The Effect of Acute Ingestion of a Large Dose of Alcohol on
the Hemostatic System and Its Circadian Variation
Heikki Numminen, MD; Martti Syrjälä, MD, PhD; Günther Benthin, PhD;
Markku Kaste, MD, PhD; Matti Hillbom, MD, PhD
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Background and Purpose—Heavy binge drinking may trigger the onset of embolic stroke and acute myocardial infarction, but
the underlying mechanisms are unclear. The effects of binge drinking on the hemostatic system and its circadian variation
have not been investigated. We investigated the effects of an acute intake of a large dose of alcohol (1.5 g/kg).
Methods—Twelve healthy, nonsmoking men participated in sessions where they were served ethanol in fruit juice or served fruit
juice alone and, lying in a supine position, were followed up for 12 to 24 hours. The treatments were randomized and separated
from each other by a 1-week washout period. Blood and urine were collected for hemostatic measurements.
Results—The urinary excretion of the platelet thromboxane A2 metabolite 2,3-dinor-thromboxane B2 was significantly (P⬍0.05)
greater during the night after an evening intake of alcohol than during the control night. A smaller increase was observed
during the daytime after an intake of alcohol in the morning. The effects on the endothelial prostacyclin metabolite
2,3-dinor-6-ketoprostaglandin F1␣ excretion were negligible. A 7-fold increase in plasminogen activator inhibitor 1 activity
was observed after both morning (P⬍0.05) and evening (P⬍0.01) intakes of alcohol.
Conclusions—This is the first study to suggest that acute ingestion of a relatively large but tolerable dose of alcohol
transiently enhances thromboxane-mediated platelet activation. The observations also demonstrate alcohol-induced
changes in the normal circadian periodicity of the hemostatic system in subjects not accustomed to consumption of
alcohol. (Stroke. 2000;31:1269-1273.)
Key Words: alcohol 䡲 circadian rhythm 䡲 hemostasis 䡲 prostaglandins 䡲 thrombolysis
M
any studies indicate that regular light-to-moderate alcohol drinking protects against coronary heart disease.1
Some studies also suggest that alcohol protects against
ischemic stroke of atherothrombotic origin2 and peripheral
arterial disease.3 These effects have been ascribed to the
antiatherogenic and antithrombotic actions of ethanol or some
other components of alcoholic beverages. However, some
investigations also suggest that heavy alcohol consumption
promotes the development of carotid arterial atherosclerosis
and that heavy binge drinking may precipitate fatal myocardial infarction and embolic stroke.4 – 6
Atherogenesis and thrombogenesis may both be influenced by
drinking patterns. Acute heavy drinking may exert different
effects compared with those of moderate regular drinking. The
favorable effects of alcohol consumption on the lipid profile
were recently observed to be independent of the drinking pattern
in moderate-to-heavy drinkers.7 However, the effects on thrombogenesis were not reported and have yet to be investigated.
The activities of some parameters of the hemostatic system
show significant circadian variation. The onsets of myocardial
infarction and ischemic stroke also show circadian variation,
with a peak at the time when people wake up and become
active.8 –12 This phenomenon has been speculated to result from
the circadian periodicity of the hemostatic system.8 –16 In fact,
increased platelet aggregability9 and decreased fibrinolytic activity13–15 occur in the morning. The former has been observed in
healthy volunteers after getting out of bed but not during steady
bed rest, which suggests that the act of getting out of bed is
responsible for the effect,9,16 whereas the morning decrease in
fibrinolytic activity has been observed to be attenuated by
keeping the volunteers in upright posture.17 The effects of acute
alcohol ingestion on platelet aggregability and fibrinolytic activity in relation to the circadian periodicity of the hemostatic
system have not yet been investigated.18
To find out whether acute ingestion of a large dose of alcohol
influences the hemostatic system and its circadian pattern, 12
healthy human volunteers were randomly assigned to ingest a
large dose of ethanol in fruit juice or fruit juice alone either in the
morning or in the evening and were then followed up in a supine
position for 12 hours. We measured plasminogen activator
inhibitor 1 (PAI-1) activity, excretion in urine of platelet
thromboxane and endothelial prostacyclin 2,3-dinor-metabolites,
Received November 2, 1999; final revision received March 17, 2000; accepted March 17, 2000.
From the Department of Neurology, Oulu University Hospital (H.N., M.H.), Oulu, Finland; and the Department of Clinical Chemistry, Helsinki
University Hospital (M.S.), Department of Clinical Physiology, Karolinska Institutet at Huddinge University Hospital (G.B.). and Department of
Neurology, Helsinki University Hospital (M.K.), Helsinki, Finland.
