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(Circulation. 1995;92:2432-2436.)
© 1995 American Heart Association, Inc.

Articles

Cigarette Smoking Acutely Increases Platelet Thrombus Formation in Patients With Coronary Artery Disease Taking Aspirin

Joseph Hung, MB, BS, FRACP; Jules Y.T. Lam, MD; Lucie Lacoste, PhD; Glaci Letchacovski, MD

From the Laboratory of Thrombosis and Atherosclerosis, the Department of Medicine, the Montreal Heart Institute and the University of Montreal, Canada.

Correspondence to Dr Jules Y.T. Lam, MD, Department of Medicine, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec H1T 1C8, Canada.

	Abstract

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Background Smoking is associated with an increased risk of myocardial infarction and sudden death. Platelet activation and thrombosis at sites of vessel stenosis and injury or plaque disruption play a crucial role in these acute coronary events. Thus, the aim of this study was to determine whether cigarette smoking acutely increases platelet thrombus formation on an injured arterial surface at local shear rates typical of a stenotic artery.

Methods and Results Twelve habitual smokers with stable coronary disease, on aspirin 325 mg/d, were studied immediately before and 5 minutes after smoking two cigarettes each. Ex vivo platelet thrombus formation on porcine arterial media (simulating deep arterial injury) was measured after exposure to the patient's circulating venous blood for 3 minutes in cylindrical flow chambers at 37°C. The flow chambers were designed to produce shear rates of 754 or 2546 s^-1, the latter being typical of the high shear rates produced by vessel stenosis. Plasma catecholamine, thromboxane B₂, and 6-ketoprostaglandin F₁ (6-keto-PGF₁) levels and whole blood platelet aggregation responses to thrombin were also measured before and after smoking. Compared with before smoking, morphometrically measured platelet thrombus formation on arterial media at shear rates of 754 and 2546 s^-1 increased by an average of 48% (P=.19) and 64% (P=.014), respectively, after smoking. Plasma epinephrine increased by more than twofold after smoking (P=.026). Plasma thromboxane B₂ and 6-keto-PGF₁ levels did not change. Smoking also increased whole blood platelet aggregation to thrombin (P.05).

Conclusions These results suggest that smoking-enhanced platelet thrombosis may be an important contributory mechanism for acute coronary events in smokers that is not prevented by aspirin treatment. Catecholamine release and heightened platelet aggregation response to in vivo agonists may contribute to the prothrombotic effects of smoking.

Key Words: smoking • platelets • thrombosis • aspirin • coronary disease

	Introduction

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Despite strong epidemiological evidence linking tobacco smoking to an increased risk of ischemic heart disease and vascular mortality,^{1 2} the precise mechanisms involved are not fully elucidated. Suggested causal mechanisms in chronic smokers include increased atherosclerosis,^{3 4} enhanced platelet aggregation and thrombosis,⁵ hypercoagulability, increased fibrinogen, and decreased fibrinolytic activity in the blood.^{6 7} Because smoking is particularly associated with an increased risk of myocardial infarction and sudden death,^{1 2} it is likely that smoking influences the terminal occlusive and thrombotic event. This is further supported by the rapid decrease in risk of myocardial infarction and coronary death among ex-smokers.⁸

Platelet activation and thrombus formation at sites of coronary stenosis and atherosclerotic plaque fissuring are thought to play a key role in the pathomechanism of acute coronary syndromes.^{9 10} A number of studies have found that smoking enhances platelet aggregation responses to ex vivo agonists,^{5 11} but other studies report no change¹² or a decrease in platelet aggregation^{13 14} by comparison with nonsmokers. The relevance of in vitro platelet aggregation responses to the in vivo events is also uncertain. Thus, the major aim of the present study was to determine the effect of cigarette smoking on platelet thrombus formation in an ex vivo flow chamber system that allowed exposure of flowing blood from human subjects to an arterial medial surface (simulating deep arterial injury) under rheological conditions of a stenotic artery.^{15 16 17} This study was performed in habitual smokers who had stable coronary artery disease, each acting as his or her own control, before and after smoking and while on aspirin treatment. To examine prothrombotic mechanisms of smoking, we also measured plasma catecholamine, plasma thromboxane B₂, and 6-ketoprostaglandin F₁ (6-keto-PGF₁), the stable metabolites of thromboxane A₂ and prostacyclin, respectively, and platelet aggregation responses in whole blood to thrombin before and after smoking.

	Methods

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Study Population
Twelve patients, 9 men and 3 women with a mean age of 55 years (range, 36 to 77 years) and with stable coronary artery disease, gave written informed consent for this study. Ten of the 12 patients had previous myocardial infarction, and 4 had previous coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. All patients were habitual smokers, smoking 15 to 60 (average, 30) cigarettes per day. Medical therapy consisted of aspirin 325 mg/d in all 12 patients, a ß-blocker (propranolol or metoprolol) in 4, a calcium antagonist in 4, transdermal nitroglycerin in 3, and a hypolipidemic agent in 3.

