NamurCorrelation between activated protein C resistance and the relative risk of venousthromboembolism in women using hormonal therapyMorimont, Laure; Didembourg, Marie; Foidart, Jean-Michel; Dogne, Jean-Michel; Douxfils,JonathanPublication date:2022Link t  publicationCitation for pulished version (HARVARD):Morimont, L, Didembourg, M, Foidart, J-M, Dogne, J-M & Douxfils, J 2022, 'Correlation between activatedprotein C resistance and the relative risk of venous thromboembolism in women using hormonal therapy', 16thESC congress, Ghent, Belgium, 25/05/22 - 28/05/22.General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 12. Oct. 2022RESULTSMATERIALS & METHODSINTRODUCTION & AIMCorrelation between activated protein C resistance and the relative risk of venous thromboembolism in women using hormonal therapy§ The frequent use of estrogens, alone or associated with progestins, throughout a woman’s life, exposes to an increased risk of venous thromboembolism (VTE). § Identifying one or several biomarkers to dress the “coagulability status” of patients before and during the course of hormonal therapy would be important to minimize the thrombotic risk. § The endogenous thrombin potential (ETP)-based activated protein C (APC) resistance assay could be a potential candidate as it is significantly impacted by the use of combined oral contraceptives (COCs) and hormone replacement therapies. The aim of this study was to assess the VTE risk prediction capacities of the normalized APC sensitivity ratio (nAPCsr), the score frequently used to express APC resistance.§ Two in silico-modeling were computed by combining both the nAPCsr for specific COC preparations with their respective VTE relative risk (RR) issued from the Danish cohort study of Lidegaard (2011) and the Cochrane network meta-analysis of de Bastos (2014). § nAPCsr values were obtained retrospectively from 147 women’s samples. § The different COC subgroups, their respective nAPCsr values and the associated RR of VTE are reported in Table 1.These prediction models are only exploratory and further investigations and validation are needed. However, these data support the concept that the nAPCsr could become a universal test to assess the hormone-induced risk of VTE in women on hormonal contraceptionThis study was financed by QUALIblood s.a. and by the Brussels-Wallonia federation (convention no. 8031)References§ M. de Bastos, B.H. Stegeman, F.R. Rosendaal, A. Van HylckamaVlieg, F.M. Helmerhorst, T. Stijnen, and O.M. Dekkers, Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev (2014) CD010813§ Lidegaard, O., Nielsen, L. H., Skovlund, C. W., Skjeldestad, F. E. & Lokkegaard, E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423, doi:10.1136/bmj.d6423 (2011).§ Douxfils J, Klipping C, Duijkers I, Kinet V, Mawet M, Maillard C, Jost M, Rosing J, Foidart JM. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6):396-402. COI§ J-M Foidart is a member of the board at Mithra Pharmaceuticals.§ J. Douxfils is CEO and founder of QUALIblood and reports personal fees from Daiichi-Sankyo, Diagnostica Stago, DOASense, Gedeon Richter, Mithra Pharmaceuticals, Norgine, Portola.SUMMARY / CONCLUSIONACKNOWLEDGEMENTSREFERENCES / COITable 1: Mean normalized APC sensitivity ratio (nAPCsr) and standard deviations (SD) depending on the type of combined oralcontraceptives (COC) and their respective relative risk (RR) [95%CI] of venous thromboembolism (VTE) issued from the study ofLidegaard and from the meta-analysis of de Bastos. .§ As shown in Figure 1, exponential growth equations best fit the correlations between nAPCsr and the RR of VTEdepending on the type of COC (either based on the study of Lidegaard or the meta-analysis of de Bastos).§ R squared of both correlations were above 0.95.§ Out of 34 women using the new combination estetrol/drospirenone, the mean nAPCsr was 2.28.§ By intrapolation, this new association might express a RR of 1.37 (0.86-1.89) based on the study of Lidegaard ora RR (95% CI) of 1.29 (0.61-1.96) based on the meta-analysis of de Bastos.