Fine particulate: it matters.

Abstract

See also Bonzini M, Tripodi A, Artoni A, Tarantini L, Marinelli B, Bertazzi PA, Apostoli P, Baccarelli A. Effects of inhalable particulate matter on blood coagulation. This issue, pp 662–8; Dales RE, Cakmak S, Vidal CB. Air pollution and hospitalization for venous thromboembolic disease in Chile. This issue, pp 669–74. See also Bonzini M, Tripodi A, Artoni A, Tarantini L, Marinelli B, Bertazzi PA, Apostoli P, Baccarelli A. Effects of inhalable particulate matter on blood coagulation. This issue, pp 662–8; Dales RE, Cakmak S, Vidal CB. Air pollution and hospitalization for venous thromboembolic disease in Chile. This issue, pp 669–74. Inland Belgium and the river Po plain of Northern Italy are among the European areas with the highest air pollution, caused mainly by automobile traffic and, to a lesser extent, by stationary sources of domestic combustion for heating purposes. Several studies have been published on the relationship between air pollution and the activation of hemostasis and thrombosis, which stem from experimental studies in animals from Leuven [1Nemmar A. Hoylaerts M.F. Nemery B. Effects of particulate air pollution on hemostasis.Clin Occup Environ Med. 2006; 5: 865-81PubMed Google Scholar] and clinical studies in humans from Milan [2Franchini M. Mannucci P.M. Short‐term effects of air pollution on cardiovascular diseases: outcomes and mechanisms.J Thromb Haemost. 2007; 5: 2169-74Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. In this issue of the Journal, epidemiologists from Canada and Chile report their data from a South American study [3Dales R.E. Cakmak S. Vidal C.B. Air pollution and hospitalization for venous thromboembolic disease in Chile.J Thromb Haemost. 2010; 8: 669-74Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Santiago is a large and densely populated metropolitan area of Central Chile, shielded from the cleaning effect of winds on air pollution by the Andes mountain range that rises nearly 7000 m above the plain upon which Santiago is located. It has been known for a long time from an array of epidemiological studies that air pollution – and particularly the finest particulate matter (PM, of 10 nm or less aerodynamic diameter) and the closely associated gaseous pollutant nitrogen dioxide (NO2) – causes several adverse effects on human health. First, and most importantly, air pollution increases overall mortality. Several studies carried out in different metropolitan areas demonstrate, consistently and unequivocally, that acute short‐term increases of as little as 10 μg per mm3 in airborne particles (a degree of increases that occurs very frequently during the year in many metropolitan areas of Europe and the USA) cause a daily increase in death rates that is very close to the impressively high figure of 1% [4Schwartz J. Particulate air pollution and daily mortality in Detroit.Environ Res. 1991; 56: 204-13Crossref PubMed Scopus (195) Google Scholar, 5Pope III, C.A. Schwartz J. Ransom M.R. Daily mortality and PM10 pollution in Utah Valley.Arch Environ Health. 1992; 47: 211-7Crossref PubMed Scopus (544) Google Scholar]. For instance, it has been calculated that of approximately 10 000 deaths that occur in Milan each year, as many as 200 of those must be attributable to air pollution. This dramatic and acute increase in mortality has multiple causes. Lung complications provide an important causal contribution, particularly in smokers and in persons with chronic obstructive pulmonary disease. However, it has become increasingly evident that atherothrombotic diseases such as myocardial infarction and ischemic stroke have a prominent mechanistic role in the increase of mortality rate and hospital admissions associated with the degree of exposure to air pollution [6Pope III, C.A. Burnett R.T. Thurston G.D. Thun M.J. Calle E.E. Krewski D. Godleski J.J. Cardiovascular mortality and long‐term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease.Circulation. 2004; 109: 71-7Crossref PubMed Scopus (2112) Google Scholar, 7Delfino R.J. Sioutas C. Malik S. Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health.Environ Health Perspect. 