Study Protocol
The subjects came to the laboratory at 7:30 to 10 AM, having fasted and abstained from smoking for at least 12 hours. Their usual medications, excluding sublingual nitroglycerin, were withdrawn for 24 hours before the study. In the laboratory, they remained seated comfortably in an armchair for 30 minutes before baseline blood sampling. A 19-gauge butterfly needle was inserted by a clean puncture without tourniquet into an antecubital fossa vein, and blood was drawn through the ex vivo superfusion flow chambers for 3 minutes by a peristaltic pump (model 7014, Masterflex, Cole-Parmer Instruments Co) placed distally, as previously described.^{15 16} A separate 8-mL sample of blood was drawn directly for plasma thromboxane B₂ and 6-keto-PGF₁ measurement. Blood was also obtained for full blood count, plasma fibrinogen, prothrombin time, and partial thromboplastin time measurements. The needle was then withdrawn, and the whole procedure was usually completed in less than 5 minutes. Immediately after their baseline study, the subjects smoked and inhaled two commercial-brand cigarettes over 10 to 15 minutes while remaining comfortably seated. Each cigarette contained tar 16 mg, nicotine 1.2 mg, and carbon monoxide 16 mg. The ex vivo flow chamber study and blood collections were then repeated at a different venipuncture site 5 minutes after smoking was finished, that is, 15 to 20 minutes after the first test. The patients' pulse rates and cuff blood pressures were measured immediately before and after cigarette smoking.

Platelet Thrombus Formation on Arterial Media
The venous blood was drawn over porcine aortic media held in Plexiglas superfusion flow chambers at a flow rate of 15 mL/min with a peristaltic pump placed distal to the chambers. The flow chambers were set in a water bath at 37°C. The superfusion chambers were designed to mimic the tubelike shape of blood vessels.¹⁷ The upper wall of the chamber had a window permitting direct exposure of flowing blood to arterial media placed over the roof of the chamber without protruding into the lumen. The internal diameters of the flow chambers were 1.5 and 1.0 mm, which at the selected flow rate provided theoretically calculated shear rates of 754 and 2546 s^-1, respectively. Exposure of the arterial media simulates a type 3 arterial wall injury with a thrombogenic response like that seen with plaque rupture.¹⁰

The aortic media used in the superfusion chambers were obtained from normal pig aortas. The aorta was opened longitudinally. A pair of fine forceps was used to peel off the intima and a small thickness of subjacent media, producing a highly thrombogenic arterial media surface.¹⁶ Previous studies have shown that this procedure consistently exposes a very thrombogenic media, much more thrombogenic than exposure of the endothelium.^{15 16 17} The aortic media was cut into segments measuring 15x35 mm to be placed inside the superfusion chambers. Aortic media from the same pig was used for the repeat study in the same patient.

At the end of each study, the aortic segments were fixed in 10% formaldehyde and processed for histological analysis. For this purpose, two cross sections were obtained from the proximal, mid, and distal thirds of each vessel segment, for a total of six histological sections for each shear rate. The tissues were stained with hematoxylin-phloxine-safranin (Fig 1). The platelet thrombi were planimetered, and thrombus size was quantified morphometrically with a light microscope (model Diaplan, Leitz Co) at x100 magnification interfaced with a digitizing tablet and an IBM-AT–compatible computer.^{15 16} The cross-sectional area of platelet thrombi in square micrometers was normalized by the cross-sectional diameter in millimeters of exposed aortic media and averaged for the six histological sections at each shear rate. The morphometric measurements of platelet thrombus had previously been validated by comparison to quantitative ¹¹¹In-labeled platelet deposition in the same sections with a high correlation coefficient between the two methods, r=.84 (P<.0001). Repeated measurements of thrombus size by the same person during 2 separate weeks in 25 patient studies yielded a correlation coefficient of r=.95 (P<.0001).¹⁵ Repeated studies the same morning in 11 patients who were taking a placebo agent and did not smoke showed no serial change in platelet thrombus size assessed by this technique.¹⁶ All platelet thrombus measurements were made by one person (J.H.), who was blinded to the order of the slides, that is, whether they were before or after smoking.

View larger version (87K): [in this window] [in a new window]   Figure 1. Representative histological section of a middle section of the porcine media showing the acute increase in platelet thrombus (pt) formation at a shear rate of 2546 s-1, after smoking compared with presmoking control. M indicates arterial media and elastic lamina.

