(Stroke. 1997;28:1557-1563.)
© 1997 American Heart Association, Inc.
Articles |
Platelet Activation and Lipid Peroxidation in Patients With Acute Ischemic Stroke
From the Department of Neurology, University Hospital Rotterdam, Netherlands (F. van K., D.W.J.D., P.J.K.); the Department of Pharmacology, Catholic University School of Medicine, Rome, Italy (G.C.); and the Department of Pharmacology, University of Chieti "G. D'Annunzio," Chieti, Italy (C.P.).
Correspondence to Fop van Kooten, MD, Department of Neurology, University Hospital Rotterdam Dijkzigt, 40 Dr Molewaterplein, 3015 GD Rotterdam, Netherlands. E-mail:vankooten{at}neuro.fgg.eur.nl
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Abstract |
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Background and Purpose Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A2, or by free radical–catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA2 and F2-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB2 and 8-epi-prostaglandin (PG) F2
, respectively, in 62 consecutive patients
(30 men, 32 women; mean age, 67±14 years) with acute ischemic
stroke. Methods At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays.
Results Repeated periods of enhanced
thromboxane biosynthesis were found in 52% of patients.
Urinary 11-dehydro-TXB2 averaged 221±207 (mean±SD; n=197;
range, 13 to 967) pmol/mmol creatinine in 30 patients
treated with cyclooxygenase inhibitors
(mostly aspirin) at the time of study versus 392±392 (n=186; range, 26
to 2533) in 32 untreated patients (P<.001). The
corresponding values for 8-epi-PGF2
excretion were 74±42 (range, 14 to 206) and 83±65 (range, 24 to 570)
pmol/mmol creatinine (P>.05). The correlation
between the two metabolites was moderate in both untreated patients
(r=.41, P<.001) and patients with
cyclooxygenase inhibitors
(r=.31, P<.001). In a multiple regression
analysis, increased thromboxane production
was independently associated with severity of stroke on admission,
atrial fibrillation, and treatment with
cyclooxygenase-inhibiting drugs.
Conclusions We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.
Key Words: cerebral ischemia • lipid peroxidation • platelet activation • thromboxanes
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, TXA2, or by free radical–catalyzed peroxidation of arachidonic acid, ie, isoprostanes. In previous studies we reported enhanced thromboxane biosynthesis, reflected by the urinary excretion of a major thromboxane metabolite, 11-dehydro-TXB2, in patients with acute stroke.1 2 Thromboxane production could be largely suppressed by low-dose aspirin, suggesting its cyclooxygenase-dependent formation in platelets. The F2-isoprostanes, a family of prostaglandin isomers, are free radical–catalyzed products of arachidonic acid metabolism, of which in vivo formation in humans was first reported by Morrow et al.3 They are initially formed in situ on phospholipids, from which they are subsequently released, preformed presumably by phospholipases.4 They circulate in plasma and are excreted in urine.5 6 Among the F2-isoprostanes, 8-epi-PGF2
is
one of the most abundantly formed under
physiological conditions.5 It was
shown to be a potent vasoconstrictive agent in animal
models in both renal3 7 and pulmonary
vessels.8 9 Furthermore,
8-epi-PGF2 was found to cause platelet
shape change but not aggregation.10 11 Increased plasma
levels of F2-isoprostanes were found in
smokers,12 in patients with the hepatorenal
syndrome,13 and in patients with non–insulin-dependent
diabetes mellitus.14 Increased urinary
8-epi-PGF2 levels were found in healthy
smokers,15 after acetaminophen
overdose,16 in patients treated with
thrombolytic therapy for acute myocardial
infarction,16 and in
hypercholesterolemia.17 Since
F2-isoprostanes are formed by means of free
radical–catalyzed peroxidation of arachidonic acid, it
is suggested that an increased production may be a reflection
of oxidative stress in these different clinical conditions. However,
recent studies suggest that relatively small amounts of
8-epi-PGF2 can also be formed in a
cyclooxygenase-dependent
manner.16 18 19 20 It is not known to what extent urinary
excretion of 8-epi-PGF2 reflects
biosynthesis in the vasculature, since no dose-response infusion
studies have yet been performed to assess its fractional elimination.
