ATVB in Focus

Tobacco Related Cardiovascular Diseases in the 21st Century

Series Editor: Muredach P. Reilly

Mechanisms of Coronary Thrombosis in Cigarette

Smoke Exposure
Rajat S. Barua, John A. Ambrose

Abstract—Acute rupture or erosion of a coronary atheromatous plaque and subsequent coronary artery thrombosis cause the
majority of sudden cardiac deaths and myocardial infarctions. Cigarette smoking is a major risk factor for acute coronary
thrombosis. Indeed, a majority of sudden cardiac deaths attributable to acute thrombosis are in cigarette smokers. Both
active and passive cigarette smoke exposure seem to increase the risk of coronary thrombosis and myocardial infarctions.
Cigarette smoke exposure seems to alter the hemostatic process via multiple mechanisms, which include alteration of the
function of endothelial cells, platelets, fibrinogen, and coagulation factors. This creates an imbalance of antithrombotic/
prothrombotic factors and profibrinolytic/antifibrinolytic factors that support the initiation and propagation of
thrombosis.   (Arterioscler Thromb Vasc Biol. 2013;33:1460-1467.)
Key Words: cigarette smoke exposure ◼ coronary thrombosis ◼ endothelial cells ◼ plasminogen activator
◼ von Willebrand factor

H emostasis is a process that maintains integrity of a cir-

culatory system after vascular injury and prevents the
sequelae of uncontrolled hemorrhage.1 This process regu-
lates the intravascular balance of antithrombotic/prothrom-
botic factors and profibrinolytic/antifibrinolytic factors via
interrelated functions of endothelial cells (ECs), platelets,
fibrinogen, and coagulation factors.1–4 Under normal physi-
ological conditions, regulatory mechanisms contain thrombus
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in the first year after quitting.8 Furthermore, public smoking
bans in Helena, Montana and Boulder, Colorado, as well as in
Scotland and France, were associated with significant reduc-
tions in thrombotic cardiovascular events.9–12
In the following sections, we review the existing data
regarding the mechanisms of thrombosis in relation to CSE.
The Table and Figure 1 summarize the effects and potential
mechanisms of thrombosis in relation to CSE.

formation temporally and spatially. When these regulatory

mechanisms of hemostasis are overwhelmed by pathologi-
cal processes, excessive quantities of thrombin form initiat-
ing pathological thrombosis. When a vessel wall is injured or
when there is a rupture/erosion of an atheromatous plaque,
collagen and tissue factor (TF) become exposed to the flowing
blood. Exposed collagen triggers the accumulation and activa-
tion of platelets, whereas exposed TF initiates the generation
of thrombin, which not only converts fibrinogen to fibrin but
also activates platelets. All these initiate the formation of an
intravascular thrombus.1–6
Cigarette smoking (CS) is a major risk factor for acute cor-
onary thrombosis leading to myocardial infarction and sud-
den cardiac death.7 Cigarette smoke exposure (CSE) seems to
alter the balance of antithrombotic/prothrombotic factors and
profibrinolytic/antifibrinolytic factors by affecting the func-
tions of ECs, platelets, fibrinogen, and coagulation factors.7
A meta-analysis of 20 studies showed a 36% reduction in
the crude relative risk of mortality for patients with coronary
heart disease who quit smoking compared with those who
continued smoking. Smoking cessation also leads to an expo-
nential reduction in acute cardiovascular events, particularly
Smoking, Endothelium, and Thrombosis
ECs play a pivotal role in vascular homeostasis by maintain-
ing a delicate balance between vasodilating (NO, prostacyclin
[PGI2]) and vasoconstricting (endothelin-1) factors, thrombotic
(TF) and antithrombotic (TF pathway inhibitor-1 [TFPI-1]
and thrombin activatable fibrinolysis inhibitor) factors, as
well as fibrinolytic (tissue-plasminogen activator [t-PA]) and
antifibrinolytic factors (plasminogen activator inhibitor-1
[PAI-1]).7,13,14 EC dysfunction precedes the thrombotic modi-
fication of an atherosclerotic plaque.7
Two EC-derived vasodilatory molecules, NO and PGI2,
also have direct antithrombogenic effects because they inhibit
platelet activation and aggregation by a cGMP-dependent
mechanism.13–15 We have demonstrated that exposure to active
smokers’ sera decreased NO availability from both human
umbilical vein ECs (HUVECs) and human coronary artery
ECs, by altering the expression and activity of the endothelial
NO synthase enzyme.16,17 Similarly, using cigarette smoke
extract or isolated components, such as nicotine, multiple
studies have found that CS was associated with decreased NO
availability.18,19 It is proposed that decreases in EC-derived