§ This is in line with data obtained so far in which estetrol 15 mg, associated with drospirenone 3 mg, shows apromising hemostatic profile compared to the other COCs.Laure.morimont@qualiblood.euContact informationL. MORIMONT 1,2 , M. DIDEMBOURG 2, J-M. FOIDART 3,4, J-M. DOGNE 2, J. DOUXFILS 1,21QUALIblood sa, Namur, Belgium 2University of Namur, Department of Pharmacy, Clinical Pharmacology Research Group, Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium 3Estetra SRL, an affiliate Company of Mithra Pharmaceuticals, Liège, Belgium4Department of Obstetrics and Gynecology, University of Liège, Liège, Belgium Subgroups nAPCsr VTE risk (Lidegaard) VTE risk (de Bastos)Mean SD RR 95%CI RR 95%CIWomen w/o COC (n=41) 1.68 0.88 1.00 - 1.00 -EE 30 µg + LNG 150 µg (n=33) 3.75 1.43 2.19 1.74 to 2.75 2.40 1.80 to 3.20 EE 20 µg + LNG 100 µg (n=15) 4.09 1.53 - - 2.20 1.30 to 3.60EE 20 µg + DSG 150µg (n=11) 4.45 1.38 3.26 2.88 to 3.69 3.40 2.50 to 4.60EE 30 µg + DSG 150 µg (n=5) 5.40 0.63 4.21 3.63 to 4.87 4.30 3.30 to 5.60EE 20 µg + GSD 75 µg (n=5) 4.60 0.87 3.50 3.09 to 3.97 - -EE 35 µg + CPA 2 mg (n=3) 5.10 0.80 4.10 3.37 to 4.99 3.90 2.70 to 5.50E4 15 mg + DRSP 3 mg (n=34) 2.28 0.93 1.37* 0.86 to 1,89* 1.29* 0.61 to 1.96*Acronyms: CPA, cyproterone acetate ; DRSP, drospirenone ; DSG, desogestrel ; EE, ethinylestradiol ; E4, estetrol ; GSD, gestodene ; LNG, levonorgestrel0 2 4 60246nAPCsrVTE RR - de BastosNo COC (n=41)EE 30 + LNG 150 (n=33)EE 20 + LNG 100 (n=15)EE 20 + DSG 150 (n=11)EE 30 + DSG 150 (n=5)R2 = 0.96E4 15 + DRSP 3 (n=34) Intrapolated VTE RR: 1.29 (95% CI: 0.61 - 1.96)EE 35 + CPA 2 (n=3)0 2 4 60246nAPCsrVTE RR - Lidegaard - all eventsNo COC (n=41)EE 20 + LNG 100 (n=15)EE 20 + DSG 150 (n=11)EE 30 + DSG 150 (n=5)R2 = 0.98EE 20 + GSD 75 (n=5)E4 15 + DRSP 3 (n=34) Intrapolated VTE RR: 1.37 (95% CI: 0.86 - 1.89)EE 35 + CPA 2 (n=3)Figure 1: Correlation between nAPCsr values and the relative risk (RR) of VTE (Lidegaard, 2011 on the left and de Bastos, 2014 on the right) for different combined oral contraceptives* Intrapolated VTE risk 

Correlation between activated protein C resistance and the relative risk of venous thromboembolism in women using hormonal therapy

RESEARCH OUTPUTS / RÉSULTATS DE RECHERCHEAuthor(s) - Auteur(s) :Publication date - Date de publication :Permanent link - Permalien :Rights / License - Licence de droit d’auteur :Bibliothèque Universitaire Moretus PlantinInstitutional Repository - Research PortalDépôt Institutionnel - Portail de la Rechercheresearchportal.unamur.beUniversity of NamurCorrelation between activated protein C resistance and the relative risk of venousthromboembolism in women using hormonal therapyMorimont, Laure; Didembourg, Marie; Foidart, Jean-Michel; Dogne, Jean-Michel; Douxfils,JonathanPublication date:2022Link t  publicationCitation for pulished version (HARVARD):Morimont, L, Didembourg, M, Foidart, J-M, Dogne, J-M & Douxfils, J 2022, 'Correlation between activatedprotein C resistance and the relative risk of venous thromboembolism in women using hormonal therapy', 16thESC congress, Ghent, Belgium, 25/05/22 - 28/05/22.General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.            • Users may download and print one copy of any publication from the public portal for the purpose of private study or research.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying the publication in the public portal ?Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 03. Jul. 2022RESULTSMATERIALS & METHODSINTRODUCTION & AIMCorrelation between activated protein C resistance and the relative risk of venous thromboembolism in women using hormonal therapy§ The frequent use of estrogens, alone or associated with progestins, throughout a woman’s life, exposes to an increased risk of venous thromboembolism (VTE). § Identifying one or several biomarkers to dress the “coagulability status” of patients before and during the course of hormonal therapy would be important to minimize the thrombotic risk. § The endogenous thrombin potential (ETP)-based activated protein C (APC) resistance assay could be a potential candidate as it is significantly impacted by the use of combined oral contraceptives (COCs) and hormone replacement therapies. The aim of this study was to assess the VTE risk prediction capacities of the normalized APC sensitivity ratio (nAPCsr), the score frequently used to express APC resistance.