The multiple known risk factors for venous thromboembolism (VTE) in women have for the first time been studied in combination by a team from Queen Mary University of London. The researchers reported that they may each contribute to a cumulative risk profile giving an up to eight-fold increased incidence of VTE for women with multiple risk factors and comorbidities.
The researchers noted that women are frequently prescribed oestrogen for oral contraception or hormone replacement therapy and that this is a known risk factor for blood clots. So is factor V Leiden (FVL), a genetic variant characterised by a single nucleotide polymorphism in the F5 gene (1691G>A substitution), which leads to a prothrombotic state that has a synergistic increase in VTE risk with exogenous estrogen use.
But although oestrogen use, FVL, and various common medical conditions are all known risk factors for VTE, studies have not looked at the combined risk of these factors together. Therefore the team used data from 20,048 British-Bangladeshi and British-Pakistani women from the Genes & Health project, a large community-based genetics study set up to investigate why South Asian people in the UK are vulnerable to high rates of heart disease, diabetes, and poor health.
Although Asian populations have lower prevalence of the FVL allele than European ancestry populations, this cohort experiences high rates of cardio-metabolic morbidity, the researchers said, and many women are likely to be exposed to exogenous estrogen across their lifetime.
Multiple Factors Increase VTE Risk Independently and Together
Their paper, published in iScience, revealed increased risks of VTE in women with any combination of oestrogen use, FVL, obesity, hypertension, dyslipidaemia, and kidney disease.
At least one copy of the FVL mutation was carried by 2.8% of the women and imparted an odds ratio (OR) for VTE of 2.2 (95% CI 1.4-3.3, p 0.0002). Oestrogen use was reported by 30% of the cohort and carried an OR of 1.3 (1.1-1.7, p 0.01). Each of four comorbidities — but not diabetes mellitus — imparted an increased risk of VTE: obesity, OR 1.5 (1.2–1.9, p 0.0001), hypertension OR 1.8(1.3–2.4, p < 0.0001), dyslipidemia OR 1.7 (1.3–2.2, 0.0002), and chronic kidney disease OR 2.0 (1.5–2.7, p < 0.0001).
VTE risk increased with increasing number of these comorbidities:
- One condition OR 1.6 (1.2-2.0, p 0.001)
- Two conditions OR 2.7 (2.0-3.7, p <0.0001)
- Three conditions OR 5.3 (3.8-7.4, p <0.0001)
- Four conditions OR 8.1 (4.9 – 13.0, p <0.0001)
A woman with obesity, high blood pressure, high cholesterol, and kidney disease — "which is not uncommon in a clinical setting", the researchers noted — had an eight-fold greater risk of VTE than a woman with none of these conditions, with around one in every six women with all four conditions also having VTE.
Risk Factors Operate in Dose-dependent Manner
All the risk factors examined were associated independently with higher VTE prevalence, and the risks were amplified in a dose-dependent fashion by the presence of an increasing number of factors. So, for example, women with the FVL gene mutation who had been prescribed oestrogen had more than double the risk of VTE compared with women who did not have the mutation (4.6% vs. 2.1%, p 0.047, OR 2.2, 95% CI 0.9–4.9).
The risk of multimorbidity was compounded by both oestrogen and VTL, so almost one in five women carrying FVL who had been prescribed oestrogen and had two medical conditions had sustained a VTE. The FVL gene made a substantial difference to this risk, with only around 5% of women taking oestrogen and having two conditions suffering a clotting event in the absence of FVL. However, the risk with FVL plus oestrogen plus three of the co-morbidities rose further, with one in three of these women having had a blood clotting event.
Combined Risk of Genetics and Health "Could be Life-threatening"
Lead author Dr Emma Magavern said: "Many women will take oestrogen at some point in their lifetime. 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."
Co-author Sir Mark Caulfield, professor of clinical pharmacology at Queen Mary University of London, said that the study gave a more complete picture of blood clotting risk in Bangladeshi and Pakistani communities, which had previously been underrepresented in research. "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."
Asked to comment by Medscape News UK, Professor Beverley Hunt, founder and trustee of Thrombosis UK, and consultant in thrombosis and haemostasis at Guy's and St Thomas' NHS Foundation Trust, said: "This study gives information about the risks of blood clots and points out that a combination of risk factor increased the risks of blood clots. It is a reminder for those with risk factors to stay slim, active, and follow a good diet."