Received on September 21, 2012; final version accepted on: December 26, 2012.
From the Department of Medicine, Division of Cardiology, University of Kansas School of Medicine, KS and Division of Cardiology, Kansas City Veterans
Affairs Medical Center, MO (R.S.B.); and Department of Medicine, Division of Cardiology, University of California San Francisco, Fresno, CA (J.A.A.).
Correspondence to John A. Ambrose, Division of Cardiovascular Medicine, University of California San Francisco, 2823 N Fresno St, Fresno, CA
93721. E-mail jamambrose@yahoo.com
© 2013 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.112.300154

1460
 Barua and Ambrose­­   Coronary Thrombosis in Cigarette Smoke Exposure   1461

Table.  Effect of Cigarette Smoking Exposure on Various Components of Hemostasis and Thrombosis
Mechanisms (Based on Combination of In
Active Cigarette Exposure Passive Cigarette Exposure Vitro and In Vivo Studies)
Endothelial cells Decreased NO and PGI2 availability. Alteration in balance Decreased NO availability Oxidative stress
of EC-derived TF, TFPI, t-PA, PAI-1
Inflammatory effect Increased adhesion molecules, CRP, IL-6, TNF, Increased adhesion molecules, CRP, IL- Inflammatory genes activation
homocysteine 6, TNF, homocysteine
Platelets Increased aggregation and activation Increased aggregation and activation Oxidative stress and reduced NO
availability
Procoagulant effects Decreased TFPI release; increased TF level, TF- Increased circulating TF-microparticles Oxidative stress and reduced NO
microparticles and fibrinogen and fibrinogen availability
Antifibrinolytic effect Decreased stimulated t-PA release; alteration of t-PA/ Change in fibrin architecture Oxidative stress and reduced NO
PAI-1 molar ratio; change in fibrin architecture availability
CRP indicates C-reactive protein; EC, endothelial cell; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor; PGI2, prostacyclin; TNF, tumor necrosis factor; t-PA,
tissue-plasminogen activator; TF, tissue factor; and TFPI, tissue factor pathway inhibitor.

NO occur via 2 mechanisms. First, cigarette smoke contains
high level of free radicals, and the scavenging activity of
cigarette smoke–derived free radicals leads to reduced
NO bioavailability.17,20,21 Second, altered endothelial NO
synthase protein and its activity also decrease NO availability
in relation to cigarette smoker exposure.16,17,19 Not only is
NO a vasoregulatory molecule but also it helps regulate
inflammation, leukocyte adhesion, platelet activation, and
thrombosis.13,14 Therefore, an alteration in NO biosynthesis
would cause both primary and secondary effects on the
initiation and progression of thrombotic events.
Similarly, PGI2 is also affected by CS. It was reported that
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HUVECs isolated from mothers who smoke have also been
shown to produce less PGI2 in vitro.24
The endothelium is a major source of both thrombotic
(TF) and antithrombotic (TFPI-1) factors, as well as fibri-
nolytic (t-PA) and antifibrinolytic factors (PAI-1).2,4,7,13 We
and others have demonstrated that CSE causes an imbalance
in EC-derived antithrombotic and fibrinolytic factors, thus
contributing to the generation of a prothrombogenic milieu
leading to an acute thrombotic event.7 Existing data regard-
ing these are discussed in more detail in a later section of
this article.