Correspondence to Prof Matti Hillbom, MD, Department of Neurology, Oulu University Hospital, FIN-90220, Oulu, Finland. E-mail
[email protected]
© 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1269
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serum thromboxane B2 which reflects the capacity of platelets to
form thromboxane in vitro and platelet aggregability ex vivo.
Subjects and Methods
Subjects and Study Design
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Twelve healthy, nonsmoking men aged 20 to 39 years volunteered
for the trial. They were all nonobese (body mass index 23.8⫾1.6
[mean⫾SD]), infrequent light drinkers (1 to 5 drinks during weekends or less frequently), and they had abstained from alcoholic
beverages and drugs for 1 week before the trial. None had arterial
hypertension, heart disease, hematological disorders, hyperlipemia,
diabetes, or any other serious disease in their history, and none were
on regular medication. After a full explanation of the purpose,
nature, and risks of the study, written informed consent was obtained
from each. The study protocol was approved by the Ethical Committee of the Helsinki University Central Hospital. The investigation
conforms with the principles outlined in the Declaration of Helsinki.
Each subject participated in 3 sessions, 2 ethanol sessions and 1
control session. The order of the sessions for each individual was
randomized, and there was a 1-week washout period between the
sessions. The 3 arrangements of treatment and control were equally
distributed. The subjects were not allowed to eat for 6 hours before
the start of the session, and they served as their own controls. The
alcohol sessions started either at 7:00 PM or at 8:00 AM and lasted for
12 hours. If the session started in the morning, the subjects had to
arrive in the hospital on the preceding evening and spend the night
sleeping in hospital beds. The control session always started in the
evening and lasted for 24 hours, including both the control night and
the control day. During every session the subjects were awakened at
7 AM. During the daytime they lay in bed, reading books or watching
TV. They were allowed to go to the toilet but not move otherwise.
All the sessions were started by taking baseline blood samples and by
voiding the urinary bladder. From 7:30 until 10:00 PM or from 8:30 until
11:00 AM, the subjects received half-hourly drinks containing either fruit
juice (not including grapefruit) or, during the ethanol session, an equal
volume of a mixture of the same fruit juice and ethanol (2 mol/L
solution). The time schedule of drinking and the total amount of ethanol
(1.5 g/kg of body weight) were chosen to provoke a tolerable but
moderately severe intoxication. During the control session, the subjects
were given carbohydrate-rich snacks together with the fruit juice to
balance their calorie intake, but no meals were served. Accordingly,
during both the alcohol and the control sessions the total energy intake
was kept constant (14.8 kcal/kg per 12 hours).
Blood and Urine Sampling
Blood samples were taken at 3-hour intervals, starting either at 7 PM
or at 8 AM After voiding the bladder, urine was collected for 12
hours. After preparation, the plasma and urine samples were frozen
at ⫺70°C for subsequent testing.
Platelet Aggregation
Platelet aggregation was measured by Born’s method.19 Blood was
collected with minimal stasis via a plastic cannula into tubes containing
3.8% sodium citrate. To obtain platelet-rich plasma (PRP) and plateletpoor plasma (PPP), the blood samples were centrifuged at 330g for 10
minutes and at 1500g for 10 minutes. PPP was used to adjust the platelet
count of PRP to 250⫻109/L. Platelet aggregations were measured with
a dual-channel aggregometer (Chrono-Log, Coulter Electronics Ltd),
starting 45 minutes after the blood sampling. Arachidonic acid (AA;
1 mmol/L, Sigma Chemical Co) and collagen (5 ␮g/mL, Hormon
Chemie GmbH) were used to stimulate platelets in PRP. The reaction
was stopped by 1 mmol/L HCl after 5 minutes. The aggregation results
were expressed as the maximum percentage change in light transmittance during the 5-minute period.
Determination of Plasminogen Activator
Inhibitor Activity
Citrated plasma was used to analyze PAI-1 activity (units per
milliliter). The blood samples were immediately put into crushed ice
Figure 1. Effect of acute ingestion of a large dose of ethanol
(1.5 g/kg in fruit juice) on urinary excretion of 2,3-dinor-PGF1␣
and 2,3-dinor-TXB2 in healthy humans. Values are mean⫾SEM.
The mean value of 2,3-dinor-TXB2 of the ethanol night (28.3
pg/␮mol creatinine, 95% CI 20.0 to 30.5) differs significantly
(**P⬍0.01) from that of the control night (15.7 pg/␮mol creatinine, 95% CI 11.6 to 19.8). Day indicates period from 8 AM to
8 PM; Night, from 7 PM to 7 AM.
and centrifuged for 20 minutes at 4°C and at 1500g. PAI-1 was
measured as duplicate determinations with a colorimetric assay
(Stachrom PAI, Diagnostica Stago) in the kinetic mode using an
automatic coagulometer (Thrombolyzer, Behnk Elektronic GmbH &
Co) equipped with a chromogenic channel.
