How to Reduce the Risk of Venous Thromboembolism in Users of Combined Hormonal Contraceptives?

Risk of Thromboembolism with the Use of Sex Hormones

The use of COCs carries an increased risk of first occurrence of venous thromboembolism (VTE) with a hazard ratio (HR) of 3.5 (95% confidence interval [CI] 2.9–4.3). This risk may further increase with preparations containing higher doses of estrogen (> 30 μg ethinylestradiol) and progestins other than levonorgestrel.^{1, 2}

The mechanism by which hormone therapy (COCs or hormone replacement therapy) leads to an increased risk of VTE is not fully explained. It has been observed that hormone therapy increases thrombin formation and D-dimer levels and also affects the regulation of endothelial function. Some studies suggest an influence of estrogens on the expression of extracellular matrix metalloproteinases of the vascular wall.¹

Risk factors increasing VTE risk include the following:

• Chronic diseases: Some autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, idiopathic inflammatory bowel diseases) or chronic congestive heart failure are associated with a moderate VTE risk. Antiphospholipid syndrome is associated with a high risk,¹ whereas diabetes is associated with a low VTE risk (HR 1.35 according to a meta-analysis of epidemiological studies with over 800 million individuals).³
• Smoking: A meta-analysis of data from over 700,000 individuals without cardiovascular disease or VTE at the start of monitoring estimated the VTE risk of smoking at an HR of 1.38.⁴
• Obesity: Considered a weaker risk factor for VTE, obesity may cause thrombosis based on higher activity of adipocytokines such as leptin and adiponectin, which increase coagulation activity, support inflammatory processes, and reduce fibrinolytic cascade activity.¹
• Individual genetic risk factors, which we will discuss in more detail below.

Genetic Risks of VTE

Many gene variants associated with an increased risk of VTE have been found. The most common include the so-called Leiden mutation in the gene for coagulation factor V (F5 Leiden; present in about 5% of the white population) and the G20210A mutation in the gene for prothrombin (F2; present in about 2% of the white population). The risk of the first occurrence of VTE in heterozygous carriers of these mutations is increased by approximately 4–8 times, while in homozygotes, the relative risk is up to 30–80 times.⁵

Several studies have demonstrated the synergistic effect of thrombophilic mutations and COCs. In these women, the resulting risk of VTE occurrence can be 34–45 times higher.⁵ Of 2,613 women treated for VTE in a Paris university hospital, 15.9% had the F5 Leiden mutation, and 69% used COCs.⁶

Identifying Women with Hereditary Thrombophilia – an Unmet Medical Need?

Although the World Health Organization (WHO) considers the administration of COCs to women with thrombophilic mutations an unacceptable health risk, it does not recommend universal screening before starting COCs due to the low prevalence of these mutations and the high cost of testing.⁵

In the Czech Republic, insurance companies cover screening for the Leiden mutation in high-risk patients – women with a positive personal history of thromboembolic disease or a positive family history in first-degree relatives in connection with the prescription of COCs. The condition for coverage is the indication by an authorized physician (gynecologist, clinical geneticist) with a demonstrable justification for the examination.⁷

Screening Pays Off

A cost-benefit analysis recently carried out in the Czech Republic examined the prevalence of thrombophilic mutations (the F5 Leiden and the F2 gene mutation for prothrombin) identified by digital droplet polymerase chain reaction (ddPCR) in a sample of 148 students from Ostrava University (20% of whom smoked).

The F5 mutation was confirmed in 6 women (4.1%), and the F2 mutation in 3 women (2%). Based on this data, researchers created a model that estimated that universal screening of 50,000 women who begin using COCs annually in the Czech Republic, assuming maximum compliance (i.e., not using COCs and quitting smoking), could prevent 68 VTE cases over the average duration of COC use (5.7 years). The cost of testing this cohort was estimated at $2.25 million, while the savings associated with VTE treatment would reach $16 million.⁸

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Sources:
1. Pastori D., Cormaci V. M., Marucci S. et al. A comprehensive review of risk factors for venous thromboembolism: from epidemiology to pathophysiology. Int J Mol Sci 2023 Feb 5; 24 (4): 3169, doi: 10.3390/ijms24043169.
2. de Bastos M., Stegeman B. H., Rosendaal F. R. et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014 Mar 3; (3): CD010813, doi: 10.1002/14651858.CD010813.pub2.
3. Bai J., Ding X., Du X. et al. Diabetes is associated with increased risk of venous thromboembolism: a systematic review and meta-analysis. Thromb Res 2015; 135 (1): 90–95, doi: 10.1016/j.thromres.2014.11.003.
4. Gregson J., Kaptoge S., Bolton T. et al. Cardiovascular risk factors associated with venous thromboembolism. JAMA Cardiol 2019; 4 (2): 163–173, doi: 10.1001/jamacardio.2018.4537. 
5. Douxfils J., Morimont L., Bouvy C. Oral contraceptives and venous thromboembolism: focus on testing that may enable prediction and assessment of the risk. Semin Thromb Hemost 2020; 46 (8): 872–886, doi: 10.1055/s-0040-1714140.
6. Hugon-Rodin J., Horellou M. H., Conard J. et al. Type of combined contraceptives, factor V Leiden mutation and risk of venous thromboembolism. Thromb Haemost 2018; 118 (5): 922–928, doi: 10.1055/s-0038-1641152.
7. Otázky týdne. Vyšetření na Leidenskou mutaci. Všeobecná zdravotní pojišťovna ČR, 5. 12. 2022. Available from: www.vzp.cz/o-nas/tiskove-centrum/otazky-tydne/vysetreni-na-leidenskou-mutaci
8. Riedlová P., Kramná D., Ostřížková S. et al. Examination of in factor V Leiden and prothrombin II thrombophilic mutations in Czech young women using ddPCR – prevalence and cost-benefit analysis. Healthcare (Basel) 2021; 9 (12): 1656, doi: 10.3390/healthcare9121656.