Anticoagulation therapy in the context of women’s health

May 10, 2024August 16, 2024 Danielle Norton

Background: Anticoagulants are frequently prescribed medications. In Ireland, direct oral anticoagulants are the anticoagulants of choice in most cases but vitamin K antagonists still have a vital role to play, especially in the management of patients with metallic heart valves and antiphospholipid syndrome. Anticoagulants remain high risk medications (https://ipu.ie/wpcontent/uploads/2022/03/highrisk-medicines.pdf). Women face specific and evolving bleeding and thrombotic challenges throughout their lives (Figure 1.)

Women and Iron deficiency: The WHO estimate that ~half a billion women worldwide aged 15-49 are anaemic. In 2019 30% of non-pregnant women and 37%of pregnant women in this age group were anaemic and the most common cause of this anaemia was iron deficiency (www. who.int/news-room/fact-sheets/ detail/anaemia). During this period, women have an increased requirement for iron in the form of menstruation and pregnancy. Iron supplementation outside of dietary sources is not always easy to tolerate so once you become iron deficient, it can be difficult to resolve. This is important in the context of anticoagulation as if you know menstruating women are commonly anaemic at baseline, putting on a treatment that leads to increased and prolonged bleeding is only likely to make things worse.

Heavy menstrual bleeding (HMB): HMB is common and can be caused by structural issues (e.g. polyps, leiomyomas, malignancy or adenomyosis) or non-structural issues (e.g. anovulatory cycles, medications, coagulopathy); (Samuelson Bannow B et al. Res Pract Thromb Haemost. 2021 Aug). Consequences of HMB include iron deficiency +/- anaemia, impaired quality of life, missing school/work, missed doses of anticoagulation due to fear of HMB and missing out on social activities and sport. A 2015 European survey (Fraser IS et al. Int J Gynaecol Obstet. 2015 Mar) found that ~27% of the women surveyed had experienced 2 or more HMB symptoms in the previous year; 46% of these women had never consulted a physician about it. 7% of the respondents completed an extended survey – 63% of these women had been diagnosed with iron deficiency or iron deficiency anaemia but only 46% had been prescribed supplementation. To identify menstrual problems, it’s important to know what is normal. A normal cycle length is 21-35 days with each cycle lasting 2-7 days and a median blood loss of 57ml/cycle. HMB is a loss of > 80mls/cycle or excessive menstrual blood loss that interferes with a woman’s physical, social, emotional, or material quality of life. It is important to identify if a woman has an underlying menstral disorder prior to starting them on anticoagulation as we know that anticoagulation is likely to make things worse. About 2/3 of women on anticoagulation experience heavy menstrual bleeding and almost ¾ of women on rivaroxaban (De Crem N et al. Thromb Res. 2015 Oct).

Table 1. Clinical Features of Heavy Menstrual Bleeding

Changing sanitary products more than every 2 hours or requiring double protection

Leaking or soaking through clothing or needing to change sanitary products overnight Periods lasting >7 days

Passing clots >2.8cm (1.1 inch)

When trying to assess if a women has an underlying menstrual disorder, Table 1 contains some things to ask women about.

Starting a menstruating women on anticoagulation: It is good practice to try to address 4 issues when starting a menstruating women on anticoagulation. (Figure 2.)

This is particularly important if a patient is going to be on indefinite anticoagulation. If a women has underlying menstrual disorders, they may need further investigations such as imaging or a review by a gynaecologist or haematologist. Different anticoagulants have different risk of menorrhagia so agent choice is important. If a women has always had HMB and sinister causes have been out-ruled, it is better to consider measures early to ameliorate the issue rather than risk the woman experiencing significant bleeding. Ensuring that women are iron replete is vital as you are lowering their bleeding threshold so you want to ensure they have some reserve. In general, a multifaceted approach works best.