aortas from rats that were chronically exposed to cigarette
smoke showed a reduction in PGI2 production.21 Reinders
et al22 showed that incubation of cultured HUVECs with ciga-
rette smoke condensate impaired the basal and stimulated
(phorbol myristate acetate) production of PGI2. Ahlsten et
al23 reported that maternal smoking significantly decreased
PGI2 production in umbilical arteries from newborn infants.
Smoking, Plaque Vulnerability, and
Thrombosis
An atherosclerotic plaque may remain silent and stable
for a long period of time.25,26 The vulnerability of a plaque
for rupture depends on its lipid composition, fibrous cap,
degradation of extracellular matrix proteins, recruitment of
inflammatory cells, and intraplaque hemorrhage.26 It was

Figure 1. Potential pathways and mecha-

nisms for cigarette smoking–mediated
thrombogenesis. The flow diagram repre-
sents the probable central mechanisms in
the complex pathophysiology of cigarette
smoking–mediated thrombogenesis.
PAI-1 indicates plasminogen activator
inhibitor; t-PA, tissue-plasminogen acti-
vator; and vWF, von Willebrand factor.
 1462   Arterioscler Thromb Vasc Biol   July 2013
found that smokers have a higher extracellular lipid content in
their plaques.27 CSE has also been reported to downregulate a
key enzyme, n-prolyl-4-hydroxylase, in arterial wall collagen
metabolism, which could contribute to development of a
thin fibrous cap in the atherosclerotic plaques of smokers.28
Matrix metalloproteinases, which are involved in degradation
of extracellular matrix proteins in plaque, were shown to
have increased expression and activity in relation to CSE.29
Similarly, CSE or components of CS were suggested
to increase intraplaque inflammation and intraplaque
neovascularization.30–33 Intraplaque inflammation and
intraplaque neovascularization lead to intraplaque hemorrhage
and subsequent necrotic core enlargement.26 Furthermore,
CSE was found to cause an increased sympathetic activity
leading to a rise in blood pressure, pulse rate, and vasospasm,
which might create a high-mechanical stress zone near a
vulnerable plaque.34 All these together are likely to cause
plaque instability that contributes toward plaque rupture. Once
plaque rupture has occurred, its progression to pathological
thrombosis depends on the local balance of platelet activation,
antithrombotic/prothrombotic factors, and profibrinolytic/
antifibrinolytic factors. Plaque erosion, the other major
mechanism for coronary thrombosis leading to myocardial
infarction, is highly dependent on prothrombotic forces and is
increased in cigarette smokers.35,36
Smoking, Proinflammatory Effects, and
Thrombosis
Thrombosis and inflammation are interrelated and mutually
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reinforcing processes. Thrombosis is proinflammatory, and
inflammation promotes thrombosis. These processes involve
inflammatory mediators (eg, tumor necrosis factor-α and
CD40 ligand), expression of adhesion molecules on ECs,
platelets, and monocytes.2–4 An inflammatory response is also
involved in TF expression on monocytes and the activated
endothelium, as well as activation of circulating TF-bearing
microparticles.7,37,38 In humans, chronic CSE was found to
be associated with increased levels of multiple inflammatory
markers, including peripheral leukocytosis, C-reactive protein,
homocysteine, interleukin-6, and tumor necrosis factor-α.39–42
Studies have demonstrated that exposure of HUVECs to
cigarette smoke condensate resulted in increased nuclear fac-
tor κB DNA binding activity, increased surface expression
of intercellular adhesion molecule-1, vascular cell adhesion
molecule-1, and platelet EC adhesion molecule-1.43–45 von
Willebrand factor (vWF) is contained in EC Weibel–Palade
bodies and is an important ligand of platelet binding. Multiple
studies have demonstrated an increased level of circulating
vWF in smokers.41
Smoking, Platelet Activation, and Thrombosis
