(Circulation. 1999;100:1374-1379.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence for Prothrombotic Effects of Exercise and Limited Protection by Aspirin
From the Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Correspondence to Paul Hjemdahl, MD, PhD, Department of Clinical Pharmacology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
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Abstract |
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Background—Exercise may activate platelets and leukocytes and promote thrombosis. The effects of aspirin treatment on the prothrombotic effects of exercise have not been established.
Methods and Results—A total of 15 healthy men performed exhaustive exercise without and with 1 week of pretreatment with aspirin (500 mg/day). Before and immediately after exercise, platelet aggregability ex vivo was measured by filtragometry, and venous blood samples were obtained. Whole-blood flow cytometry was used to determine platelet and leukocyte activation and platelet-leukocyte aggregates. Exercise increased platelet P-selectin expression, CD11b expression in neutrophils and lymphocytes, and platelet and leukocyte responses to thrombin, ADP, platelet activating factor, and N-formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. Consistent with enhanced platelet and leukocyte activation, more circulating platelet-platelet and platelet-leukocyte aggregates were detected after exercise (P<0.001 for both). Filtragometry readings were shortened, and plasma soluble P-selectin and prothrombin fragment 1+2 were elevated. Aspirin markedly reduced the urinary excretion of 11-dehydrothromboxane B2, decreased P-selectin expression in single platelets at rest (P<0.05), and inhibited fMLP-induced neutrophil CD11b expression, but it did not attenuate exercise-induced increases in platelet aggregability, platelet P-selectin expression, leukocyte CD11b expression, platelet-leukocyte aggregate formation, soluble P-selectin, or prothrombin fragment 1+2.
Conclusions—Exercise induced platelet and leukocyte activation and platelet-leukocyte aggregation in vivo, and it increased platelet and leukocyte responsiveness to in vitro stimulation. Aspirin treatment attenuated certain signs of platelet activity in vivo at rest and fMLP-induced neutrophil activation in vitro, but it did not attenuate the prothrombotic effects of exercise.
Key Words: exercise • aspirin • platelets • leukocytes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Strenuous exertion promotes a prothrombotic state1 and may trigger acute myocardial infarction.2 Exercise may induce thrombocytosis and platelet activation in vivo and enhanced platelet reactivity in vitro, but results concerning exercise-induced platelet activation are far from unanimous.1 3 4 Strenuous exercise also induces leukocytosis and leukocyte activation, especially in patients with ischemic heart disease.5 Previous studies focused on either platelet or leukocyte activation, and little is known about their interaction during exercise, although the prothrombotic state involves multicellular activation. Therefore, it is of interest to evaluate how exercise influences multicellular activation in vivo, the responsiveness of the cells to in vitro stimulation, and platelet-leukocyte aggregate formation in vivo and in vitro.
Aspirin is a widely accepted antiplatelet drug that lowers cardiovascular mortality and morbidity.6 Aspirin exerts its antithrombotic effects mainly through inhibition of thromboxane formation, which may be overemphasized when platelet aggregation is evaluated under conditions of low extracellular calcium concentrations.7 Aspirin treatment does not influence the activation of single platelets, when evaluated by whole-blood flow cytometry,8 9 suggesting that thromboxane becomes important only during platelet aggregation. Aspirin has little or no effect on exercise-10 or norepinephrine-induced11 platelet aggregability in vivo. The antithrombotic effect of aspirin may, however, also involve other mechanisms, such as attenuation of erythrocyte-mediated activation of platelets,12 inhibition of platelets via a neutrophil-mediated, nitric oxide/cGMP dependent mechanism,13 and reduced thrombin generation.14 15 Moreover, aspirin may attenuate superoxide anion generation by neutrophils,16 inhibit adhesion molecule expression of monocytes,17 and inhibit lipid body and eicosanoid generation in leukocytes.18 Therefore, further investigation of the possible influence of aspirin treatment on platelet-leukocyte interactions and on the prothrombotic effects of exercise is of interest.
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Methods |
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Subjects
A total of 16 healthy, nonsmoking men aged 28±4 years (height, 183±1 cm; weight, 78±2 kg), gave informed consent to participate in the study, which was approved by the Ethics Committee of the Karolinska Institute. One subject was excluded before the data analysis due to an infection 1 week before his second visit.