Determination of Prostanoids and Other
Laboratory Parameters
Urine was collected for the determination of 2,3-dinor-6-ketoprostaglandin F1␣ (2,3-dinor-PGF1␣) and 2,3-dinor- thromboxane B2
(2,3-dinor-TXB2). The samples were analyzed by a stable isotope
dilution assay with a mass spectrometer (Finnigan MAT 4500)
coupled to a gas chromatographer (Varian Vista 6000), as previously
described.20,21 The urinary excretion of prostanoids was related to the
amount of creatinine excreted.
The capacity of platelets to form thromboxane was measured as
serum thromboxane B2 (TXB2). For the measurement of serum
TXB2, 2 mL of blood was drawn into a glass tube and incubated at
37°C for 60 minutes to allow clotting. The amount of TXB2 was
measured from the serum by ELISA (Cayman Co).
Creatinine in urine and blood ethanol were determined by routine
liquid chromatographic and gas-liquid chromatographic techniques,
respectively. The ingestion of 1.5 g/kg ethanol in fruit juice within 2.5
hours resulted in peak blood concentrations of 32.3⫾4.4 mmol/L (95%
CI 29.3 to 35.2) and 31.0⫾9.3 mmol/L (95% CI 28.7 to 33.4) in the
evening and in the morning, respectively. These values correspond to
blood levels that cause a moderately severe but tolerable acute alcoholic
intoxication (1.5/1000) in a subject who has not developed central
nervous system tolerance to alcohol. The time needed to eliminate the
dose of alcohol from the body was more than 12 hours.
Statistical Methods
The results were expressed as mean⫾SEM, SD, or 95% CI. The
time-dependent changes, including the testing of trend during each
session, were compared by repeated-measures ANOVA, either as a
1-way analysis for a single session or as a 2-way analysis between
the sessions. A paired t test was also used to test the differences in
urinary excretion of prostanoids and the Wilcoxon signed rank test to
test the differences in plasma PAI-1 values between the control and
alcohol sessions. The associations between the different parameters
were calculated by simple regression. All the analyses were made
with Statview II or SuperAnova (Abacus Concepts).
Results
Alcohol drinking in the evening produced a significant
increase in urinary excretion of 2,3-dinor-TXB2 (Figure 1).
Numminen et al
Effect of a Large Dose of Ethanol on Hemostasis
1271
Urinary Excretion of Prostaglandin Metabolites, Urine Volume, and Creatinine Concentration in Each Session
Day
Night
Control
Ethanol
Control
Ethanol
2,3-dinor TXB2, ng/12 h
140.9 (97.2–184.6)
153.0 (123.5–182.4)
140.1 (100.2–180.0)
216.3 (160.2–272.5)
2,3-dinor PGF1␣, ng/12 h
161.5 (104.2–218.8)
123.6 (95.4–151.8)
152.9 (112.9–193.0)
145.4 (89.2–201.6)
Volume of urine, mL/12 h
1180 (890–1480)
2100 (1870–2330)
1010 (800–1210)
1790 (1560–2020)
Creatinine concentration, mg/mL
0.84 (0.55–1.12)
0.37 (0.29–0.46)
1.15 (0.77–1.53)
0.49 (0.39–0.60)
Values are presented as mean, with 95% CIs in parentheses.
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The mean difference was 13.0 pg/␮mol creatinine (95% CI
6.2 to 19.8, P⬍0.01) between the values of the night (from
7 PM to 7 AM) following alcohol ingestion and those of the
night following fruit juice ingestion (control night). Alcohol
drinking during the daytime also caused an increase. In
contrast, the urinary excretion of 2,3-dinor-PGF1␣ was similar
during the day (from 8 AM to 8 PM) and the night, irrespective
of whether alcohol was consumed or not. The urinary
excretion of 2,3-dinor-TXB2 decreased during the control
night compared with the control day (mean difference 3.3
pg/␮mol creatinine, 95% CI 1.0 to 5.7, P⬍0.01). The urinary
excretion of 2,3-dinor-TXB2 correlated positively with the
serum TXB2 values (r2⫽0.18, slope 0.20, 95% CI 0.01 to
0.40, P⬍0.05). The correlation was not significantly influenced by alcohol.