Moreover, the metabolism in humans has been only
incompletely characterized.21
In patients with ischemic stroke, both activation of
platelet and monocyte
cyclooxygenases20 and the free
radical–catalyzed pathway are potential sources of
8-epi-PGF2 formation. Moreover, by its
potential effect on vessel walls and platelets, this eicosanoid may
have a negative influence on stroke outcome.
To investigate the actual rate of 8-epi-PGF2
biosynthesis in vivo, we studied the urinary excretion of this
prostaglandin in patients with acute ischemic
stroke. In addition, we related the production of
8-epi-PGF2 to thromboxane
biosynthesis, as reflected by urinary 11-dehydro-TXB2
production. Finally, we evaluated the effect of
cyclooxygenase inhibition on the production
of both eicosanoids.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Patients
We prospectively studied 62 consecutive patients (30 men and 32 women; mean age, 67±14 years) with acute ischemic stroke who were admitted to the Dijkzigt University Hospital Rotterdam and were included in the Rotterdam Stroke Databank between March and December 1994. The University Hospital Rotterdam is an area hospital serving an urban population. This center has no specific selection criteria for the admission of stroke patients; however, young stroke patients are referred more frequently to this center than to the nonacademic centers in the region.
All patients were screened according to a strict protocol consisting of
a full neurological examination, standardized blood tests, at least one
and usually two CT scans of the brain, duplex scanning of the carotid
arteries, and a cardiac analysis that included standard 12-lead
electrocardiography and, if indicated, 24-hour
electrocardiographic monitoring and
echocardiography. All patients were examined within
72 hours, and 42 of them were examined within 24 hours after onset of
neurological symptoms. In patients with stroke in the carotid
territory, the symptoms were further subdivided according to the
presence of cortical signs (aphasia, dysgraphia, dyslexia, or
hemianopia) or one of the following lacunar syndromes: pure motor
hemiplegia, pure sensory stroke, or sensorimotor stroke.22
The CT scans were reviewed by at least two neurologists without
knowledge of the clinical features or the results of the biochemical
studies. Cerebral infarctions were classified according to location and
vascular territory.23 Subcortical infarctions were further
classified as small (
15 mm) or large (>15 mm).
Apart from the neurological history, the following risk factors were
recorded: smoking habits,
hypercholesterolemia (history of
hypercholesterolemia and/or fasting total
cholesterol level >6.5 mmol/L),24
hypertension (history of hypertension and/or systolic blood
pressure >160 mm Hg and/or diastolic blood
pressure >90 mm Hg, treated or not), diabetes mellitus
(history of diabetes mellitus type I or II and/or a random blood
glucose of 
8.0 mmol/L together with an HbA1c
level of 6.3%, treated or not),25 atrial fibrillation
(history of atrial fibrillation and/or atrial fibrillation on
electrocardiogram), and a history of intermittent
claudication, angina pectoris, prior myocardial infarction, or prior
vascular surgery (carotid, coronary, aortic bifurcation, or
peripheral vascular surgery). We carefully recorded the
medication that was used in the days before the stroke and during the
study period, distinguishing patients without antithrombotic or
anticoagulant therapy and those using
cyclooxygenase inhibitors, heparin,
oral anticoagulant therapy, or a combination of these. Patients with
atrial fibrillation were heparinized and received oral anticoagulant
treatment. In patients with aspirin for secondary prevention after
stroke or myocardial infarction, treatment was continued during the
study period. The other patients were included in the IST and were
randomized for treatment with aspirin, heparin, both, or
neither.26 Stroke severity was assessed by means of the
modified Rankin scale27 on admission, and functional
outcome was assessed by means of this scale at 3-month follow-up.
The routine laboratory investigations included hemoglobin, hematocrit, leukocyte, erythrocyte and platelet counts, erythrocyte sedimentation rate, blood urea, creatinine, fasting cholesterol and glucose, and liver enzymes.
