Original Articles
Vol. 1 No. 3 (2022)
Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: 2 June 2022
Accepted: 10 October 2022
Accepted: 10 October 2022
1037
Views
322
Downloads
Authors
Antithrombin, protein C and S defects are well-recognized inherited risk factors for venous thromboembolism (VTE). Although these defects have been reported to increase the risk of VTE in fertile women under combined oral contraceptives (COCs), the magnitude of this association is uncertain. In a sub-analysis of a prospective cohort study, we evaluated the incidence of VTE occurring during treatment with COCs in fertile women who were family members of a proband with an objectively diagnosed VTE event and a documented defect of antithrombin, protein C or S. Of the 197 women of child-bearing age from 88 families who qualified for this analysis in a 17-year period, 112 (57%) were carriers of an inherited defect (23 antithrombin, 41 protein C and 48 protein S), whereas the remaining 85 were free from these abnormalities. Estrogen-progestin therapy was used by 19 of the 112 (17%) carriers of inherited thrombophilia for an overall period of 276 months, and by 17 of the 85 (20%) non-carriers for an overall period of 992 months. VTE events developed in 12 of the 19 (63%) carriers, leading to a monthly event rate of 4.3% (95% CI: 2.2 to 7.6), and in 2 of the 17 (12%) non-carriers, leading to a monthly rate of 0.2% (95% CI: 0.02 to 0.7), for a relative risk of 21 (95% CI, 4.7 to 92). Among family members of probands with inherited defects of antithrombin, protein C or S defects, the use of estrogen-progestin therapy in carriers of these abnormalities results in a risk of VTE events that is more than 20 times as high as that expected in non-carriers. Accordingly, the systematic screening for thrombophilia in these families has the potential to identify those subjects in whom this kind of hormonal treatment should be strongly discouraged.
Downloads
Download data is not yet available.
Citations
Lidegaard A, Lakkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:2890. DOI: https://doi.org/10.1136/bmj.b2890
de Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014;3:CD010813. DOI: https://doi.org/10.1002/14651858.CD010813.pub2
Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135. DOI: https://doi.org/10.1136/bmj.h2135
van Vlijmen EF, Wiewel-Verschueren S, Monster TB, Meijer K. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2016;14:1393-403. DOI: https://doi.org/10.1111/jth.13349
Tormene D, Guerra L, Gavasso S, et al The incidence of VTE in asymptomatic carriers of a deficiency of at PC OR PS: a prospective cohort study. XXV Congress of the International Society on Thrombosis and Haemostasis and 61st Annual SSC Meeting. 20-25 June 2015. Toronto, Canada.
Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999;81:198-202. DOI: https://doi.org/10.1055/s-0037-1614442
Simioni P, Tormene D, Manfrin D, et al. Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol 1998;103:1045-50. DOI: https://doi.org/10.1046/j.1365-2141.1998.01112.x
van Vlijmen EF, Brouwer JL, Veeger NJ, et al. Oral contraceptives and the absolute risk of venous thromboembolism in women with single or multiple thrombophilic defects: results from a retrospective family cohort study. Arch Intern Med 2007;167:282-9. DOI: https://doi.org/10.1001/archinte.167.3.282
Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-93. DOI: https://doi.org/10.1016/S0140-6736(95)91928-7
Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001;323:131-4. DOI: https://doi.org/10.1136/bmj.323.7305.131
van Vlijmen EF, Veeger NJ, Middeldorp S, et al. The impact of a male or female thrombotic family history on contraceptive counseling: a cohort study. J Thromb Haemost 2016;14:1741-8. DOI: https://doi.org/10.1111/jth.13393
Hugon-Rodin J, Horellou MH, Conard J, et al. Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism. Thromb Haemost 2018;118:922-8. DOI: https://doi.org/10.1055/s-0038-1641152
Dinger J. COCs containing dienogest and 30 µg ethinylestradiol may carry a higher VTE_risk compared to corresponding preparations with levonorgestrel: A metaanalysis of four large cohort studies. Front Womens Health 2020;5:175. DOI: https://doi.org/10.15761/FWH.1000175
Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005;3:459-64. DOI: https://doi.org/10.1111/j.1538-7836.2005.01197.x
Lussana F, Dentali F, Abbate R, et al. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009;124:e19-25. DOI: https://doi.org/10.1016/j.thromres.2009.06.031
How to Cite
1.
