Venous thromboembolism (VTE) refers to blood clots that develop in the veins [1]. The two most common manifestations of VTE are deep vein thrombosis (DVT) and pulmonary embolism (PE) [1]. DVT is when a blood clot develops in a deep vein, and PE occurs when a clot breaks loose, travels through the bloodstream, and lodges in the lungs [1].

VTE occurs in both men and women, and can occur throughout their lives [2]. However, the estimated lifetime risk for VTE in women, especially during their reproductive years, is higher than in men [2].

The incidence of VTE

The global incidence of VTE in the general population is estimated to be 1-2 per 1000 persons each year, 3 or 10 million cases of VTE per year [4]. However, there is still a paucity of data for definitively determining the incidence of VTE, specifically in women.

Until recently, the occurrence of VTE in the Asian population was thought to be lower than in Caucasians. However, studies suggest that this may be due to an underestimation of VTE in Asia because of the underdiagnosis and under-reporting [5,6]. With better awareness that VTE is an issue in the Asian population, and improved diagnosis, the reported number of VTE cases appears to increase [5].

Risk factors for VTE in women

The risk factors for VTE in women are similar to that of the general population, except that they increase during their reproductive years [1,2].

Hormonal therapies prescribed to women—notably combined oral contraceptives (COC) and hormone replacement therapies (HRT)—have demonstrated effects on coagulation and increased the risk of VTE 2-4-fold compared to non-users. They have been shown to induce an acquired resistance to activated protein C, which is required for the production of a naturally occurring anti-coagulant, protein S. In addition, the hormone combinations in COC and HRT increase certain clotting factors (prothrombin, factors VII, VIII and X) and reduce other naturally occurring anti-coagulants (antithrombin) [8,9].

Hormonal therapies have also been associated with accentuating the effect of inherited thrombophilia (a genetic condition that increases blood hypercoagulability) [9,11]. The common types of thrombophilia are factor V Leiden, protein C deficiency, protein S deficiency, and antithrombin deficiency [11].

The risk of developing VTE in women who are on hormonal therapy or pregnant is shown in the tables below. As inherited thrombophilia is rare, screening for them is not recommended. However, testing, is recommended for women who are asymptomatic relatives of carriers of severe thrombophilia (factor V Leiden) [12].

70-80% of VTE episodes during pregnancy are DVT in the lower limbs, and 43-60% of PE episodes occur during the first 6 weeks postpartum [8].

Other factors that increase the risk of VTE in women may include lack of movement during recovery from major surgeries; large-untreated varicose veins; cancer and treatment for cancer; heart conditions and stroke; family history of VTE; obesity; smoking; and alcohol consumption.

Assessing VTE risk in Asian populations

The availability of lower-risk COCs and reduction of HRT prescription has helped, in part, to reduce the risk of VTE in women at risk. However, the potential complex interplay of other risk factors and the inherent risks of pregnancy requires the development of comprehensive and localised guidelines for the Asia-Pacific region.

As an example, the Singaporean guidelines modified the Royal College of Obstetricians and Gynaecologists to reflect the higher rates of potent thrombophilia in the Asian population, incorporated ages >35 years old as a risk factor for post-partum VTE, included guidance on epidural administration in patients at risk of VTE, and modified treatment regimens to fit the local population.

How is VTE diagnosed?

VTE (DVT) is diagnosed mainly by medical history and physical examination, though laboratory tests also play a role. The key diagnostic modalities are as follows:

• Clinical assessment – typically via the Wells scoring system, a pre-test probability scoring system that is based on clinical features [6]
• D-dimer tests – D-dimer is a fibrin-related degradation product that is typically elevated in VTE. However, it is also elevated in infection, malignancy, pregnancy, surgery, trauma, and stroke. As such, the value of testing for D-dimer lies in its ability to exclude the presence of VTE when used in combination with the Wells scoring system [6]
• Ultrasound – to identify DVT [1]
• Computed tomography – to identify clots in the legs (DVT) and lungs (PE) [1]

VTE risk assessment tool for women

There are various tools in the form of questionnaires that can be used to assess the risk of VTE in women. Some of the questions within these assessment tools include questions on:

Prevention of VTE in women

Prevention of VTE (thromboprophylaxis) for women who are not pregnant is similar to the treatment for men. Prophylaxis is given to those undergoing high-risk surgeries, depending on the bleeding risk [6].