During the process of thrombus formation, 2 distinct path-
ways acting in parallel or separately can activate platelets.5 In
the first pathway, exposure of subendothelial collagen initi-
ates platelet activation. The interactions of platelet glycopro-
tein VI with the collagen of the exposed vessel wall and of
platelet glycoprotein Ib-V-IX with collagen-bound vWF result
in adhesion of platelets to the site of injury.46 In the second
pathway, platelet activation does not require disruption of the
endothelium and is independent of vWF and glycoprotein
VI.5,47 TF derived from the vessel wall or present in flowing
blood initiates a proteolytic cascade that generates thrombin.48
Thrombin cleaves and activates protease-activated receptors
on the surface of platelets. Protease-activated receptor-1 and
-4 are particularly important for platelet activation. Once
activated, platelets further stimulate thrombus formation and
recruit additional platelets by releasing ADP and serotonin,
producing thromboxane A2 and amplifying the signals for
thrombus formation.5,46,47 CSE seems to activate platelets by
both pathways.
Platelets isolated from smokers exhibited an increased
stimulated and spontaneous aggregation.49 Platelet α-granule
constituents, such as platelet factor-4, β-thromboglobulin, and
platelet activating factor, are increased in the plasma of smok-
ers, suggesting increased platelet activation.50–52 Using a mod-
ified prothrombinase method, Rubenstein et al53 compared
the effects of sidestream and mainstream smoke on platelet
function. Interestingly, the impact of sidestream smoke was
as pronounced as that of mainstream smoke. Our group, using
thromboelastography, demonstrated that acute CSE was asso-
ciated with functional changes in platelets and these changes
affected the dynamics of clot formation. These clots were
more resistant to thrombolysis as compared with clots of non-
smokers.54,55 Smokers also have higher P2Y12 expression in
platelet lysates than nonsmokers.56
Platelet activation and recruitment are partly regulated by
products of the endothelium, including PGI2 and NO.14,15 NO
inhibits platelet adhesion and aggregation; loss of platelet-
derived NO promotes platelet recruitment.57 Furthermore, NO
insufficiency combined with increased reactive oxygen species
cause an increase in intracellular calcium levels in platelets.
Increased intracellular levels of calcium induce cytoskeletal
rearrangement, trigger α and dense granule release, and pro-
mote platelet activation. We and others have demonstrated that
EC-derived NO, as well as platelet-derived NO, is decreased
in relation to CSE.16–19,58–60 Impaired NO bioavailability also
causes secretion of thromboxane A2 from the platelets, which
consequently activates additional platelets.14,15,57 These acti-
vated platelets show conformational changes in their cell
surface integrin (glycoprotein IIb-IIIa [GP IIb-IIIa]) receptor
that result in heightened affinity for its ligands (fibrinogen and
vWF). Fibrinogen, vWF, and GP IIb-IIIa receptors cross-link
these activated platelets, leading to platelet aggregation.14,15,57
CSE by affecting the levels of vWF and of fibrinogen contrib-
ute to increased cross-linking of platelets, which will further
enhance the strength of a thrombus.7,39,54,55
Smoking, TF, and Thrombosis
TF is proposed to be a major initiator of thrombin generation
and fibrin formation.6 TF is constitutively expressed on
fibroblasts and pericytes in the adventitia and medial
smooth muscle cells of the vessel wall. Its expression on
monocytes and ECs can be induced by various stimuli.6,61 TF
is also present in circulating blood in association with micro
particles. These vesicular structures (microparticles), which
are <1000 nm in diameter, are derived from leukocytes,
platelets, ECs, smooth muscle cells, and monocytes.5,62–64
Microparticle-associated TF is thought to exist in a latent
 Barua and Ambrose­­   Coronary Thrombosis in Cigarette Smoke Exposure   1463