Because alcohol ingestion could have influenced the urinary excretion of creatinine, we also calculated urinary
excretion of the prostaglandin metabolites per total volume
urine excreted to avoid bias due to a possible effect of alcohol
on creatinine excretion (Table). A significant effect of alcohol
drinking was confirmed. During the evening drinking session
the mean difference in urinary excretion of TXB2 was 78.6
ng/12 h (95% CI 21.1 to 136.0, P⬍0.05). The urinary
excretion of 2,3-dinor-TXB2 expressed in this way also
correlated positively with the serum TXB2 values (r2⫽0.20,
slope 0.22, 95% CI 0.1 to 0.35, P⬍0.01).
The platelet aggregability observed during the daytime
(control session) showed significant variation over time when
tested with both AA (P⬍0.05) and collagen (P⬍0.001).
During the control session, platelet aggregability decreased
from morning to afternoon, as was expected (Figure 2). It
decreased from 8 AM until 2 PM, after which it increased
again. A comparison between the values obtained during the
control night and the control day also showed significant
heterogeneity in collagen-induced aggregation (P⬍0.05) but
not in AA-induced aggregation (P⬎0.05). The differences in
the curves for the alcohol and control periods were not
statistically significant, although drinking of alcohol tended
to inhibit the daytime decrease in platelet aggregability.
PAI-1 activity was significantly increased by the intake of
alcohol (Figure 3). An increase was observed irrespective of
whether the alcohol was ingested in the morning (P⬍0.05) or
in the evening (P⬍0.01). The alcohol-induced increase was
transient and peaked at about 3 hours after the discontinuation
of drinking. Thereafter, PAI-1 started to decrease, and it
decreased rapidly until the end of the session. Unfortunately,
we have no data to show the levels shortly after the end of
each session. We did not follow the PAI-1 value after alcohol
had been eliminated from the blood. PAI-1 showed circadian
Figure 2. Circadian variation of mean platelet aggregation
(mean⫾SEM) during the alcohol (⽤) and control (F) sessions.
Aggregations were induced by AA (1 mmol/L) and collagen
(5 ␮g/mL).
Figure 3. Effect of acute ingestion of a large dose of ethanol (1.5
g/kg in fruit juice) on PAI-1 activity. * P⬍0.05 compared with the
respective baseline value (7 PM or 8 AM, by paired t test).
1272
Stroke
June 2000
variation during the control session, as was expected. The
PAI-1 levels were lowest in the evening and remained higher
from 1 AM until 5 PM.
Discussion
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The main finding of our experiment was the significant
increase in urinary excretion of 2,3-dinor-TXB2 in the absence of a simultaneous change in urinary excretion of
2,3-dinor-PGF1␣ after acute ingestion of a large dose of
alcohol. Another interesting finding was a significant alcoholinduced increase in plasma PAI-1 activity.
The increased urinary excretion of 2,3-dinor-TXB2 reflects
increased platelet activation in vivo.22,23 Platelets are activated in the arterial circulation, particularly at sites that are
stenosed or ulcerated by atherosclerosis, but also at sites of
bifurcation and sharp bends in the absence of atherosclerosis.
The extent of activation could be influenced by hemodynamic
factors, such as the velocity of blood flow and vasospasm.
The absence of a simultaneous change in urinary excretion
of 2,3-dinor-PGF1␣ suggests that factors capable of influencing endothelial prostacyclin were not significantly stimulated
in subjects who were kept in a supine position. Unfortunately,
we did not measure markers of endothelial activation, such as
von Willebrand’s factor or thrombomodulin. However, other
investigators have found these 2 markers to be uninfluenced
or negatively associated with alcohol intake.24 –26 The subjects
were kept supine during the day and were asleep during the
night. In fact, it has been shown that the endothelial formation
of prostacyclin is low at rest but increases during physical
activity.27,28
Acute drinking of a large dose of alcohol produces
tachycardia and increases blood flow. The effect is transient
and dose dependent, and may lead to platelet activation
because of increased shear. The increased urinary excretion
of 2,3-dinor-TXB2 in our experiment was possibly due to
acute platelet activation caused by a change in turbulence and
shear associated with an alcohol-induced rapid increase in
blood flow.
Alcohol drinking increases urinary excretion of 2,3-dinorTXB2 dose dependently. In this study, a rather large dose of
alcohol was ingested. We have recently shown that acute
drinking of a moderate dose of alcohol does not increase
urinary excretion of 2,3-dinor-TXB2.28a Our findings seem to
be reliable because the levels of prostanoids did not markedly
deviate from those reported in physiological conditions.29
The rapid increase in PAI-1 activity after an acute ingestion of
a large dose of alcohol suggests decreased fibrinolytic activity.