Determination of Plasma Thromboxane B₂ and 6-keto-PGF₁
Whole nonanticoagulated blood (8 mL) was collected and immediately mixed with 800 µL physiological saline containing 12.8 mg EDTA and 430 µg aspirin in a silicone glass tube. The plasma was obtained by centrifugation at 3000 rpm at 4°C for 30 minutes and stored at -70°C until assay. Thromboxane B₂ and 6-keto-PGF₁ were extracted from plasma by a solid-phase extraction procedure and then measured by specific radioimmunoassay using commercially available kits (Amersham UK). The lower limit of sensitivity of this assay for thromboxane B₂ and 6-keto-PGF₁ is 3.1 pg/mL.

Platelet Aggregation Studies
Ex vivo platelet aggregation in whole blood was performed with an impedance aggregometer (Chronolog Corp) and fresh venous blood.¹⁸ After a 1:1 dilution of native blood with normal saline, the aggregation was induced by addition of 50 µL of the aggregating agent thrombin, 0.075 NIH units/mL (Hoechst Behringet). All aggregation studies were performed within the first minute after blood sampling. The amplitude (in ohms) of platelet aggregation in whole blood was measured at 3 minutes after addition of thrombin agonists, and results were obtained by use of AGGRO/LINK software (Chronolog Corp).

Statistical Analysis
Data values are given as mean±SEM. Pairwise comparisons were made by Student's paired t test. Results were considered significant at P.05, two-tailed value.

	Results

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Hematologic Parameters
The mean hemoglobin level; hematocrit; total leukocyte, polymorphonuclear leukocyte, and platelet counts; prothrombin time; activated partial thromboplastin time; and plasma fibrinogen were not significantly different in the 12 patients before and after they each had smoked two cigarettes (Table 1).

View this table: [in this window] [in a new window]   Table 1. TABLE 1. Hematologic Parameters Before and After Smoking

Heart Rate, Blood Pressures, and Plasma Catecholamines
There were significant increases in heart rate and systolic and diastolic blood pressures after smoking (Table 2). Smoking caused a more than twofold increase in plasma epinephrine (P=.026) but no significant increase in plasma norepinephrine (Table 2).

View this table: [in this window] [in a new window]   Table 2. TABLE 2. Effect of Smoking on Heart Rate, Blood Pressure, and Catecholamines

Platelet Thrombus Formation on Arterial Media
The photomicrographs in Fig 1 show the acute increase in platelet thrombus formation after smoking in a typical study patient. There were no significant differences between thrombus formation in the proximal, mid, or distal portion of the vessel, and the average of the three was calculated. Fig 2 shows the individual changes in platelet thrombus formation from before to after smoking in the 12 patients. The total thrombus formation on the exposed arterial media increased nonsignificantly, by an average of 48% at a shear rate of 754 s^-1, from 2.3±0.4 µm²/mm before to 3.4±0.7 µm²/mm after smoking (P=.19). However, thrombus formation increased significantly, by an average of 65% at a high shear rate of 2546 s^-1, from 2.6±0.4 µm²/mm before to 4.3±0.8 µm²/mm after smoking (P=.014).

View larger version (26K): [in this window] [in a new window]   Figure 2. Graph showing platelet thrombus size (µm2/mm) comparing presmoking and postsmoking effects in the 12 patients. Average platelet thrombus size at a shear rate of 754 s-1 increased by 48% after smoking (P=.19) and by 65% at a high shear rate of 2546 s-1 (P=.014).

Platelet–Vessel Wall Prostanoids and Whole Blood Platelet Aggregation
There was no significant change in plasma thromboxane B₂ levels before and after smoking (58±12 and 57±16 pmol/mL, respectively) or in 6-keto-PGF₁ levels (31±3 and 36±9 pmol/mL, respectively). Fig 3 shows the typical aggregation curves in a study patient, demonstrating the increased amplitude of whole blood platelet aggregation responses to thrombin. The amplitude (in ohms) of platelet aggregation to thrombin 0.075 U/mL increased on average by 25% after smoking (P=.05 versus before smoking), from 17.3±2.2 to 21.7±2.1 .

View larger version (13K): [in this window] [in a new window]   Figure 3. Graph showing whole blood platelet aggregation curve after thrombin stimulation comparing effects before (A) and after (B) smoking in one patient (patient 430). After smoking, there is an increased amplitude (in ohms) of platelet aggregation to thrombin 0.075 U/mL.

	Discussion

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This study demonstrates for the first time in human subjects that smoking acutely increases platelet thrombus formation on arterial media wall (simulating deep arterial injury) exposed to circulating blood under rheological conditions associated with vessel stenosis. This model simulates the in vivo circumstances of vessel stenosis and plaque rupture typical of unstable coronary syndromes, for which smoking is a known risk factor. Furthermore, this study suggests that aspirin inhibition of platelet cyclooxygenase is not sufficient to prevent the acute increase in platelet thrombus formation after smoking. This increase in platelet thrombus formation was associated with an enhanced aggregation response to thrombin.