Study Design
The study was an open crossover study comparing no treatment and
aspirin treatment (500 mg/day for 7 days) during exercise. The interval
between experiments was 
2 weeks; aspirin preceded control in 8
subjects. The volunteers were instructed to refrain from caffeine
intake 12 hours before experiments, to take the medication between 7
and 8 AM, to collect all their morning urine, and to have a
light lunch 2 hours before their visit. On arrival (at 1
PM), they rested for 30 minutes in the supine position.
Thereafter, blood samples were taken, and a resting filtragometry
measurement was performed on the other arm. After another 30 minutes of
rest (to process resting samples), exercise commenced on a computerized
bicycle ergometer (Siemens-Elema AB), with a starting workload
of 30 W and increments of 10 W/min. Blood pressure and heart rate were
monitored, and fatigue was estimated by the 20-grade Borg scale;
exercise was terminated on exhaustion. Sampling and a filtragometry
measurement were repeated immediately thereafter.
Flow Cytometric Analysis
Platelets were identified with the fluorescein
isothiocyanate (FITC)-conjugated anti-CD42a (GPIX) monoclonal
antibody (MAb) Beb1 (Becton Dickinson); leukocytes were
identified with the R-phycoerythrin (RPE)-conjugated pan-leukocyte
CD45-MAb T29/33 (Dakopatts AB). Platelet P-selectin expression was
determined by the RPE-conjugated anti–P-selectin MAb AC1.2 (Becton
Dickinson), and leukocyte CD11b expression by the FITC-conjugated MAb
BEAR 1 (Immunotech). FITC- and RPE-conjugated isotypic MAb DAK-GO1 were
used as negative controls. The agonists used were ADP, human
-thrombin, platelet activating factor (PAF), and
N-formyl-methionyl-leucyl-phenylalanine (fMLP). When thrombin was used,
clotting was prevented by the peptide GPRP (reagents were from
Sigma).
Samples were prepared as described previously.19 20 Within 3 minutes of collection, 5 µL of citrated whole blood was added to 45 µL of HEPES-buffered saline containing appropriately diluted antibodies and agonists; the mixture was then incubated at room temperature for 20 minutes. Samples were diluted and mildly fixed with formaldehyde saline (0.2% for platelet analyses19 and 0.5% for leukocyte and aggregate measurements20 ) before analysis using a Coulter EPICS XL-MCL flow cytometer.
Platelet P-Selectin Expression
The flow cytometric analysis of platelets in whole
blood has been described previously.19 We made this minor
modification: a RPE-CD62P MAb was used to monitor P-selectin positive
cells in the platelet population.
Platelet-Platelet Aggregates
The method of determining platelet-platelet aggregates
(PPAs) was adapted from previous methods,20 21 and it
reflects circulating PPAs.21 Briefly, the cytometer was
triggered by FITC-CD42a fluorescence. Samples were diluted so
that <50 FITC-positive events/s were detected to minimize the risk of
coincidence in the flow chamber. Events were subjected to
2-parameter (forward scatter versus side scatter)
analysis, and FITC-positive events larger than single
platelets were regarded as PPAs; the percentage of PPAs in the
total platelet population was calculated.
Platelet-Leukocyte Aggregates
Platelet-leukocyte aggregates (PLAs) were determined as
described previously.20 The percentages of
platelet-conjugated leukocytes among total leukocytes, lymphocytes,
monocytes, and neutrophils were obtained.
Leukocyte CD11b Expression
The protocol for leukocyte CD11b analysis was modified
from the method for PLA analysis.20 Total
leukocytes, lymphocytes, monocytes, and neutrophils were gated and
subjected to single-color (FITC-CD11b) analysis. Mean
fluorescence intensities in leukocytes and subpopulations were
determined.
Filtragometry Ex Vivo
Filtragometry was used to measure platelet aggregates ex
vivo.3 22 Blood was drawn from an antecubital vein and
anticoagulated by heparin before passing through a nickel filter (pore
size, 20 µm). Rapid filter occlusion with a low
tA value (ie, aggregation time)
indicates high platelet aggregability.