(or encrypted) form that lacks coagulant activity.5,63 Currently,

it is unclear how microparticle-associated TF becomes active.
It has been hypothesized that activated platelets and ECs
secrete protein disulfide isomerase, and this enzyme converts
the inactive microparticle-associated TF to its active form.62–65
CS seems to affect TF expression and activation in cells, as
well as in the circulation. Atherosclerotic plaques isolated
from ApoE−/− mice exposed to nonfiltered research cigarettes
showed an increased TF immunoreactivity and an increase in
TF activity.66 In smokers, 2 hours after smoking 2 cigarettes,
an increase in circulating TF activity has also been reported
in human plasma.67 In vitro, HUVECs exposed to serum from
chronic smokers showed a relatively higher increase in TF level
after 12 hours.68 However, it was not statistically significant.68
In the same cell culture supernatant, there was a significant
decrease in EC-derived TFPI-1 secretion in the smoking
group..68 TFPI-1 is a potent regulator of TF factor VIIa-
dependent activation of the TF pathway. In the same study, EC
culture supernatant in smokers group had a relative increase of Figure 2.  Electron microscopic image of fibrin clots from a
the TF/TFPI-1 ratio, and this alteration conceivably denoted an smoker (A and B, pre- and postsmoking samples from the same
increase in thrombotic potential. Additionally, TFPI-1 showed subject) at 20K magnification.
a significant positive correlation with NO.68. This suggested that
the prothrombotic alteration in TF/TFPI-1 could be partially All these suggest that endogenous fibrinolytic activity is impaired
mediated by decreased NO bioavailability. Similarly, an in smokers.
increase in TF-containing microparticles in the circulation was
reported in multiple studies in relation to CSE.5,67,69 Smoking, Oxidative Stress, and Thrombosis
Cigarette smoke contains >4000 identified and >100 000
Smoking, Fibrinogen, and Thrombosis unidentified components, of which only a few components
Fibrinogen, a bivalent molecule, augments platelet aggre- have been examined in isolation, such as carbon monoxide
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gation by linking GPIIb/IIIa receptors between activated
platelets. The structural support of a thrombus is provided
by a matrix of cross-linked fibrin.70 Dotevall et al71 found that
plasma fibrinogen levels were significantly higher among
smokers. Factor XIII covalently cross-links and stabilizes
fibrin clots. It was reported that factor XIII A-subunit levels
were significantly increased in smokers.72 Our group, using
thromboelastography, demonstrated that acute CS was asso-
ciated with functional changes in fibrin, which increased
the kinetics of clot formation, the rapidity of fibrin build-
up, and clot strength.54,55 In the same study by using electron
microscopy, we found these effects were partly mediated by
changes in fibrin clot architecture. CS was associated with
thinner and denser fibrin fibers that were resistant to throm-
bolysis (Figure 2).54,55
A timely dissolution of the fibrin matrix is essential to inhibit
pathological propagation of a thrombus. The lysis of fibrin is
mediated by plasmin. Plasminogen is activated to plasmin by
t-PA.68 On the contrary, t-PA is inhibited by PAI-1.68 Smokers
have higher PAI-1, which correlated with the estimated pack-
years of cigarettes smoked.73 It has been suggested that the
t-PA/PAI-1 molar ratio is a useful indicator of fibrinolytic bal-
ance.68 Newby et al74 have shown that, in smokers, substance
P–stimulated t-PA antigen and activity are decreased with no
change in PAI-1 antigen or activity in both the peripheral and
coronary circulation.7 Using HUVECs and smokers serum, we
demonstrated that substance P–stimulated t-PA release was
decreased in smokers with no change in basal and stimulated
PAI-1 antigen. Additionally, basal t-PA production and t-PA/
PAI-1 molar ratio were also significantly reduced in smokers.68
(CO), nicotine, and particulate matter.7,75 An earlier study
suggested that CO could be responsible for smoking-related
atherothrombotic events.7,75 However, more recent data suggest
that CO from cigarette smoke has been shown to exhibit
antithrombotic properties.7,76 Nicotine is the only known
addictive substance in cigarette smoke, and it is also its most
studied component.7,75 Although the role of nicotine in the
hemodynamic effects of smoking is well accepted, its effect
on thrombohemostatic factors, such as platelets, fibrinogen,
t-PA, or PAI-1, seems to be small and probably plays only a
minor role in atherothrombotic events directly.7,75 Current data
suggest that particulate matter contributes to atherothrombotic
events by increasing the inflammatory response and oxidative