For pregnant women, the anticoagulant of choice for prophylaxis is LMWH. The timing of prophylaxis treatment will depend on the risk assessment scores. Those with a higher risk are started with prophylaxis once pregnancy is confirmed, while those with a lower risk are started from 28 weeks of pregnancy (3rd trimester) [13]. Women who need prophylaxis during pregnancy will also require the same for at least 6 weeks post-delivery.

Treatment for VTE in women

The treatment for VTE in women, except in pregnancy, is similar to the treatment for men. The mainstay treatment is the use of anticoagulants like heparin, low molecular weight heparin (LMWH), vitamin K antagonists, and direct oral anticoagulants (DOAC). Of these, LMWH and DOACs have a lower risk of bleeding.

For VTE during pregnancy, LMWH is the anticoagulant of choice. Anticoagulants are given in therapeutic doses for the duration of pregnancy and up to 6 weeks postpartum, for a minimum of 3 months. While on treatment, VTE risk scoring should be repeated before dose reduction or cessation of treatment [13].

References: 

[1] National Heart, Lung, and Blood Institute. What is venous thromboembolism. Available at: https://www.nhlbi.nih.gov/health/venous-thromboembolism. Accessed October 2022.

[2] Arnesen CAL, Veres K, Horváth-Puhó E, Hansen JB, Sørensen HT, Brækkan SK. Estimated lifetime risk of venous thromboembolism in men and women in a Danish nationwide cohort: impact of competing risk of death. Eur J Epidemiol. Feb 2022;37(2):195-203. doi:10.1007/s10654-021-00813-w.

[3] Scheres LJJ, Lijfering WM, Cannegieter SC. Current and future burden of venous thrombosis: Not simply predictable. Res Pract Thromb Haemost. Apr 2018;2(2):199-208. doi:10.1002/rth2.12101.

[4] World Thrombosis Day. Open your eyes to venous thromboembolism (VTE). Available at: https://www.worldthrombosisday.org/issue/vte/#:~:text=Every%20year%2C%20there
%20are%20approximately%2010%20million%20cases%20of%20VTE%20worldwide. Accessed October 2022.

[5] Lee LH, Gallus A, Jindal R, Wang C, Wu CC. Incidence of Venous Thromboembolism in Asian Populations: A Systematic Review. Thromb Haemost. Dec 2017;117(12):2243-2260. doi:10.1160/th17-02-0134.

[6] Wang KL, Yap ES, Goto S, Zhang S, Siu CW, Chiang CE. The diagnosis and treatment of venous thromboembolism in asian patients. Thromb J. 2018;16:4. doi:10.1186/s12959-017-0155-z.

[7] National Blood Clot Alliance. Women and blood clots risk timeline. Available at: https://www.stoptheclot.org/news/may-is-womens-health-month/. Accessed October 2022.

[8] de Oliveira A, Paschôa AF, Marques MA. Venous thromboembolism in women: new challenges for an old disease. J Vasc Bras. Jul 6 2020;19:e20190148. doi:10.1590/1677-5449.190148.

[9] Jacobsen AF, Sandset PM. Venous thromboembolism associated with pregnancy and hormonal therapy. Best Pract Res Clin Haematol. Sep 2012;25(3):319-32. doi:10.1016/j.beha.2012.07.006.

[10] Sennström M, Rova K, Hellgren M, et al. Thromboembolism and in vitro fertilization – a systematic review. Acta Obstet Gynecol Scand. Sep 2017;96(9):1045-1052. doi:10.1111/aogs.13147.

[11] National Health Services (United Kingdom). Thrombophilia. Available at: https://www.nhs.uk/conditions/thrombophilia/. Accessed October 2022.

[12] Gialeraki A, Valsami S, Pittaras T, Panayiotakopoulos G, Politou M. Oral Contraceptives and HRT Risk of Thrombosis. Clin Appl Thromb Hemost. Mar 2018;24(2):217-225. doi:10.1177/1076029616683802.

[13] Academy of Medicine Singapore, College of Obstetricians & Gynaecologists Singapore, Chapter of Haematologists College of Physicians Singapore. Venous thrombolism in pregnancy – Recommendation for prevention, treatment and investigation. March 2021. Available at: https://www.ams.edu.sg/view-pdf.aspx?file=media%5C6016_fi_257.pdf&ofile=CPS-COGS+VTE+Consensus+Statement+2021+0326.pdf. Accessed October 2022.