2005; 113: 934-46Crossref PubMed Scopus (740) Google Scholar, 8Bhatnagar A. Environmental cardiology: studying mechanistic links between pollution and heart disease.Circ Res. 2006; 99: 692-705Crossref PubMed Scopus (350) Google Scholar]. Several potential mechanisms have been postulated to cause the increase in atherothrombotic events, such as activation of inflammatory pathways, production of reactive oxygen species and alterations in vascular tone [6Pope III, C.A. Burnett R.T. Thurston G.D. Thun M.J. Calle E.E. Krewski D. Godleski J.J. Cardiovascular mortality and long‐term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease.Circulation. 2004; 109: 71-7Crossref PubMed Scopus (2112) Google Scholar, 7Delfino R.J. Sioutas C. Malik S. Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health.Environ Health Perspect. 2005; 113: 934-46Crossref PubMed Scopus (740) Google Scholar, 8Bhatnagar A. Environmental cardiology: studying mechanistic links between pollution and heart disease.Circ Res. 2006; 99: 692-705Crossref PubMed Scopus (350) Google Scholar, 9Mills N.L. Tornqvist H. Robinson S.D. Gonzalez M. Darnley K. MacNee W. Boon N.A. Donaldson K. Blomberg A. Sandstrom T. Newby D.E. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis.Circulation. 2005; 112: 3930-6Crossref PubMed Scopus (522) Google Scholar]. In addition, a study conducted in an animal model showed that fine particulate matter and the gaseous pollutant, NO2, accelerate the development of atherosclerosis [10Sun Q. Wang A. Jin X. Natanzon A. Duquaine D. Brook R.D. Aguinaldo J.‐.G.S. Fayad Z.A. Fuster V. Lippmann M. Chen L.C. Rajagopalan S. Long‐term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model.JAMA. 2005; 294: 3003-10Crossref PubMed Scopus (670) Google Scholar]. It is likely that heightened thrombus formation over atherosclerotic plaques is an important mechanistic player, and is supported by the close temporal relationship between short‐term peaks of pollutants and concomitant increases in acute thrombotic events such as myocardial infarction and ischemic stroke. Several studies have demonstrated an activation of the hemostatic system upon acute exposure to air pollutants [1Nemmar A. Hoylaerts M.F. Nemery B. Effects of particulate air pollution on hemostasis.Clin Occup Environ Med. 2006; 5: 865-81PubMed Google Scholar, 2Franchini M. Mannucci P.M. Short‐term effects of air pollution on cardiovascular diseases: outcomes and mechanisms.J Thromb Haemost. 2007; 5: 2169-74Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 11Franchini M. Mannucci P.M. Particulate air pollution and cardiovascular risk: short‐term and long‐term effects.Semin Thromb Hemost. 2009; 35: 665-70Crossref PubMed Scopus (71) Google Scholar]. For instance, the experiments carried out in hamsters by the Leuven group led by Nemmar [12Nemmar A. Hoylaerts M.F. Hoet P.H. Dinsdale D. Smith T. Xu H. Vermylen J. Nemery B. Ultrafine particles affect experimental thrombosis in an in vivo hamster model.Am J Respir Crit Care Med. 2002; 166: 998-1004Crossref PubMed Scopus (286) Google Scholar] demonstrated that the intratracheal administration of ultrafine polystyrene particles enhanced thrombus formation, mainly through a mechanism involving platelet activation. In subsequent experiments in which diesel exhaust was used as a proxy for particulate air pollutants, heighten thrombus formation was observed as a result of particles penetration into the circulating blood [13Nemmar A. Hoet P.H. Dinsdale D. Vermylen J. Hoylaerts M.F. Nemery B. Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis.Circulation. 2003; 107: 1202-8Crossref PubMed Scopus (249) Google Scholar]. On the whole, these and other seminal experiments [14Vermylen J. Hoylaerts M.F. The procoagulant effects of air pollution.J Thromb Haemost. 2007; 5: 250-1Crossref PubMed Scopus (16) Google Scholar] indicate that the inhalation of particulate matter that contains an array of toxic substances, followed by translocation into the blood stream, leads to the activation of platelets and coagulation factors. Hypercoagulability and heightened platelet activation also occurs more indirectly through pulmonary and systemic inflammation and the ensuing production of a cytokine storm, a mechanism that facilitates atherogenesis [10Sun Q. Wang A. Jin X. Natanzon A. Duquaine D. Brook R.D. Aguinaldo J.