Unfortunately, we did not measure plasminogen activator (tPA)
activity, which is the most important parameter reflecting fibrinolytic activity. However, Hendriks et al30 have shown that an
acute intake of even a moderate dose of beer, spirits, or wine, if
ingested with an evening meal, causes a significant decrease of
tPA activity. Our observations indicate that the alcohol-induced
increase of PAI-1 activity occurs to the same extent during the
night and the day, and that an acute intake of a relatively large
dose of alcohol disturbs the normal circadian pattern of PAI-1
activity. Accordingly, it is likely that the decrease of fibrinolytic
activity observed by Hendriks et al30 also occurs irrespective of
whether alcohol is ingested in the evening or in the morning.
A high shear and a sudden increase in shear could cause the
activation of circulating platelets.31 This may not be a harmful
effect if the vessels are nonatheromatous. However, a rapid
increase in shear-induced platelet activation may aggravate
the imbalance between thromboxane and prostacyclin at sites
of severe atherosclerosis, because it has been shown that
prostacyclin synthesis is deficient in atherosclerotic carotid
plaques.32 Such an imbalance could rapidly develop during
heavy alcoholic intoxication and lead to local thrombus
formation if not simultaneously compensated for by enhanced
prostacyclin formation. Because fairly heavy physical activity
is needed to stimulate prostacyclin formation,27 bed rest and
severe alcoholic intoxication could be a harmful combination
for individuals with atherosclerotic arteries. In addition, sleep
apneas are aggravated by alcohol and may precipitate atrial
fibrillation.33 Acute intake of large doses of alcohol by those
who snore and experience sleep apnea may therefore be
detrimental. Drinking of alcohol may promote thrombogenesis, and atrial fibrillation may detach emboli from intracardiac thrombi. Palomäki and Kaste34 have already observed
increased morning production of platelet thromboxane B2 in
subjects suffering from the obstructive sleep apnea syndrome.
The sharp increase of PAI-1 activity caused by acute
alcohol intake could result in a transient decrease of fibrinolysis. PAI-1 is released into the vasculature by platelets and
endothelial cells. It has recently been shown that the
thrombolysis resistance of platelet-rich thrombi is largely due
to the presence of PAI-1.35 Accordingly, the increase of
PAI-1 activity in vivo by moderate-to-heavy acute alcohol
intake suggests that alcohol ingestion could transiently enhance thrombolysis resistance and thereby retard lysis of the
already-formed thrombi. However, the effect seems to be
rapidly compensated for,30 and regular alcohol intake results
in enhanced fibrinolytic activity.36,37 In vitro experiments
indicate enhancement of fibrinolysis by alcohol,38,39 but the
significance of such findings with regard to alcohol intake in
humans is unclear.
The present study is the first to show effects of acute heavy
alcohol ingestion on urinary excretion of prostanoids. The
increase in the urinary excretion of 2,3-dinor-TXB2 by
alcohol intake, a parameter of platelet function in vivo, was
modest compared with the effects observed in clinical cardiovascular disease causing signs and symptoms.40,41 None of
our healthy volunteers showed signs or symptoms of any
cardiovascular disease, nor did they report any adverse events
after drinking the relatively large dose of alcohol. Heavy
drinkers who suffer a stroke after binge drinking certainly
have other factors that predispose to stroke, such as underlying atherosclerotic lesions and cardiac abnormalities. Our
findings could be among those which contribute, but alcohol
drinking may cause also other effects that are still more
important and need to be identified.
Taken together, the present results indicate that acute
ingestion of a relatively large but tolerable dose of alcohol
results in a marked elevation of plasma PAI-1 activity and a
modest increase of urinary excretion of 2,3-dinor-TXB2. The
effects seem to be independent of the circadian variation of
the hemostatic system and may favor thrombogenesis. The
circadian variation in hemostatic factors that maintains resis-
Numminen et al
tance to thrombosis in healthy men during sleep seems to be
disturbed by acute heavy drinking of alcohol. Therefore,
heavy drinking in the evening before going to bed could be
more hazardous than heavy drinking during the daytime.
Acknowledgments
This study was supported by the Oulu Medical Research Foundation
(Drs Numminen and Hillbom). We wish to thank Mrs Saija Eirola
for technical assistance.
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The Effect of Acute Ingestion of a Large Dose of Alcohol on the Hemostatic System and Its
Circadian Variation
Heikki Numminen, Martti Syrjälä, Günther Benthin, Markku Kaste and Matti Hillbom
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Stroke. 2000;31:1269-1273
doi: 10.1161/01.STR.31.6.1269
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