the procoagulant effects of air pollution
TRANSCRIPT
COMMENTARY
The procoagulant effects of air pollution
J . VERMYLEN and M. F . HOY LAERTSCentre for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
To cite this article: Vermylen J, Hoylaerts MF. The procoagulant effects of air pollution. J Thromb Haemost 2007; 5: 250–1.
See also Baccarelli A, Zanobetti A, Martinelli I, Grillo P, Hou L, Giacomini S, Bonzini M, Lanzani G, Mannucci PM, Bertazzi PA, Schwartz J. Effects of
exposure to air pollution on blood coagulation. This issue, pp 252–60.
The effects of air pollution on health have become a major
concern for politicians and an almost daily topic for newspa-
pers. A Google search using �air pollution and health� providesover 18 000 000 entries. Air pollution has been linked not only
to pulmonary disease, but also to cardiovascular disease. Both
acute [1,2] and chronic [3] exposure to polluted air are
associated with an increased incidence of acute myocardial
infarction. Mechanistic explanations for this association are
actively being sought [4].
The current issue of this Journal contains a remarkable
piece of detective work that took place in the region of
Lombardy, northern Italy. This region contains both the
often heavily polluted industrial area around Milan, and
idyllic places such as the Como lake and the southern Alpine
slopes. The A. Bianchi Bonomi Haemophilia and Thrombo-
sis Centre in Milan collected blood over a period of 10 years
from 1218 healthy individuals from this region, who were
partners or friends of patients with thrombosis, and who
agreed to undergo thrombophilia testing. The very original
feature of this study by Baccarelli et al. [5] is that it relates
the results of the clotting tests to the degree of air pollution,
in the hours and days before sampling, in the area where the
subject lived. Surprisingly, a weak but significant negative
correlation was found between the prothrombin time and
the degree of air pollution at the time of sampling or the
average air pollution in the 30 days prior to sampling. The
degree of air pollution had no effect on the activated partial
thromboplastin time or on the levels of fibrinogen, anti-
thrombin, protein C or protein S. In a separate paper on the
same healthy subjects, Baccarelli et al. [6] report that
particulate air pollution interacts with cigarette smoking to
increase plasma homocysteine levels.
Until now, relatively little attention has been paid to slight
shortenings of the prothrombin time, a very frequently
performed global coagulation test. Infusion of recombinant
factor VIIa, however, results in a markedly shortened pro-
thrombin time [7]. As Baccarelli et al. [5] suggest, the somewhat
shortened prothrombin time following exposure to polluted air
could well result from an increased FVIIa level, in view of the
absence of any shortening of the activated partial thrombo-
plastin time. Measurement of FVIIa was, however, not
included in the screening of these healthy individuals.
An increase in FVIIa levels may reflect exposure of the blood
to tissue factor. What could be the link between air pollution
and tissue factor? Associations have already been found
between smoking and circulating tissue factor activity [8] and
FVIIa levels [9]. Exposure to polluted air causes pulmonary
inflammation in humans, as evidenced by the presence of
inflammatory cells in sputum [10] and in bronchoalveolar
lavage fluid [11]. Following intratracheal instillation of diesel
exhaust particles in hamsters, there is a strict link between the
degree of lung inflammation and the extent of thrombosis
following minor vascular injury [12]. Inflamed pulmonary
endothelial cells would expose adhesionmolecules, including P-
selectin and vonWillebrand factor [13], resulting in binding and
mutual activation of leukocytes and platelets, which could then
lead to the release of leukocyte-derived tissue factor-containing
microparticles into the circulation [14]. Alternatively, pulmon-
ary inflammation because of air pollution is known to be
associated with release of proinflammatory cytokines into the
circulation, namely interleukin-1b, interleukin-6 and granulo-
cyte–macrophage colony-stimulating factor [15]. Exposure to
polluted air further stimulates the release of neutrophils [16,17]
and monocytes [18] from the bone marrow. One could assume
that inhalation of pollutants may also release hematopoietic
cell-derived microparticles carrying tissue factor [19] from the
bone marrow into the circulation.
