A series of clinical observations of venous thrombosis in women taking combined oral contraceptives
DOI:
https://doi.org/10.15574/HW.2025.5(180).95100Keywords:
venous thromboembolism, combined oral contraception, factor V Leiden, hypercoagulation, activated partial thromboplastin time, risk of thrombosisAbstract
Aim - to analyze the issue of comprehensive assessment of the risk of venous thromboembolism (VTE) when prescribing combined hormonal contraceptives (CHCs), to determine the significance of genetic, clinical and laboratory risk factors, including thrombophilias and other indicators of hemostasis, and to justify approaches to individual decision-making regarding the safe use of CHCs.
The article analyzes the issues of comprehensive assessment of the risk of VTE when prescribing CHCs. It is justified that the patient's clinical characteristics - efficacy and tolerability - are not sufficient; the risk of VTE should be taken into account, in particular, taking into account genetic factors such as factor V Leiden mutation, anticoagulant deficiencies: antithrombin, protein C and S; other laboratory indicators of hemostasis. It has been shown that the presence of a heterozygous Leiden mutation increases the risk of VTE by 30 times, and homozygous - up to 100 times when taking combined hormonal contraception. In cases with existing “severe” thrombophilia (antithrombin, protein C and S deficiency), try to avoid the use of combined oral contraceptives with ethinylestradiol. At the same time, the absence of hereditary thrombophilia does not eliminate the risk of thrombosis, namely situational factors, such as increased levels of clotting factors, a shortened activated partial thromboplastin time due to being overweight, smoking, varicose veins of the lower extremities, or prolonged immobilization increases the likelihood of VTE. The author emphasizes that the decision to use hormonal contraception should be based on a comprehensive individual assessment of thrombotic risk, taking into account genetic, clinical and laboratory factors and suggests evaluating the activated partial thromboplastin time as a simple, accessible, and fairly informative screening test before prescribing contraceptives.
The study was conducted in accordance with the principles of the Declaration of Helsinki. The informed consent was obtained from all participants.
The author declares no conflict of interest.
References
Ahrendt HJ, Makalova D, Parke S, Mellinger U, Mansour D. (2009). Bleeding Pattern and Cycle Control With an Estradiol-Based Oral Contraceptive: A Seven-Cycle, Randomized Comparative Trial of Estradiol Valerate/Dienogest and Ethinyl Estradiol/Levonorgestrel. Contraception. 80: 436-444. https://doi.org/10.1016/j.contraception.2009.03.018; PMid:19835717
Blanco-Molina MA, Lozano M, Cano A, Cristobal I, Pallardo LP, Lete I. (2012). Progestin-Only Contraception and Venous Thromboembolism. Thromb Res. 129: e257-e262. https://doi.org/10.1016/j.thromres.2012.02.042; PMid:22425318
Bonnar J. (1987). Coagulation Effects of Oral Contraception. Am J Obstet Gynecol. 157: 1042-1048. https://doi.org/10.1016/S0002-9378(87)80129-1; PMid:2960241
Cosmi B, Legnani C, Bernardi F, Coccheri S, Palareti G. (2003, Aug 11-25). Role of Family History in Identifying Women With Thrombophilia and Higher Risk of Venous Thromboembolism During Oral Contraception. Arch Intern Med. 163(9):1105-9. doi: 10.1001/archinte.163.9.1105. Erratum in: Arch Intern Med. 163(15): 1778. https://doi.org/10.1001/archinte.163.9.1105; PMid:12742811
Dahlbäck B. (1994). Physiological Anticoagulation: Resistance to Activated Protein C and Venous Thromboembolism. J Clin Invest. 94: 923-927. https://doi.org/10.1172/JCI117458; PMid:8083377 PMCid:PMC295127
Hannaford PC. (2011). Epidemiology of the Contraceptive Pill and Venous Thromboembolism. Thromb Res. 127: S30-S34. https://doi.org/10.1016/S0049-3848(11)70009-3; PMid:21262435
Hematology. (2024). Estrogen, progestin, and beyond: thrombotic risk and contraceptive choices. ASH Education Program. 2024(1): 644-651. https://doi.org/10.1182/hematology.2024000591; PMid:39644023 PMCid:PMC11665608
Hotoleanu C. (2017). Genetic Risk Factors in Venous Thromboembolism. Adv Exp Med Biol. 906: 253-272. https://doi.org/10.1007/5584_2016_120; PMid:27638626
Inman WHW, Vessey MP, Westerholm B, Engelund A. (1970). Thromboembolic Disease and the Steroidal Content of Oral Contraceptives: A Report to the Committee on Safety of Drugs. Br Med J. 2: 209-209. https://doi.org/10.1136/bmj.2.5703.203; PMid:5443406 PMCid:PMC1700093
Jordan WM, Anand JK. (1961). Pulmonary Embolism. Lancet. 278: 1146-1147. https://doi.org/10.1016/S0140-6736(61)91061-3
Khialani D, le Cessie S, Lijfering WM, Cannegieter SC, Rosendaal FR, van Hylckama Vlieg A. (2020). The Joint Effect of Genetic Risk Factors and Different Types of Combined Oral Contraceptives on Venous Thrombosis Risk. Br J Haematol. 191: 90-97. https://doi.org/10.1111/bjh.16666; PMid:32342502 PMCid:PMC7586802
Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. (1995). Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep vein thrombosis. Lancet. 345: 152-155. https://doi.org/10.1016/S0140-6736(95)90166-3; PMid:7823669
Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briet E, Vandenbroucke JP. (1994). Factor VII and fibrinogen levels as risk factors for venous thrombosis: a case-control study of plasma levels and DNA polymorphism. The Leiden Thrombophilia Study (LETS). Thromb Haemost. 71: 719-722. https://doi.org/10.1055/s-0038-1642511; PMid:7974338
Kyrle PA, Minar E, Hirschl M et al. (2000). High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. New Engl J Med. 343: 457-462. https://doi.org/10.1056/NEJM200008173430702; PMid:10950667
Mannucci PM, Franchini M. (2015). Classic Thrombophilic Gene Variants. Thromb Haemost. 114: 885-889. https://doi.org/10.1160/TH15-02-0141; PMid:26018405
Meade TW, Haines AP, North WRS, Chakrabarti R, Howarth DJ, Stirling Y. (1977). Haemostatic, Lipid, and Blood-Pressure Profiles of Women on Oral Contraceptives Containing 50 µg or 30 µg Oestrogen. Lancet. 2(8045): 948-951. https://doi.org/10.1016/S0140-6736(77)90888-1; PMid:72289
Meijers JCM, Tekelenburg WLH, Bouma BN, Bertina RM, Rosendaal FR. (2000). High levels of factor XI as a risk factor for venous thrombosis. New Eng J Med. 342: 696-701. https://doi.org/10.1056/NEJM200003093421004; PMid:10706899
Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton D et al. (2023). American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv. 22: 7101-7138. https://doi.org/10.1182/bloodadvances.2023010177; PMid:37195076 PMCid:PMC10709681
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. (1996). A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thrombosis. Blood. 88: 3698-3703. https://doi.org/10.1182/blood.V88.10.3698.bloodjournal88103698; PMid:8916933
Rayamajhi S, Lopez Capa GS, Ligia CFR, Sunkara V et al. (2024). Massive Pulmonary Embolism Associated With Factor V Leiden Mutation in a Young Female on Oral Contraceptive Pills. Thromb Haemost. 16(6): e62451. https://doi.org/10.7759/cureus.62451
Stadel B. (1981). Oral Contraceptives and Cardiovascular Disease (First of Two Parts). N Engl J Med. 305: 612-618. https://doi.org/10.1056/NEJM198109103051104; PMid:7022208
Suchon P, Al Frouh F, Henneuse A, Ibrahim M, Brunet D, Barthet MC et al. (2016). Risk Factors for Venous Thromboembolism in Women Under Combined Oral Contraceptive. The Pill Genetic Risk Monitoring (PILGRIM) Study. Thromb Haemost. 115: 135-142. https://doi.org/10.1160/TH15-01-0045; PMid:26290123
Tripodi A, Chantarangkul V, Martinelli I, Bucciarelli P, Mannucci PM. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood. 2004 Dec 1;104(12):3631-4. Epub 2004 Aug 5. https://doi.org/10.1182/blood-2004-03-1042; PMid:15297315
United Nations, Department of Economic and Social Affairs, Population Division. (2019). Contraceptive Use by Method. 2019: Data Booklet (ST/ESA/SER.A/435).
Van Hylckama A, van der Linden IK, Bertina RM, Rosendaal FR. (2000). High levels of factor IX increases the risk of venous thrombosis. Blood. 95: 3678-3682. https://doi.org/10.1182/blood.V95.12.3678
Van Vlijmen EFW, Wiewel-Verschueren S, Monster TBM, Meijer K. (2016). Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 14(7): 1393-1403. https://doi.org/10.1111/jth.13349; PMid:27121914
Vessey MP, Inman WHW. (1973). Speculation About Mortality Trends From Venous Thromboembolism Disease in England and Wales and Their Relation to the Pattern of Oral Contraceptive Usage. J Obstetrics Gynaecology Br Commonwealth. 80: 562-566. https://doi.org/10.1111/j.1471-0528.1973.tb15981.x; PMid:4720533
Wessler S, Gitel SN, Wan LS, Pasternack BS. (1976). Estrogen-Containing Oral Contraceptives Agents: A Basis for Their Thrombogenicity. JAMA. 236: 2179-2182. https://doi.org/10.1001/jama.1976.03270200017021; PMid:989807
Wiegratz I, Kuhl H. (2006). Metabolic and Clinical Effects of Progestogens. Eur J Contracept Reprod Health Care. 11: 153-161. https://doi.org/10.1080/13625180600772741; PMid:17056444
Zeun S, Lu M, Uddin A, Zeiler B, Morrison D, Blode H. (2009). Pharmacokinetics of an Oral Contraceptive Containing Oestradiol Valerate and Dienogest. Eur J Contracept Reprod Health Care. 14: 221-232. https://doi.org/10.1080/13625180902850039; PMid:19565420
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Ukrainian Journal Health of Woman
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The policy of the Journal UKRAINIAN JOURNAL «HEALTH OF WOMAN» is compatible with the vast majority of funders' of open access and self-archiving policies. The journal provides immediate open access route being convinced that everyone – not only scientists - can benefit from research results, and publishes articles exclusively under open access distribution, with a Creative Commons Attribution-Noncommercial 4.0 international license (СС BY-NC).
Authors transfer the copyright to the Journal UKRAINIAN JOURNAL «HEALTH OF WOMAN» when the manuscript is accepted for publication. Authors declare that this manuscript has not been published nor is under simultaneous consideration for publication elsewhere. After publication, the articles become freely available on-line to the public.
Readers have the right to use, distribute, and reproduce articles in any medium, provided the articles and the journal are properly cited.
The use of published materials for commercial purposes is strongly prohibited.