Urinary 11-Dehydrothromboxane B2
Urinary 11-dehydrothromboxane
B2 was determined by enzyme immunoassay (SPI-BIO)
using a sample work-up procedure developed in our laboratory. Aliquots
of morning urine were stored at -80°C. After thawing, samples were
centrifuged (1400g at 4°C for 5 minutes). The
supernatant was diluted 1:2 with 63 mmol/L ammonium bicarbonate
buffer (pH 8.6) and incubated 3 hours to convert
11-dehydrothromboxane B2 to its open
ring form before extraction with Bond-Elute Certify II columns (Varian)
and elution of the analyte with 2% formic acid in methanol. The eluate
was cryoevaporated, resuspended (pH 8.6), and incubated 6 hours before
analysis. Data are expressed in relation to urinary
creatinine.
Plasma Variables and Cell Counting
Blood was immediately centrifuged (1400g at
4°C for 10 minutes), and plasma was stored at -80°C. Plasma
soluble P-selectin (R&D Systems), von Willebrand factor
(Diagnostica Stago), elastase (DPC Biermann GmbH), and
prothrombin fragment 1+2 (F1+2; Behringwerke AG)
were determined by enzyme immunoassay. Plasma
catecholamines were determined as previously
described.23 Red cell counts, total and differential
leukocyte counts, platelet counts, and hematocrit were
analyzed by a Technicon H.3 RTX cell counter (Miles Inc).
Statistics
Data are presented as mean±SEM (n=15 unless specified).
Effects of exercise and aspirin were analyzed by 2-factor
repeated measures ANOVA (SuperANOVA, Abacus Concepts). Individual
measurements were compared with Wilcoxon's signed rank test
(StatView 4.5, Abacus Concepts), and P<0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Physiological and Hematologic Parameters
Maximal workload was 283±9 W without and 284±11 W with aspirin treatment (exercise duration, 25±1 minutes). Physiological responses to exercise were also similar on the 2 occasions (data without treatment are given). Exercise increased heart rate (from 60±2 to 199±3 bpm), systolic blood pressure (from 120±3 to 190±4 mm Hg), and plasma norepinephrine (from 1.49±0.08 to 14.28±1.01 nmol/L) and epinephrine levels (from 0.14±0.02 to 1.09±0.31 nmol/L) (P<0.001 for all). Exercise also increased blood cell counts (Table
).
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Platelet Activation
Exercise increased P-selectin–positive single platelets in
unstimulated samples (Figure 1) and
enhanced responses to thrombin and ADP (Figure 2). Aspirin decreased
P-selectin–positive platelets at rest (from 1.1±0.2% to
0.8±0.2%; P<0.05), but it failed to protect against the
exercise-induced activation of single platelets (Figure 1),
and it did not attenuate responses to agonist stimulation in vitro
(data not shown). Exercise increased soluble P-selectin (n=14) from
55.3±4.7 to 69.4±6.4 µg/L without aspirin and from 53.7±2.7 µg/L
to 71.4±3.7 µg/L with aspirin (P<0.001 for exercise
effect; no aspirin effect).
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Exercise increased circulating PPAs from 0.71±0.06% to 0.95±0.08%
and PPA counts from 1.63±0.16 to 2.74±0.23
x109/L. Aspirin treatment did not significantly
reduce PPAs either at rest or after exercise (Figure 1
). In
agreement with PPA data, exercise shortened filtragometry readings
(Figure 1), from 209±51 to 75±18 s without aspirin and from
314±79 to 70±4 s with aspirin treatment (P<0.001 for
exercise effect). Aspirin did not attenuate the filtragometry response
to exercise.
Aspirin decreased the urinary excretion of 11-dehydrothromboxane B2 from 50.4±3.9 to 10.9±0.9 ng/mmol creatinine (P<0.001) or by 77±2% (range, 60 to 91%), indicating good compliance.
Leukocyte Activation
Exercise increased leukocyte counts (Table). Increased
CD11b expression was found in neutrophils (mean fluorescence
intensities increased from 0.63±0.07 to 0.72±0.07;
P<0.05) and lymphocytes (from 0.32±0.01 to 0.39±0.02;
P<0.01). Exercise enhanced agonist-stimulated CD11b
expression in neutrophils (Figure 3) and
lymphocytes (P<0.01) but not in monocytes.
