Air pollution and venous thromboembolism

Although the visible smog of air pollution is concerning, its hidden dangers to human health are even more alarming. In this issue of Blood, Lutsey et al have shown that air pollution is associated with an increased risk of venous thromboembolism (VTE), highlighting yet another health effect of polluted air.¹ The World Health Organization (WHO) reported that in 2019, ≈6.5 million deaths were caused by air pollution.² A wide range of diseases are linked to air pollution, such as ischemic heart disease, stroke, lung cancer, asthma, chronic obstructive pulmonary disease, and diabetes. VTE was not specifically mentioned in the WHO report.

Lutsey et al describe a cohort of 6651 participants, who were recruited into the Multi-Ethnic Study of Atherosclerosis. The participants lived at 6 different sites in various regions of the United States, where fine particulate matter (PM_2.5), oxides of nitrogen (NO_x)_, nitrogen dioxide (NO₂), and ozone (O₃) were measured each fortnight. The numbers of participants were well balanced across the sites and with regard to age, sex, and educational level. Notably, a higher number of White participants than other races/ethnicities were included. In the data analysis, the authors controlled for all relevant baseline characteristics, including body mass index, smoking status, and physical activity, in various models and provided several sensitivity analyses. The participants were followed up for a median of nearly 17 years (2000-2018), and incident VTE was identified through hospital discharge codes. A 1–interquartile range increase in the estimated concentrations of chronic air pollutants, PM_2.5, NO_x, and NO₂, was significantly associated with a higher incidence of VTE, whereas no increased risk was observed for O₃. This association was even more pronounced when patients with cancer-associated VTE were excluded and when the analysis was restricted to the first 10 years of follow-up. The highest hazard ratios, with up to a 2.7-fold (PM_2.5) and 5-fold elevated risk (NO₂), were seen for noncancer VTE within the first 10 years of observation. This is an alarming signal. The elevated risk of VTE is superimposed on the well-known increased risk of cardiovascular events and cardiovascular-related mortality caused by air pollution. In an umbrella review of systematic reviews and meta-analyses, the strength of evidence of long- and short-term exposure to pollutants, like particulate matter (PM) and NO_x, has been supported, as >75% of the meta-analyses found a significant association with all-cause cardiovascular disease mortality and morbidity, along with sufficient evidence for ischemic heart disease and myocardial infarction with long-term exposure.³ 

Why is air pollution so deleterious to our bodies? PM, the best studied component of air pollution, is a mixture of solid and liquid particles in the air that are small enough, as classified by aerodynamic diameter, not to settle out to the Earth's surface under the influence of gravity.⁴ In animal experiments, it has been demonstrated that ultrafine particles can cross through the lungs and enter the circulation, and they can also interact with lung receptors to induce an acute cardiorespiratory response.⁵ Exposure to PM₁₀ and PM_2.5 induces sustained oxidative stress and inflammation.⁶ Elevated levels of inflammatory biomarkers and coagulation parameters (eg, fibrinogen, factor VIII, or D-dimer) are associated with short- or long-term air pollution, as has been demonstrated in several studies, including in the current study.¹ Both inflammation and a prothrombotic state may contribute to the elevated risk of VTE. However, results are inconsistent, and more research is needed to uncover the underlying biological mechanisms that lead to the increased risk of cardiovascular disease, including VTE.

The study by Lutsey et al has certain limitations and strengths. Only hospitalized cases were counted as outcome events, and no differentiation was made between pulmonary embolism and deep vein thrombosis. The strengths include its prospective design, long observation period, and regular measurement of 4 distinct parameters of air pollution. Thus, the study delivers reliable and valuable data on the association between long-term air pollution and incident VTE, which could help to raise awareness and to put the utmost emphasis on improving the air quality globally.

What is the current status of quality standards with regard to air pollution? The WHO recommends a standard of <5 μg/m³ PM_2.5 annually.⁴ However, in most countries, both the standards and the actual levels are much higher. Most of the global population breathes air that exceeds the WHO guideline limits. Recently, in February 2024, the US Environmental Protection Agency set a more rigorous standard for fine particles of primary annual PM_2.5, lowering it from 12 to 9 μg/m³.⁷ Similarly, the Council of the European Union reached a provisional political agreement to bring down the air quality standards from 25 to 10 μg/m³ PM_2.5 and from 40 to 20 μg/m³ NO₂.⁸ There are promising data that lowering PM_2.5 may be associated with a decrease of cardiovascular death; however, a reduction in VTE has not yet been demonstrated.⁹ Most probably, a holistic approach, including change to renewable energy, increased mass transit, increasing green spaces, and reducing urbanization, could be the mitigation strategy to reduce air pollution, counteract climate change, and bring down the risk of cardiovascular diseases, including VTE.¹⁰ 

Conflict-of-interest disclosure: I.P. declares personal fees for lectures and/or participation in advisory boards for Bayer, Bristol Myers Squibb/Pfizer, Rovi, and Sanofi. C.A. declares personal fees for lectures and/or participation in advisory boards for Bayer, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, and Sanofi.