stress.75,77 Regardless of the components of CS, current
available data suggest that free radical–mediated oxidative
stress and the loss of the protective effect of NO are the
key steps in the prothrombogenic modification of the ECs,
platelets, fibrin, and prothrombogenic factors in the vessel
wall, as well as in the circulation.,7,16,17,20 These 2 processes are
interrelated. In a setting of CSE, free radicals could potentially
arise from the following: (1) cigarette smoke directly, (2)
circulating or in situ-activated macrophages and neutrophils,
and (3) endogenous sources of reactive oxygen species, such
as uncoupled endothelial NO synthase, xanthine oxidase, and
the mitochondrial electron transport chain. A reaction between
free radicals, such as superoxide and NO, not only decreases
NO availability but also generates peroxynitrite, which
further potentiates the oxidative stress. Increased oxidative
stress with the loss of the protective effect of NO tips the
 1464   Arterioscler Thromb Vasc Biol   July 2013
cellular and intravascular balance toward a prothrombogenic
milieu.7,16,17,20,75,76 Indeed, in various experimental models,
antioxidants or agents that reduced the oxidative stress
or increased NO availability have been shown to either
improve or reverse the proinflammatory and prothrombotic
characteristics associated with CS.17,78–81
Passive Smoking and Thrombosis
Like active CS, passive smoke exposure is also associated with
an increase in the incidence of myocardial infarction.82,83 The
risk of death attributable to cardiovascular disease increases
by 30% in nonsmokers who live together with smokers. It is
estimated that >50 000 deaths annually from ischemic heart
disease are associated with passive smoking.82,83 A meta-anal-
ysis of large cohort studies showed that, in active smokers, the
risk for ischemic heart disease with 5 cigarettes per day was
not a quarter but about half that associated with 20 cigarettes
per day.84 More importantly, it has been estimated that with
environmental smoke exposure, even though the exposure to
tobacco smoke was <1% of the exposure from smoking 20
cigarettes per day, the excess risk for ischemic heart disease
was ≈33% of that experienced by a person who smoked 20
cigarettes per day.85,86
All these epidemiological data suggest a nonlinear dose–
response relationship in the intensity of exposure to passive
smoking.85 These findings are consistent with experimental
data showing a nonlinear effect on platelet activation and
aggregation.82,86–88 Public smoking bans in multiple coun-
tries were associated with rapid and significant reductions
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in thrombotic cardiovascular events.9–11 In a study in France,
it was reported that smoke-free legislation led to a 40%
reduction in fibrin-rich clot stiffness coupled with a drop
in clotting time and fiber density among exposed subjects.
This change in fibrin structure led to a 22% reduction in the
clot lysis-time.12 These results were similar to the change
in fibrin architecture seen by our group in relation to active
smoking.54,55 Similarly vWF, TF-containing microparticles,
fibrinogen, and inflammatory markers were reported to be
elevated in passive smokers.82–89
Smoker’s Paradox
Although thrombosis is the main mechanism for smoking-
related cardiovascular mortality, in a seemingly contradic-
tory observation, it has been reported that there is a reduced
mortality for smokers with ST-elevation myocardial infarc-
tion, and it was proposed that based on higher thrombolysis in
myocardial infarction-3 (TIMI-3) flow after t-PA, thromboly-
sis was enhanced in smokers.90,91 Furthermore, post hoc anal-
yses of pivotal clinical trials (Clopidogrel for the Reduction
of Events During Observation [CREDO], Clopidogrel for
High Atherothrombotic Risk and Ischemic Stabilization,
Management and Avoidance [CHARISMA], Clopidogrel
as Adjunctive Reperfusion Therapy [CLARITY]-TIMI 28),
comparing dual antiplatelet therapy consisting of aspirin and
clopidogrel versus aspirin alone, showed that clopidogrel ther-
apy may be more effective in current smokers compared with
nonsmokers.92–94 These findings have been suggested to reflect
a smoker’s paradox. One of the hypotheses is that thrombus
in smokers may be more fibrin-rich and, therefore, more ame-
nable to fibrinolytic therapy.90,91 However, in an experimental
study, our group demonstrated that clots from smokers were
significantly more resistant to lysis when exposed to t-PA
compared with nonsmokers. This seems to contradict this
hypothesis.55
As for the increased effectiveness of clopidogrel in
smokers, CS is a known inducer of cytochrome P450 1A2
(CYP1A2), and its activity increases relative to the number