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) and with
(•) aspirin treatment. The agonists dose-dependently increased CD11b
expression before exercise (solid lines), and responses were enhanced
(P<0.001) after exercise (dotted lines). Aspirin
treatment inhibited (P<0.05) fMLP-induced neutrophil
CD11b expression (D).
Aspirin did not influence basal CD11b expression before or after
exercise; it did attenuate fMLP-induced CD11b expression in leukocytes
(P<0.05) and neutrophils (Figure 3) but not in
lymphocytes or monocytes.
Plasma elastase (n=15) increased from 30.9±2.6 to 75.1±7.0 ng/mL after exercise without aspirin and from 35.9±3.3 to 75.2±6.3 ng/mL after exercise with aspirin treatment (P<0.001 for exercise effect; P=0.47 for aspirin effect).
Platelet-Leukocyte Aggregates
Exercise increased PLAs from 2.8±0.3% to 3.9±0.5%
(P<0.001); PLA counts increased markedly, with responses in
all leukocyte subpopulations (Figure 4).
Aspirin treatment had no effect on this (PLAs were 2.5±0.2% before
and 3.6±0.3% after exercise).
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Thrombin, ADP, and PAF enhanced heterotypic aggregate formation
dose-dependently, but to different extents. PLAs increased from
2.8±0.3% to 7.3±1.6% and 34.4±3.0% with
3x10-7 and 10-5 mol/L ADP,
respectively, and to 26.6±4.5% and 57.6±2.1% with 0.02 and 0.08
U/mL thrombin, respectively. At 10-9 mol/L PAF,
PLAs increased to 7.4±2.6% (P<0.01). Despite maximal
leukocyte activation (Figure 3D), 10-6
mol/L fMLP only increased PLAs to 3.5±0.3% (P<0.01). The
propensity to form PLAs differed among leukocyte subpopulations. For
example, with 0.08 U/mL thrombin, lymphocytes had a 10% propensity to
form PLAs, monocytes had a 60% propensity, and neutrophils had a 90%
propensity.
Consistent with platelet and leukocyte sensitization,
agonist-induced PLA formation in vitro increased after exercise
(P<0.001), as illustrated for thrombin in Figure 5. Similar results were obtained with ADP
and PAF, whereas fMLP had minor effects (data not shown).
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Other Variables
Exercise increased plasma von Willebrand factor antigen
(n=13) from 0.91±0.06 to 1.60±0.10 U without aspirin and from
1.03±0.07 to 1.61±0.11 U with aspirin (P<0.001 for
exercise effect; no effect of aspirin). Plasma
F1+2 (n=14) was 0.60±0.05 nmol/L at rest on both
occasions and, after exercise, it increased to 0.70±0.06 nmol/L
without aspirin and 0.82±0.07 nmol/L with aspirin (P<0.001
for exercise effect; no effect of aspirin).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Strenuous exercise induced in vivo activation and sensitization of platelets, leukocytes, and endothelial cells (as reflected by von Willebrand factor levels). Interestingly, exercise also enhanced platelet-leukocyte aggregate formation and thrombin generation (F1+2 levels). Aspirin treatment afforded little protection against these prothrombotic effects of exercise, but it attenuated neutrophil responsiveness to agonist stimulation in vitro.
Platelet responses to exercise depend on several factors, such as exercise intensity, the exercise protocol used, and physical fitness. Mild exercise may even suppress platelet function, whereas more strenuous exercise seems to cause intensity-dependent platelet activation.1 3 4 10 24 However, results are inconsistent,1 3 4 presumably for methodological reasons, and responsiveness may be attenuated by endurance training.4 25 In the present study, exercise activated platelets in vivo, as reflected by several methods, in relatively fit men. Thus, exercise increased circulating P-selectin–positive single platelets, platelet sensitivity to in vitro stimulation, and circulating platelet-platelet aggregates. Filtragometry readings, which reflect platelet aggregability, were shortened. Soluble P-selectin, which reflects activation of platelets rather than endothelial cells,26 also increased. Exercise-induced thrombocytosis due to mobilization of platelets from storage pools1 may further promote a prothrombotic state.
