Blood clot risk factors identified in women

Researchers from Queen Mary University of London have revealed an increased risk of blood clots in women who have any combination of a particular gene mutation, oestrogen use or common medical conditions — specifically obesity, high blood pressure, high cholesterol and kidney disease.

While oestrogen use (both through oral contraception and as part of hormone replacement therapy), the Factor V Leiden (FVL) gene mutation and common medical conditions are all known risk factors of blood clots, previous studies have not looked at the combined risk of these factors together on blood clot prevalence. The researchers sought to remedy this by examining the health data of 20,048 British-Bangladeshi and British-Pakistani women from the Genes & Health project, a large community-based genetics study. Their results were published in the journal iScience.

Women with FVL who had been prescribed oestrogen had more than double the risk of blood clotting compared to women who did not have this mutation — and almost 20% of the women who carry FVL were prescribed oestrogen and had two medical conditions suffered a blood clot. The presence of the FVL gene made a substantial difference to risk, with only around 5% of women taking oestrogen and having two conditions suffering a clotting event.

The study also found that a woman with obesity, high blood pressure, high cholesterol and kidney disease — which is not uncommon in a clinical setting — had an eight times greater chance of blood clotting compared to a woman with none of these conditions. This amounted to roughly one in every six women with the four conditions in the study suffering a blood clot. Three medical conditions meant a five times greater chance of blood clotting, and two medical conditions meant a two times greater chance. One in three women who had the FVL gene mutation and three of the medical conditions examined also suffered a blood clotting event.

“Many women will take oestrogen at some point in their lifetime,” said Dr Emma Magavern, lead author of the study. “Overall, this is very safe and there are far more positives to taking it than negatives when it’s prescribed. But these women may not be aware of the combined risk of their genetics and overall health and how it affects their risk of developing a blood clot, which could be life-threatening for some individuals.

“It’s important that women have all the information they need to make an informed choice. While our results are important for women everywhere, they are especially relevant for South Asian women with multiple existing health conditions.”

Co-author Professor Sir Mark Caulfield added, “Genetic testing of the FVL gene mutation could give a clearer sense of someone’s personalised risk of this potentially fatal complication if they were prescribed oestrogen.”

Separate to the Queen Mary study, a large Danish study recently found that women who use common painkillers known as non-steroidal anti-inflammatory drugs (NSAIDs) — such as ibuprofen, diclofenac and naproxen — alongside hormonal contraception appear to be at a small increased risk of blood clots known as venous thromboembolism (VTE). The risk was greater in women using combined oral contraceptives containing third- or fourth-generation progestins, but smaller in women using progestin-only tablets, implants and coils.

NSAIDs have previously been linked to blood clots, but little is known about whether using NSAIDs influences the risk of VTE in otherwise healthy women using hormonal contraception. To address this, researchers used national medical records to track first time diagnoses of VTE among 2 million women aged 15 to 49 years living in Denmark between 1996 and 2017 with no history of blood clots, cancer, hysterectomy or fertility treatment.

Hormonal contraception was divided into high, medium and low risk, according to their association with VTE based on previous studies. High-risk hormonal contraception included combined oestrogen and progestin patches, vaginal rings and pills containing either 50 mcg oestrogen or third- or fourth-generation progestins. Medium-risk contraception included all other combined oral contraceptives and the medroxyprogesterone injection, while progestin-only tablets, implants and hormone intrauterine devices (coils) were classed as low or no risk. A number of potentially influential factors, such as age, education level, pregnancy history, prior surgery, high blood pressure and diabetes, were also taken into account.

In the study, which was published in The BMJ, NSAIDs were used by 529,704 women while using hormonal contraception. Over an average 10-year monitoring period, 8710 VTE events occurred (2715 pulmonary embolisms and 5995 deep venous thromboses), and 228 (2.6%) women died within 30 days of their diagnosis.

In absolute terms, NSAID use was associated with four extra VTE events per week per 100,000 women not using hormonal contraception, 11 extra events in women using medium-risk hormonal contraception and 23 extra events in women using high-risk hormonal contraception. Among individual NSAIDs, the association was strongest for diclofenac compared with ibuprofen and naproxen.

The researchers acknowledged that their study was observational in nature and so can’t establish cause, and that it was missing information about smoking and obesity, which may have affected the results. Nevertheless, they said it was a large study based on high-quality registry data; that they were able to adjust for a wide range of potentially influential factors; and that the associations persisted after further analysis, suggesting that they are robust.

“Using high-quality, linkable, national registries, this nationwide study adds new knowledge on the risk of a potentially fatal event during concomitant use of two drug classes often prescribed to otherwise healthy women,” the researchers wrote. And while the absolute risk of developing a serious blood clot remains low, even in women using high-risk hormonal contraception, they concluded: “Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.”

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