Anticoagulant choice: Rivaroxaban appears to be associated with the highest rates of menorrhagia, when compared with apixaban, dabigatran or warfarin (Samuelson Bannow B et al. Res Pract Thromb Haemost. 2021) – see Table 2. Quality of life is also differently impacted (Patel JP et al. Res Pract Thromb Haemost. 2023). The ongoing randomized MEDEA (Hamulyák EN et al. Res Pract Thromb Haemost. 2020 Dec) study will hopefully provide further evidence to guide agent choice in the future.

Concurrent medications: It is important to review a patients regular medications to look for drug-drug interactions as well as those that may increase the bleeding risk. Co-prescription of antiplatelet agents increases the risk of bleeding. The prescription of an anticoagulant may negate the need for an antiplatelet agent. Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly prescribed antidepressant medications. Many of the haemostatic functions of platelets are mediated through serotonin so SSRIs potentially can make the haemostatic function of platelets less effective and increase the bleeding risk (Ann Med. 2022 Dec). Over the counter medications such as non-steroidal anti-inflammatory drugs (NSAIDs) are also important to ask about as they also have an antiplatelet effect. It may not be possible to stop these medications but at least you can flag that the patient may be at a higher risk for bleeding and counsel them regarding this.

Hormonal therapy: The combined oral contraceptive pill (COCP) is associated with an increased risk of venous thrombosis. Women are prescribed it for many reasons, including contraception, HMB, acne, endometriosis, polycystic ovarian syndrome, dysmenorrhoea, cycle regulation. It is important to find out what the indication for the COCP was when you are considering if it should continue or be changed to an alternative. Whatever their indication, it is reassuring the note that if a women is on therapeutic anticoagulation, then their risk of recurrent VTE appears similar if they are on oestrogen containing therapies or no hormonal therapy (Martinelli I et al. Blood. 2016 Mar). Therefore, if a woman is remaining on anticoagulation, they can stay on the COCP but if they are stopping anticoagulation, an alternative needs to be found. Different modalities have different levels of efficacy in terms of contraception thrombosis risk and amenorrhoea rates (DeLoughery E et al. Hematology Am Soc Hematol Educ Program. 2022 Dec). Exploring these factors allows clinicians to counsel women about the most appropriate modality for them.

Tranexamic acid (TXA): TXA is an antifibrinolytic agent which stops the breakdown of clots. A Danish historical prospective cohort study attempted to estimate the risk of thrombosis in women aged 15-49, not on anticoagulation with a standard risk of thrombosis. They looked at data on 2 million women followed for 13.8 million person years. The incidence of venous thrombosis appeared to be increased but the number of women who needed to get a 5 day course of TXA to cause harm was >78,000 (Meaidi A et al. EClinicalMedicine. 2021). There was no increased risk of thrombosis in the high risk patients recruited to the CRASH2 and WOMAN studies which is reassuring. It is frequently used in the prevention and management of bleeding in patients with bleeding disorders. It is not well studied in patients with thrombosis or on anticoagulation. A survey of clinicians’ prescribing habits showed that there is often a reluctance to use it in the acute setting, with 1/3 of those surveyed never prescribing it in the first 3 months and 46% very concerned with the risk of progression or recurrence. (Abdulrehman J et al. Thromb Res. 2024 Jan).

Conclusion: It’s important to be both frank and open when starting a woman on anticoagulation. Heavy Menstrual Bleeding is common, especially in woman on anticoagulation. Women are often reluctant to talk about it without prompting. Discussing where they are at present in terms of menstruation and their past experiences will help you predict how they will be on anticaogulation. If they are anaemic or iron deficient, this is a good time to address it.

Anticoagulation stewardship is an emerging movement focusing on the appropriate use of anticoagulants, which persist in being high risk medications despite the availability of newer agents. Choosing the correct agent, following consideration of patient and disease factors, at the correct dose, for an appropriate duration should ensure maximum efficacy with the minimal amount of harm.

Educational resource: The team in Kings College hospital have developed a short educational video for patients entitled ‘anticoagulants and your periods’ which is freely available on youtube https: //youtu.be/ kAIirzFVFKc?si=IrSfQUGvygKQcZDS