Platelet activation during exercise may be related to several
mechanisms. Anaerobic metabolism may be
involved.1 Catecholamines in plasma increased
10-fold, and they might act synergistically with other agonists to
promote platelet activation.11 27
Norepinephrine is more likely to be involved than
epinephrine.11 Furthermore, the
cardiovascular responses to exercise (ie, increases in
cardiac output and blood pressure and alterations in blood flow
resulting in increased shear forces) and enhanced thrombin generation
may contribute to exercise-induced platelet
activation.28
Exercise induced leukocytosis, but responses differed among leukocyte
subpopulations. Leukocytosis may be due to the release and
demarginalization of leukocytes from the bone marrow, the spleen, and
other organs; elevations of cardiac output and
catecholamines may contribute to it.29
Interestingly, exercise markedly enhanced the resting and
agonist-stimulated expression of CD11b in neutrophils and lymphocytes,
with only slight increases in monocytes. Plasma elastase also
increased, supporting the contention that exercise activates
neutrophils in vivo. Elastase is secreted by activated
neutrophils, and it may influence platelets by promoting fibrinogen
binding to platelet glycoprotein IIb/IIIa receptors and
attenuating thrombin effects by cleaving the platelet
glycoprotein Ib subunit.30 Elastase
attacks elastic fibers of the vascular extracellular matrix and may
contribute to arterial wall aging.31 Moreover,
elastase activity is positively correlated to
cardiovascular risk factors, such as hypertension and
diabetes.32
Exercise enhanced PLA formation, both in the absence and presence of in vitro stimulation. Although the implications of this are presently unclear, evidence suggests that there are functional consequences of PLAs. Conjugated platelets may facilitate leukocyte rolling, adhesion, and migration into the vessel walls33 and enhance leukocyte accumulation at inflammatory sites and, thus, tissue damage. Conjugated platelets may also help to clear activated leukocytes from the circulation.34 Moreover, platelet-monocyte aggregates may enhance thrombin generation by bringing together tissue factor expressed on monocytes, platelet-released coagulation factor Va, and a catalytic surface on the platelet phospholipid bilayer membrane.
Taken together, the present data support the idea that exercise causes multicellular activation, which may promote thrombosis. However, exercise also activates fibrinolysis,1 35 and a disturbed fibrinolytic response to exercise seems to have prognostic implications.36 The thrombotic risk during exercise will depend on the balance between platelet activity, fibrin formation, and fibrinolysis.
The protective effect of aspirin treatment involves complex mechanisms, some of which were evaluated in the present study. We found that aspirin inhibited P-selectin expression on single platelets in vivo at rest, although this was not seen by previous investigators.8 9 However, we found no effect of aspirin on thrombin generation in vivo or soluble P-selectin, circulating PPAs, or PLAs at rest. Furthermore, aspirin did not attenuate the responses to exercise of any of these parameters, despite good compliance, as verified by consistent decreases of urinary 11-dehydrothromboxane B2 excretion.
Interestingly, aspirin inhibited fMLP-induced neutrophil CD11b expression, both at rest and after exercise. Aspirin and other nonsteroidal antiinflammatory drugs may inhibit neutrophil adhesion,37 transmigration,38 superoxide anion generation,16 and adhesion-molecule expression.17 The mechanisms involved in the present findings are not clear, and further investigation is warranted.
In conclusion, the present data demonstrate that strenuous exercise induces multicellular activation in vivo, enhances the in vitro responsiveness of both platelets and leukocytes, and promotes a prothrombotic state. Novel findings are that exercise increases platelet-leukocyte aggregation and that aspirin treatment may reduce resting platelet P-selectin expression in vivo and agonist-induced neutrophil CD11b expression. However, the prothrombotic effects of exercise were not attenuated by aspirin.
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Acknowledgments |
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The authors thank Maud Daleskog, Maj-Christina Johansson, Pia Hillelson, and Lena Höjvall for expert technical assistance, Christina Perneby for her important contributions to the development of the thromboxane metabolite assay, and Drs Marianne Yngen, Johanna Albert, Henrik Arnell, and Carl-Olav Stiller for help with the monitoring of exercise tests. Supported by grants from the Swedish Medical Research Council (5930), the King Gustaf V and Queen Victoria Foundation, and the Swedish Heart-Lung Foundation.
Received April 27, 1999; revision received June 15, 1999; accepted June 22, 1999.
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