‐.G.S. Fayad Z.A. Fuster V. Lippmann M. Chen L.C. Rajagopalan S. Long‐term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model.JAMA. 2005; 294: 3003-10Crossref PubMed Scopus (670) Google Scholar, 14Vermylen J. Hoylaerts M.F. The procoagulant effects of air pollution.J Thromb Haemost. 2007; 5: 250-1Crossref PubMed Scopus (16) Google Scholar]. Until recently, very few studies in humans had attempted to establish experimentally and/or epidemiologically whether hemostatic factors are influenced by changes in the concentration of air pollutants. Baccarelli et al. [15Baccarelli A. Zanobetti A. Martinelli I. Grillo P. Hou L. Giacomini S. Bonzini M. Lanzani G. Mannucci P.M. Bertazzi P.A. Schwartz J. Effects of exposure to air pollution on blood coagulation.J Thromb Haemost. 2007; 5: 252-60Crossref PubMed Scopus (182) Google Scholar] employed the accurate and detailed information regularly collected throughout the Lombardy Region on the concentrations of air pollutants, and demonstrated that a global coagulation test such as the prothrombin time (PT) becomes shorter during exposure to high ambient air concentrations of PM10 [15Baccarelli A. Zanobetti A. Martinelli I. Grillo P. Hou L. Giacomini S. Bonzini M. Lanzani G. Mannucci P.M. Bertazzi P.A. Schwartz J. Effects of exposure to air pollution on blood coagulation.J Thromb Haemost. 2007; 5: 252-60Crossref PubMed Scopus (182) Google Scholar]. They also showed that homocysteine levels in plasma increased proportionately with the degree of exposure to various air pollutants, but only in smokers [16Baccarelli A. Zanobetti A. Martinelli I. Grillo P. Hou L. Lanzani G. Mannucci P.M. Bertazzi P.A. Schwartz J. Air pollution, smoking, and plasma homocysteine.Environ Health Perspect. 2007; 115: 176-81Crossref PubMed Scopus (62) Google Scholar]. In this issue of the Journal, Bonzini et al. [17Bonzini M. Tripodi A. Artoni A. Tarantini L. Marinelli B. Bertazzi P.A. Apostoli P. Baccarelli A. Effects of inhalable particulate matter on blood coagulation.J Thromb Haemost. 2010; 8: 662-8Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar] used another natural model of well‐characterized exposure to ultrafine (PM1) and coarser particles (PM10), to confirm that high levels of PM exposure are associated with a shorter PT. For the first time, they used a global functional assay of coagulability (i.e. the thrombin generation test [17Bonzini M. Tripodi A. Artoni A. Tarantini L. Marinelli B. Bertazzi P.A. Apostoli P. Baccarelli A. Effects of inhalable particulate matter on blood coagulation.J Thromb Haemost. 2010; 8: 662-8Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]) and demonstrated heightened thrombin formation in workers from a steel‐production plant who were exposed to high concentrations of inhalable particulate matter. The link between inflammation and hypercoagulability was further emphasized by the simultaneous increase in C‐reactive protein [17Bonzini M. Tripodi A. Artoni A. Tarantini L. Marinelli B. Bertazzi P.A. Apostoli P. Baccarelli A. Effects of inhalable particulate matter on blood coagulation.J Thromb Haemost. 2010; 8: 662-8Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. The animal experiments and ex vivo human studies outlined above convincingly demonstrated that a hypercoagulable state occurs after exposure to PM of small aerodynamic diameter that is mediated directly by PM or indirectly via inflammation. Therefore, it was only logical to try to establish whether air pollution was a determinant not only of atherothrombotic events but also of venous thrombosis – the third most frequent cardiovascular disease. Surprisingly, the series of epidemiological studies on the effect of air pollution upon cardiovascular diseases had not evaluated any association with venous thromboembolism until recently. Such a study was performed by Baccarelli et al. [18Baccarelli A. Martinelli I. Zanobetti A. Grillo P. Hou L.F. Bertazzi P.A. Mannucci P.M. Schwartz J. Exposure to particulate air pollution and risk of deep vein thrombosis.Arch Intern Med. 2008; 168: 920-7Crossref PubMed Scopus (177) Google Scholar]. They first examined the relationship between exposure to particulate matter of 10 nm or less (PM10) and the occurrence of deep vein thrombosis (DVT) in 870 patients and 1210 healthy individuals from the Lombardy Region, and found that for each