§ Two in silico-modeling were computed by combining both the nAPCsr for specific COC preparations with their respective VTE relative risk (RR) issued from the Danish cohort study of Lidegaard (2011) and the Cochrane network meta-analysis of de Bastos (2014). § nAPCsr values were obtained retrospectively from 147 women’s samples. § The different COC subgroups, their respective nAPCsr values and the associated RR of VTE are reported in Table 1.These prediction models are only exploratory and further investigations and validation are needed. However, these data support the concept that the nAPCsr could become a universal test to assess the hormone-induced risk of VTE in women on hormonal contraceptionThis study was financed by QUALIblood s.a. and by the Brussels-Wallonia federation (convention no. 8031)References§ M. de Bastos, B.H. Stegeman, F.R. Rosendaal, A. Van HylckamaVlieg, F.M. Helmerhorst, T. Stijnen, and O.M. Dekkers, Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev (2014) CD010813§ Lidegaard, O., Nielsen, L. H., Skovlund, C. W., Skjeldestad, F. E. & Lokkegaard, E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423, doi:10.1136/bmj.d6423 (2011).§ Douxfils J, Klipping C, Duijkers I, Kinet V, Mawet M, Maillard C, Jost M, Rosing J, Foidart JM. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6):396-402. COI§ J-M Foidart is a member of the board at Mithra Pharmaceuticals.§ J. Douxfils is CEO and founder of QUALIblood and reports personal fees from Daiichi-Sankyo, Diagnostica Stago, DOASense, Gedeon Richter, Mithra Pharmaceuticals, Norgine, Portola.SUMMARY / CONCLUSIONACKNOWLEDGEMENTSREFERENCES / COITable 1: Mean normalized APC sensitivity ratio (nAPCsr) and standard deviations (SD) depending on the type of combined oralcontraceptives (COC) and their respective relative risk (RR) [95%CI] of venous thromboembolism (VTE) issued from the study ofLidegaard and from the meta-analysis of de Bastos. .§ As shown in Figure 1, exponential growth equations best fit the correlations between nAPCsr and the RR of VTEdepending on the type of COC (either based on the study of Lidegaard or the meta-analysis of de Bastos).§ R squared of both correlations were above 0.95.§ Out of 34 women using the new combination estetrol/drospirenone, the mean nAPCsr was 2.28.§ By intrapolation, this new association might express a RR of 1.37 (0.86-1.89) based on the study of Lidegaard ora RR (95% CI) of 1.29 (0.61-1.96) based on the meta-analysis of de Bastos.§ This is in line with data obtained so far in which estetrol 15 mg, associated with drospirenone 3 mg, shows apromising hemostatic profile compared to the other COCs.Laure.morimont@qualiblood.euContact informationL. MORIMONT 1,2 , M. DIDEMBOURG 2, J-M. FOIDART 3,4, J-M. DOGNE 2, J. DOUXFILS 1,21QUALIblood sa, Namur, Belgium 2University of Namur, Department of Pharmacy, Clinical Pharmacology Research Group, Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium 3Estetra SRL, an affiliate Company of Mithra Pharmaceuticals, Liège, Belgium4Department of Obstetrics and Gynecology, University of Liège, Liège, Belgium Subgroups nAPCsr VTE risk (Lidegaard) VTE risk (de Bastos)Mean SD RR 95%CI RR 95%CIWomen w/o COC (n=41) 1.68 0.88 1.00 - 1.00 -EE 30 µg + LNG 150 µg (n=33) 3.75 1.43 2.19 1.74 to 2.75 2.40 1.80 to 3.20 EE 20 µg + LNG 100 µg (n=15) 4.09 1.53 - - 2.20 1.30 to 3.60EE 20 µg + DSG 150µg (n=11) 4.45 1.38 3.26 2.88 to 3.69 3.40 2.50 to 4.60EE 30 µg + DSG 150 µg (n=5) 5.40 0.63 4.21 3.63 to 4.87 4.30 3.30 to 5.60EE 20 µg + GSD 75 µg (n=5) 4.60 0.87 3.50 3.09 to 3.97 - -EE 35 µg + CPA 2 mg (n=3) 5.10 0.80 4.10 3.37 to 4.99 3.90 2.70 to 5.50E4 15 mg + DRSP 3 mg (n=34) 2.28 0.93 1.37* 0.86 to 1,89* 1.29* 0.61 to 1.96*Acronyms: CPA, cyproterone acetate ; DRSP, drospirenone ; DSG, desogestrel ; EE, ethinylestradiol ; E4, estetrol ; GSD, gestodene ; LNG, levonorgestrel0 2 4 60246nAPCsrVTE RR - de BastosNo COC (n=41)EE 30 + LNG 150 (n=33)EE 20 + LNG 100 (n=15)EE 20 + DSG 150 (n=11)EE 30 + DSG 150 (n=5)R2 = 0.96E4 15 + DRSP 3 (n=34) Intrapolated VTE RR: 1.29 (95% CI: 0.61 - 1.96)EE 35 + CPA 2 (n=3)0 2 4 60246nAPCsrVTE RR - Lidegaard - all eventsNo COC (n=41)EE 20 + LNG 100 (n=15)EE 20 + DSG 150 (n=11)EE 30 + DSG 150 (n=5)R2 = 0.98EE 20 + GSD 75 (n=5)E4 15 + DRSP 3 (n=34) Intrapolated VTE RR: 1.37 (95% CI: 0.86 - 1.89)EE 35 + CPA 2 (n=3)Figure 1: Correlation between nAPCsr values and the relative risk (RR) of VTE (Lidegaard, 2011 on the left and de Bastos, 2014 on the right) for different combined oral contraceptives* Intrapolated VTE risk 

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Correlation between activated protein C resistance and the relative risk of venous thromboembolism in women using hormonal therapy

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