Tormene D, Campello E, Simion C, Poretto A, Prandoni P, Simioni P. Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study. Bleeding Thromb Vascul Biol [Internet]. 2022 Nov. 3 [cited 2025 Nov. 10];1(3). Available from: https://www.btvb.org/btvb/article/view/42
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Share
Similar Articles
- Nadim Tawil, Lata Adnani, Janusz Rak, Coagulome and tumor microenvironment: impact of oncogenes, cellular heterogeneity and extracellular vesicles , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. s1 (2024)
- PO46 | Intravitreal treatment with faricimab in patients with age-related macular degeneration , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- CS06 | Patient specific iPSCs-derived sinusoidal endothelial cells for phenotypic correction of haemophilia A , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- PO96 | Patient management with arteriovenous thrombotic manifestation and hemorrhagic complications , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Bianca Clerici, Mariangela Scavone, Gian Marco Podda, Recent advances in classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, spontaneous HIT, and vaccine-induced immune thrombotic thrombocytopenia , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- Silvia Linari, Renato Marino, Marzia Leotta, Antonio Coppola, Patrizia Di Gregorio, Augusto Bramante Federici, Flora Peyvandi, Cristina Santoro, Ezio Zanon, Rita Carlotta Santoro, The landscape of rare coagulation factor deficiency management in Italy: a national hemophilia center survey , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. 3 (2025)
- Paolo Simioni, Vittorio Pengo, Paolo Prandoni, Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 3 (2022)
- Francesco Cicconi, Ankle brachial index for the diagnosis of asymptomatic lower extremity peripheral arterial disease , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- CO39 | Artificial intelligence in hemophilia management: challenging the need for experts , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Daniela Poli, Riccardo Tartaglia, Doris Barcellona , Paolo Bucciarelli , Antonio Ciampa, Elvira Grandone, Giuseppe Malcangi, Giuseppe Rescigno, Vincenzo Toschi, Sophie Testa, Alessandro Squizzato, Attitude to clinical research among health professionals affiliated with the Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 1 (2023)
You may also start an advanced similarity search for this article.
Most read articles by the same author(s)
- Paolo Prandoni, Franca Bilora, Raffaele Pesavento, Giorgina Salgueiro, Angeles Blanco-Molina, Raquel Lòpez-Reyes, Manuel Monreal, and the RIETE Investigators, Treatment of venous thromboembolism in pregnancy: findings from the RIETE Registry , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 2 (2022)
- Samantha Pasca, Cristina Santoro, Chiara Ambaglio, Marisanta Napolitano, Marta Milan, Letizia Natali, Silvia Nannizzi, Filippo Mori, Paolo Simioni, Ezio Zanon, Comparison among three different bleeding scores and the thrombin generation assay to assess the different hemorrhagic phenotypes in patients with FVII deficiency , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 2 (2022)
- Paolo Simioni, Vittorio Pengo, Paolo Prandoni, Thrombosis and hemostasis at the University of Padua: a reappraisal on the occasion of its 800th year of history , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 3 (2022)
- Paolo Prandoni, New perspectives for prevention of the post-thrombotic syndrome , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 1 (2022)
- Paolo Prandoni, Personalized bleeding risk assessment for atrial fibrillation patients on direct oral anticoagulants: the DOAC score , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Gualtiero Palareti, Paolo Prandoni, Cristina Legnani, Emilia Antonucci, Serena Zorzi, Alberto Tosetto, Lorenza Bertù, Sophie Testa, Vittorio Pengo, Walter Ageno, Ida Martinelli, Benilde Cosmi, Eugenio Bucherini, Daniela Poli, Rationale and design of a study on D-dimer use to stratify patients after a first unprovoked venous thromboembolism for their risk of recurrence: extended low-dose Apixaban given only to patients with positive D-dimer results , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 1 (2022)
- Anna Poretto, Elisabetta Borella, Giacomo Turatti, Michelangelo Marobin, Elena Campello, Daniela Tormene, Paolo Simioni, Luca Spiezia, Association between non-O blood type and early unexplained recurrent spontaneous abortion in women with and without inherited thrombophilia , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 3 (2022)
- Giovanni Di Minno, Gaia Spadarella, Ilenia Lorenza Calcaterra, Giancarlo Castaman, Paolo Simioni, Raimondo De Cristofaro, Cristina Santoro, Flora Peyvandi, Matteo Di Minno, The evolving landscape of gene therapy for congenital severe hemophilia: a 2024 state of the art , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- Giuseppe Camporese, Paolo Prandoni, Walter Ageno, Aspirin or low-molecular weight heparin for thromboprophylaxis after a fracture? That is the question , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