Tissue factor-bearing microparticles derived from leukocytes
deposit on a layer of activated platelets [20,21]. Activated
platelets accumulate clotting factors [22–26]. The interaction of
tissue factor with clotting factors concentrated on a platelet
layer overlying a vascular lesion would result in a local burst of
thrombin activity that could readily lead to an occlusive
thrombosis. It thus becomes understandable how exposure to
polluted air may trigger within hours amyocardial infarction in
a susceptible individual [27–29].
But enough speculation! The time has come to verify
whether circulating tissue factor activity and FVIIa level do
Correspondence: Jos Vermylen, Centre for Molecular and Vascular
Biology, University of Leuven, Herestraat 49, B3000 Leuven, Belgium.
Tel.: +32 16 34 57 75; fax: +32 16 34 59 90; e-mail:
Journal of Thrombosis and Haemostasis, 5: 250–251
� 2006 International Society on Thrombosis and Haemostasis
indeed rise in humans following acute exposure to polluted air,
and whether this is related to the gaseous or the particulate
matter in the inhaled air, and to the extent of the resulting
inflammation.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interest.
References
1 Peters A, Dockery DW, Muller JE, Mittleman MA. Increased
particulate air pollution and the triggering of myocardial infarction.
Circulation 2001; 103: 2810–5.
2 Peters A, vonKlot S, HeierM, Trentinaglia I, HormannA,Wichmann
HE, Lowel H. Exposure to traffic and the onset of myocardial
infarction. N Engl J Med 2004; 351: 1721–30.
3 Pope III CA, Burnett RT, ThurstonGD, ThunMJ, Calle EE, Krewski
D, Godleski JJ. Cardiovascular mortality and long-term exposure to
particulate air pollution: epidemiological evidence of general patho-
physiological pathways of disease. Circulation 2004; 109: 71–77.
4 Vermylen J, Nemmar A, Nemery B, Hoylaerts MF. Ambient air
pollution and acute myocardial infarction. J Thromb Haemost 2005; 3:
1955–61.
5 Baccarelli A, Zanobetti A, Martinelli I, Grillo P, Hou L, Giacomini S,
Bonzini M, Lanzani G, Mannucci PM, Bertazzi PA, Schwartz J.
Effects of exposure to air pollution on blood coagulation. J Thromb
Haemost 2007; 5: 252–60.
6 Baccarelli A, Zanobetti A, Martinelli I, Grillo P, Hou L, Lanzani G,
Mannucci PM, Bertazzi PA, Schwartz J. Air pollution, smoking
and plasma homocysteine. Environ Health Perspect; DOI: 10.1289/
ehp.9517.
7 Lindley CM, Sawyer WT, Macik BG, Lusher J, Harrison JF, Baird-
Cox K, Birch K, Glazer S, Roberts HR. Pharmacokinetics and
pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther
1994; 55: 638–48.
8 Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V,
Crandall J, Badimon JJ. Role of risk factors in themodulation of tissue
factor activity and blood thrombogenicity. Circulation 2003; 107: 973–
7.
9 Danielsen R, Onundarson PT, Thors H, Vidarsson B, Morrissey JH.
Activated and total coagulation factor VII, and fibrinogen in coronary
artery disease. Scand Cardiovasc J 1998; 32: 87–95.
10 Nightingale JA, Maggs R, Cullinan P, Donnelly LE, Rogers DF,
Kinnersley R, ChungKF, Barnes PJ, AshmoreM,Newman-Taylor A.
Airway inflammation after controlled exposure to diesel exhaust par-
ticles. Am J Respir Crit Care Med 2000; 162: 161–6.
11 Ghio AJ, Kim C, Devlin RB. Concentrated ambient air particles in-
duce mild pulmonary inflammation in healthy human volunteers. Am
J Respir Crit Care Med 2000; 162: 981–8.
12 Nemmar A, Nemery B, Hoet PH, Vermylen J, Hoylaerts MF. Pul-
monary inflammation and thrombogenicity caused by diesel particles
in hamsters: role of histamine. Am J Respir Crit Care Med 2003; 168:
1366–72. Erratum in: Am J Respir Crit Care Med 2004; 169: 885.
13 Wagner JG, Roth RA. Neutrophil migration mechanisms, with an
emphasis on the pulmonary vasculature. Pharmacol Rev 2000; 52: 349–
74.
