In this study of DVT cases and healthy controls, exposure to increased concentrations of particulate air pollution in the year before diagnosis was associated with increased DVT risk after controlling for clinical and environmental covariates. PM10 average level before the examination was also correlated with shorter PT in both cases and controls. The DVT risk increase associated with PM10 level was smaller in women and limited to those who were not using oral contraceptives or hormone replacement therapy at the time of diagnosis.
Long-term exposure to particulate air pollution has been associated with increased risk of coronary heart and cerebrovascular disease in multiple investigations conducted in several countries.4
A systemic increase in thrombotic tendency, secondary to the induction of inflammatory mediators produced in the lungs and released in the circulation, or to the translocation of particles of smaller diameter from the lungs into the circulation,6
has been frequently proposed to account for the cardiac and cerebrovascular effects of particulate air pollution. In contrast, venous thrombosis has received little attention in studies on the cardiovascular outcomes of air pollution. In a time-series analysis from the Netherlands, Hoek et al.15
reported an association of short-term exposure to ambient ozone, and to lesser extent to black smoke and PM10
, with increased mortality from embolism and thrombosis, a broad category that included arterial and venous thromboses in various sites. To date, no study has specifically addressed the association between particulate air pollution and DVT. In our population, we estimated an overall 70% increase in DVT risk with each increase of 10 µg/m3
level during the year before diagnosis. For comparison, in the Harvard Six Cities Study the risk of death from cardiopulmonary diseases was 37% higher in the most polluted compared with the least polluted cities.1
In the Women Health Initiative Study, an increase of 10 µg/m3
of annual average concentrations of PM2.5
— which is considered a stronger predictor than PM10
level of air pollution effects — was associated with a 24% increase in the risk of cardiovascular events and a 76% increase in the risk of death from cardiovascular disease.2
The estimated increase in risk of death from all cardiovascular causes associated with 10 µg/m3
in long-term PM2.5
level was 19% in the Harvard Six Cities study and 13% in the American Cancer Society's study.3
In the present study, PM10
exposure did not increase the risk of DVT in women as much as in men. By evaluating additional risk factors, we found that part — if not all — of such risk attenuation was due to the lack of association between PM10
and the risk of DVT among women using oral contraceptives or hormone replacement therapy. Such hormone therapies are independent risk factors for DVT,10
as also confirmed in this study by the higher prevalence of oral contraceptives and hormone replacement use in cases than controls. Use of oral contraceptives and hormone replacement therapy induces changes in coagulation factors, such as increased levels of the procoagulant factors VII, IX, X, XII, XII, von Willebrand factor and fibrinogen, and a reduced level of the anticoagulant proteins antithrombin and protein S, 16–18
that are similar in characteristics and degree to the coagulation changes observed after exposure to air particles. 7, 8, 19–22
We surmise that prothrombotic mechanisms are already activated in hormone users, so that they undergo less or no further induction after air particle exposure.
In our analyses, we evaluated DVT risk in association with the level of PM10
measured during the year before diagnosis. In this study, the use of short term (hourly or daily) air pollution levels would not have been appropriate, because DVT presentation is often subtle and its diagnosis has been shown to lag as long as four weeks after the initial DVT symptoms.23
In the present work, we demonstrated that average PM10
level in the year before the examination was associated with shortened PT, extending our previous observation of an association with shorter exposure time windows.16
Interestingly, while the negative effects of PM10
average levels on PT were rather independent of the time-window selected, the one-year PM10
average was the only exposure metric significantly associated with shortened PT among cases. In addition, while in our previous work we could not find any relation between 30-day average PM10
level and aPTT, a suggestive, though non significant aPTT shortening was observed in association with the one-year PM10
average among controls in the present analysis. Thus, the use of PM10
level in the year before diagnosis appeared to capture a fuller range of prothrombotic effects, while also contributing to reduce the risks of confounding by seasonal patterns and ambient temperature. This study has the advantage of being based on a large number of DVT cases and controls recruited using a standardized protocol over a long time span. Cases had objective diagnoses of DVT, and both cases and controls were well characterized for inherited and acquired risk factors for DVT. In the statistical analysis, we used models that included non-linear regression terms to adjust for long-term time trends and day of the year — thus controlling for confounding from year of the study and seasonal variations —, in addition to age, sex, area of residence, education, factor V Leiden, G20210A prothrombin mutation, use of oral contraceptive or hormone-replacement therapy, body mass index, and ambient temperature.
Healthy controls, also due to their selection among nonblood relatives and friends of the DVT cases, tended to be distributed in the nine study areas with proportions that were very similar to those of the DVT cases. This might have generated overmatching in our study, i.e., the exposure levels of controls may have been more similar to those of DVT cases than they actually are in the population at risk. Therefore, it is possible that risk estimates were underestimated in our study. A limitation of this study is that we used ambient air pollution estimated at the subjects’ address as a surrogate for personal exposure, which may have resulted in measurement error, as most subjects conduct a large part of their daily activities away from their residence. A detailed questionnaire was used to ascertain known risk factors for DVT, but no information was collected concerning daily activities, such as time spent outside or in traffic, that could have refined the assessment of PM10
exposure. In addition, our exposure assessment was done by dividing Lombardia region in nine areas for which average PM10
levels were assigned by averaging measurements from multiple monitors. Although these areas were selected to group together territories with similar population density and geographical characteristics, thus likely reducing within-area variations of the exposure, we were not able to obtain PM10
level estimates at a smaller scale. However, PM10
levels tend to be spatially homogenous and a recent study comparing personal exposures to site monitoring in Boston reported that monitor readings and personal exposure are highly correlated.24
In addition, it has been shown that using ambient measures to estimate individual exposure is likely to produce an underestimation of pollution effects25
rather than causing the increased risk of DVT found in our study population.
In conclusion, this study provides evidence in support of an association of exposure to particulate air pollution with enhanced prothrombotic mechanisms and risk of DVT. Given the magnitude of the observed effects and the widespread diffusion of particulate pollutants, our findings introduce a novel and common risk factor into the pathogenesis of DVT and, at the same time, give further substance to the call for tighter standards and continued efforts aimed at reducing the impact of urban air pollutants on human health.