increase of 10 ng mm−3 in PM10 there was a 70% increase in the risk of DVT, independent of other clinical and environmental variables [18Baccarelli A. Martinelli I. Zanobetti A. Grillo P. Hou L.F. Bertazzi P.A. Mannucci P.M. Schwartz J. Exposure to particulate air pollution and risk of deep vein thrombosis.Arch Intern Med. 2008; 168: 920-7Crossref PubMed Scopus (177) Google Scholar]. In the same study, they also confirmed that exposure to PM was associated with a shortened PT, extending their own previous observations based upon a shorter time window of exposure to pollution [18Baccarelli A. Martinelli I. Zanobetti A. Grillo P. Hou L.F. Bertazzi P.A. Mannucci P.M. Schwartz J. Exposure to particulate air pollution and risk of deep vein thrombosis.Arch Intern Med. 2008; 168: 920-7Crossref PubMed Scopus (177) Google Scholar]. In a subsequent study, Baccarelli et al. [19Baccarelli A. Martinelli I. Pegoraro V. Melly S. Grillo P. Zanobetti A. Hou L. Bertazzi P.A. Mannucci P.M. Schwartz J. Living near major traffic roads and risk of deep vein thrombosis.Circulation. 2009; 119: 3118-24Crossref PubMed Scopus (115) Google Scholar] found that the increase in DVT risk was nearly linearly associated with the living proximity to major traffic routes, extending previous findings by other investigators who had shown the same linear association for arterial cardiovascular events [19Baccarelli A. Martinelli I. Pegoraro V. Melly S. Grillo P. Zanobetti A. Hou L. Bertazzi P.A. Mannucci P.M. Schwartz J. Living near major traffic roads and risk of deep vein thrombosis.Circulation. 2009; 119: 3118-24Crossref PubMed Scopus (115) Google Scholar]. That air pollution is associated with an increase of venous thromboembolism is now independently replicated by Dales et al. [3Dales R.E. Cakmak S. Vidal C.B. Air pollution and hospitalization for venous thromboembolic disease in Chile.J Thromb Haemost. 2010; 8: 669-74Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar], who report in this edition of the Journal of Thrombosis and Haemostasis that the short‐term increase of hospital admissions for venous thrombosis and pulmonary embolism in Santiago is proportional to the concentration of particulate and gaseous air pollutants. Importantly, the Canadian and Chilean epidemiologists have also demonstrated that these events are more frequent in the elderly than in the young [3Dales R.E. Cakmak S. Vidal C.B. Air pollution and hospitalization for venous thromboembolic disease in Chile.J Thromb Haemost. 2010; 8: 669-74Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. Which messages from these reports are important for the clinician? The first is that there is currently enough evidence to include air pollution among the acquired risk factors for venous thromboembolism [20Anderson Jr, F.A. Spencer F.A. Risk factors for venous thromboembolism.Circulation. 2003; 107: I9-16Crossref PubMed Scopus (1284) Google Scholar, 21Blann A.D. Lip G.Y. Venous thromboembolism.BMJ. 2006; 332: 215-9Crossref PubMed Scopus (129) Google Scholar]. Some episodes that we might call unprovoked, only because none of the established risk factors are identified [20Anderson Jr, F.A. Spencer F.A. Risk factors for venous thromboembolism.Circulation. 2003; 107: I9-16Crossref PubMed Scopus (1284) Google Scholar, 21Blann A.D. Lip G.Y. Venous thromboembolism.BMJ. 2006; 332: 215-9Crossref PubMed Scopus (129) Google Scholar], are perhaps provoked by air pollution when affected people come from metropolitan areas with intensive car traffic coupled with stagnation of the air. The second message is that these studies provide overwhelming evidence that air pollution increases the incidence of the three most frequent cardiovascular diseases (ischemic heart disease, cerebrovascular disease and venous thromboembolism), still the major killers in high‐income as well as in the rapidly developing economies. Hence, at least the same attention that is currently devoted to the control of such risk factors as smoking, diabetes, hypertension and obesity should be directed towards the effective control of air pollution. It is, however, still premature to recommend pharmacological prophylaxis during periods of high and growing concentrations of air pollutants. The author states that he has no conflict of interest.