14 Hrachovinova I, Cambien B, Hafezi-Moghadam A, Kappelmayer J,
Camphuisen RT, Widom A, Xia L, Kazazian Jr HH , Schaub RG,
McEver RP, Wagner DD. Interaction of P-selectin and PSGL-1
generates microparticles that correct hemostasis in a mouse model of
hemophilia A. Nat Med 2003; 9: 1020–5.
15 van Eeden SF, TanWC, Sawa I, Mukae H, Terashima T, Fujii T, Qui
D, Vincent R, Hogg JC. Cytokines involved in the systemic inflam-
matory response induced by exposure to particulate matter air pol-
lutants (PM(10)). Am J Respir Crit Care Med 2001; 164: 826–30.
16 Salvi S, Blomberg A, Rudell B, Kelly F, Sandstrom T, Holgate ST,
Frew A. Acute inflammatory responses in the airways and peripheral
blood after short-term exposure to diesel exhaust in healthy human
volunteers. Am J Respir Crit Care Med 1999; 159: 702–9.
17 Tan WC, Qiu D, Liam BL, Ng TP, Lee SH, van Eeden SF,
D’Yachkova Y, Hogg JC. The human bone marrow response to acute
air pollution caused by forest fires. Am J Respir Crit Care Med 2000;
161: 1213–7.
18 Goto Y, Ishii H, Hogg JC, Shih CH, Yatera K, Vincent R, van Eeden
SF. Particulate air matter stimulates monocyte release from the bone
marrow. Am J Respir Crit Care Med 2004; 170: 891–7.
19 Chou J, Mackman N, Merrill-Skoloff G, Pedersen B, Furie BC, Furie
B. Hematopoietic cell-derivedmicroparticle tissue factor contributes to
fibrin formation during thrombus propagation.Blood 2004; 104: 3190–
7.
20 Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT,
Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tis-
sue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999;
96: 2311–5.
21 Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E,
Celi A, Croce K, Furie BC, Furie B. Accumulation of tissue factor into
developing thrombi in vivo is dependent upon microparticle P-selectin
glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197:
1585–98.
22 Scandura JM, Ahmad SS, Walsh PN. A binding site expressed on the
surface of activated human platelets is shared by factor X and pro-
thrombin. Biochemistry 1996; 35: 8890–902.
23 Gould WR, Simioni P, Silveira JR, Tormene D, Kalafatis M, Tracy
PB. Megakaryocytes endocytose and subsequently modify human
factor V in vivo to form the entire pool of a unique platelet-derived
cofactor. J Thromb Haemost 2005; 3: 448–9.
24 Kawasaki T, Kaida T, Arnout J, Vermylen J, Hoylaerts MF. A new
animal model of thrombophilia confirms that high plasma factor VIII
levels are thrombogenic. Thromb Haemost 1999; 81: 306–11.
25 Hoffman M, Monroe DM, Roberts HR. Coagulation factor IXa
binding to activated platelets and platelet-derived microparticles: a
flow cytometric study. Thromb Haemost 1992; 68: 74–8.
26 Baglia FA, Shrimpton CN, Emsley J, Kitawaga K, Ruggeri ZM,
Lopez JA, Walsh PN. Factor XI interacts with the leucine-rich repeats
of glycoprotein Ib alpha on the activated platelet. J Biol Chem 2004;
279: 49323–9.
27 Goldberg MS, Burnett RT, Bailar III JC, Tamblyn R, Ernst P, Flegel
K, Brook J, Bonvalot Y, Singh R, Valois MF, Vincent R. Identifica-
tion of persons with cardiorespiratory conditions who are at risk of
dying from the acute effects of ambient air particles. Environ Health
Perspect 2001; 109 (Suppl. 4): 487–94
28 Zanobetti A, Schwartz J. Cardiovascular damage by airborne particles:
are diabetics more susceptible? Epidemiology 2002; 13: 588–92.
29 Pope CA 3rd, Muhlestein JB, May HT, Renlund DG, Anderson JL,
Horne BD. Ischemic heart disease events triggered by short-term ex-
posure to fine particulate air pollution. Circulation 2006; 114: 2443–8.
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� 2006 International Society on Thrombosis and Haemostasis