Previous studies of the effects of smoking on platelet behavior have produced conflicting and inconsistent results. Whether smoking effects are studied in habitual smokers or nonsmokers, the period of smoking abstinence, the number of cigarettes smoked, and the time of postsmoking study all may affect the results. Our patients were habitual smokers with known coronary artery disease and represented a clinically high-risk group for further thrombotic events. To enhance platelet responses and obviate possible downregulatory effects of chronic smoking, these patients were asked to refrain from smoking for at least 12 hours before study. The postsmoking study was performed 5 minutes after they each had completed smoking two cigarettes, taking into account previous studies suggesting maximal platelet aggregation and elevation of catecholamine and nicotine levels within 10 to 20 minutes after exposure to one or more cigarettes.^{5 19} Consistent with these previous studies, we also found an elevation of plasma catecholamine, mainly epinephrine, and associated increases in heart rate and blood pressure after smoking.^{12 19 20}

Platelet aggregometry and the response to a variety of aggregating agents frequently have been used to study the platelet effects of smoking. In these studies, exposure of platelet-rich plasma to ADP, thrombin, epinephrine, or collagen after smoking sometimes caused increased aggregation,^{5 11} normal aggregation,¹² or diminished aggregation.^{13 14} Many technical variables such as preparation of platelet-rich plasma, duration of time between blood sampling and testing, or the absence of other blood elements that affect platelet behavior may generate different results. To obviate some of these difficulties, we tested platelet aggregation in whole blood and within 1 minute of obtaining the blood sample. We found that smoking causes a significant increase in platelet aggregation to thrombin, despite the patient's being on aspirin. It is of note that thrombin is a particularly important in vivo agonist of platelet aggregation at sites of vessel stenosis, plaque disruption, and high shear forces.^{9 10} Even platelet aggregation in whole blood may not adequately reflect in vivo platelet activation, since the effects of shear forces and arterial wall components are not examined by specific agonist–induced platelet aggregation in vitro. To partially overcome this situation, we assessed the effects of smoking in an ex vivo flow chamber model that simulates plaque rupture, deep arterial injury, and rheological conditions typical of vessel stenosis. This model has been validated by Badimon et al¹⁷ from experiments in pigs and by our laboratory in human subjects.^{15 16} The shear rates tested correspond to values from those of normal unobstructed arteries (106 to 500 s^-1) to values typical of stenotic arteries (1680 to 3380 s^-1). There was an average 50% increase in platelet thrombus formation on arterial media after smoking. Although this prothrombotic effect of smoking has not been demonstrated previously in human subjects, Folts and Bonebrake²¹ provided supportive evidence from a dog coronary stenosis model in which inhaled cigarette smoke greatly exacerbated cyclic flow reductions owing to platelet thrombus formation at the site of endothelial injury and coronary stenosis.

There are a number of mechanisms by which smoking may increase platelet thrombus formation. Nicotine, directly or indirectly through the release of endogenous epinephrine, has been shown to increase platelet aggregation.¹¹ Previous studies have reported an excessive in vivo platelet thromboxane generation in chronic smokers.²² However, other studies in habitual smokers have not shown that platelet generation of thromboxane B₂ is acutely increased by smoking.^{12 21} In our study, patients were on aspirin treatment, and baseline thromboxane B₂ levels were low and unaffected by smoking, which is consistent with other reported studies.²³ In our study, the acute increase in platelet thrombus formation after smoking could be related to the increased epinephrine level, which can enhance platelet aggregation despite aspirin treatment.^{10 24 25} Two of the 12 patients we studied were also taking verapamil, a calcium channel blocker with demonstrated antithrombotic effects.¹⁵ However, this number was too small to test the interaction of such agents with aspirin.

In conclusion, our results in coronary disease patients strongly suggest that smoking-enhanced platelet aggregation and platelet thrombus formation may be important mechanisms for the increased risk of acute coronary events in smokers. This acute increase in platelet thrombus formation was not prevented by aspirin. Other deleterious effects of smoking, such as increased arteriosclerosis and leukocyte activation, which can promote thrombosis, vascular damage, and microvascular occlusion, may also play a role. Thus, every effort should be made to encourage smokers to stop.

	Acknowledgments

 
Dr Hung was supported by the University of Western Australia, Queen Elizabeth II Medical Center, Nedlands, Perth, Western Australia. Dr Lacoste was supported by a Faculté des Etudes Supérieures scholarship from the University of Montreal. Dr Lam was supported in part by the Medical Research Council of Canada, the Heart and Stroke Foundation of Canada–Quebec Affiliate, and the Fonds de Recherche en Santé du Québec.

Received December 27, 1994; revision received April 17, 1995; accepted May 25, 1995.

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