of cigarettes smoked per day.95 CYP1A2 is the predominant
isoenzyme responsible for the first of the 2 oxidative steps
required for clopidogrel to be metabolized into its active
metabolite. However, contradictory data exist and, addition-
ally, a smoking paradox was not demonstrated in trials with
newer antiplatelet agents, such as prasugrel (Trial to Assess
Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with Prasugrel [TRITON]-TIMI 38) and
ticagrelor (Platelet Inhibition and Patient Outcomes [PLATO]
trials).96,97 Furthermore, other studies proposed that smokers
have a lower mortality after myocardial infarction because of
their younger age and lower rates of other coexisting cardio-
vascular risk factors compared with nonsmokers.98,99
Future Direction
Although CS is very hazardous, not all smokers seem to be
affected similarly from their addiction.100 For example, 50%
of lifelong smokers die prematurely from smoking-related
diseases, but the other 50% do not.100 The sources of vari-
ability are partly attributable to the presence of other risk fac-
tors and partly attributable to genetic predisposition. It was
reported that there is a differential effect of smoking on cyto-
chrome P450 system polymorphism.100,101 Current smokers
and ex-smokers with uncommon endothelial NO synthase 4a
gene polymorphism have been reported to have severe coro-
nary stenosis.101 Several studies have reported that smokers
with the A-455 allele (G-455A b-fibrinogen gene promoter
polymorphism) experienced a greater rise in fibrinogen than
those lacking this allele.102 Similarly, the presence of the gly-
coprotein IIIa P1(A2) polymorphisms are associated with
increased risk of acute ST-elevation myocardial infarction
in smokers.103 Polymorphisms of factor XIII genes are also
reported to affect fibrin architecture and fibrinolysis.55 The
combination of the FXIII L34-allele and nonsmoking status
increased the risk of nonreperfusion and worse outcomes.55
The mechanisms of gene CSE interactions in atherothrom-
botic disease have not been well studied. Future focus stud-
ies examining the interaction between CSE and these genetic
variations will be needed to further understand the differen-
tial effect of genetic polymorphisms in CSE-related athero-
thrombotic diseases, which will potentially allow improved
targeted therapies in these individuals.
Biomarkers can be used as indicators for certain
biological states, pathogenetic processes, or responses to
pharmacological treatments. An ideal biomarker would show
a dose–response relationship with smoking and a change with
cessation or reduced exposure. So far, no existing biomarkers
have been demonstrated to be predictive of smoking-related
atherothrombotic disease, which highlights a need for research
 Barua and Ambrose­­   Coronary Thrombosis in Cigarette Smoke Exposure   1465
in this field. MicroRNAs are involved virtually in every
cellular process, and aberrant expression is associated with
cellular dysfunction and disease.104 Recently, evaluation of
microRNAs showed some promise as potential biomarkers
for atherothrombotic diseases, as well as CSE-related
diseases.104,105 Additional research in these areas will be needed
if one is to develop effective diagnostic or prognostic tools in
CSE-related atherothrombotic diseases.
The most effective prevention for CSE-related athero-
thrombotic diseases is to avoid all exposure to CS. However,
for those who have previously been exposed to CS or continue
to be exposed, whether actively or passively, there is further
need for a mechanistic understanding of molecular pathways
linking individual smoke constituents or classes thereof to
the process of atherothrombotic diseases and their outcome.
Improved mechanistic understanding in this area might sup-
port the development of novel products that would help for
the general prevention, diagnosis, and therapy, in CSE-related
atherothrombotic diseases.
Conclusions
Epidemiological studies have established that CSE is an
important cause of cardiovascular morbidity and mortality
worldwide. Clinical and experimental studies indicate that
either active or passive cigarette exposure promotes thrombo-
sis in multiple vascular beds by affecting the function of ECs,
platelets, fibrinogen, and coagulation factors. Although the
precise mechanisms responsible for these alterations remain to
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be confirmed, a growing body of evidence supports free radi-
cal–mediated oxidative stress and loss of the protective effect
of NO playing a central role in CSE-mediated thrombotic
diseases. However, future studies with a multidisciplinary
approach will be needed to further define these mechanisms.
Disclosures
None.
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