Exclusions
Patients were excluded if they required invasive investigations,
in particular angiography, during the study period. Also excluded were
patients with vasculitis, renal disease (creatinine
>200 µmol/L), unstable angina pectoris (recent onset of
class III to IV chest pain according to the Canadian Heart Association,
in the absence of an increase in the MB fraction of plasma
creatinine kinase), or macroscopic hematuria.
Urine Measurements
Two to eight 6-hour samples of urine were collected during the
first 72 hours after the onset of symptoms, starting as soon as
possible after admission to the hospital. The average delay between
onset of symptoms and the start of urinary sampling was 14±12 hours.
The volume of each urine sample was recorded, and the
creatinine concentration was measured. Samples of 50 mL,
containing 1 mmol/L 4-hydroxy-TEMPO as an antioxidant, were
stored in the refrigerator until they were frozen every 6 hours and
stored at -70°C until extraction. Analytical measurements related to
eicosanoid biosynthesis were performed in a manner blinded to the
pharmacological treatments.
Immunoreactive 11-dehydro-TXB2 and
8-epi-PGF2 were extracted from 10-mL
aliquots of each coded urine sample (the pH was adjusted to 4.0 with
formic acid) on SEP-PAK C18 cartridges (Waters Associates) and eluted
with ethyl acetate. The eluates were subjected to silicic acid column
chromatography and further eluted with benzene/ethyl
acetate/methanol (60:40:30, vol/vol). The overall recovery
averaged 74.5±5.1%. The eluates were dried, recovered with 5 mL of
buffer, and assayed in the radioimmunoassay system at a final dilution
ranging from 1:30 to 1:1000 for 11-dehydro-TXB2 and 1:30 to
1:1000 for 8-epi-PGF2.28 29 The
urinary excretion rate of 11-dehydro-TXB2 and
8-epi-PGF2 was expressed as picomoles per
millimole of creatinine.
Validation of the 8-epi-PGF2 assay in urine
was provided by comparison of values obtained by thin-layer
chromatography/enzyme immunoassay (with the same
antibody used in the present study) with an independent analytical
approach, negative ion chemical ionization–gas
chromatography/mass spectrometry. An excellent
correlation between the two methods was obtained: r=.99,
n=9, P<.001, slope of regression line=1.01. Moreover, 12
urine samples were extracted and measured by radioimmunoassay with the
use of two different antisera with different cross-reactivities toward
8-epi-PGE2, and similar values were obtained
(r=.99, n=12, P<.001).29
Statistical Analysis
Mean values between groups were compared with the use of
Student's t test. Values of P<.05 were
considered statistically significant. For time series analysis,
all potential prognostic variables were dichotomized by their
medians or trichotomized at the P33 and P67 when deemed appropriate. In
an exploratory analysis, the relationship between the levels of
8-epi-PGF2 and 11-dehydro-TXB2
in consecutive urine samples and these variables was
analyzed with ANOVA for repeated measures with the use of the
BMDP program 9d.30 The difference between mean levels of
8-epi-PGF2 and 11-dehydro-TXB2
for a certain variable was considered clinically meaningful when
there was a statistically significant difference (P<.05;
ANOVA) for at least two consecutive samples or for a total of four
samples in the series in the same direction. In a logistic regression
analysis with stepwise forward selection of variables, we
identified those factors that were independently related with
repeatedly increased (ie, more than once) 11-dehydro-TXB2
levels.
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Results |
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In the majority of patients (42) sampling started within 24 hours after stroke onset, and in 28 sampling started within 12 hours. Two to eight consecutive 6-hour urinary samples were obtained during the first 48 hours after admission. Thirty patients were treated with cyclooxygenase inhibitors, 26 used aspirin, 1 aspirin and the NSAID indomethacin, and 3 NSAIDs only, of whom 1 used ibuprofen, 1 diclofenac, and 1 naproxen. Three patients with NSAIDs were using this drug before onset of stroke, and during the study it was continued. The patient on diclofenac started with this medication on admission. Of the 27 patients on aspirin, 13 were using it as secondary prevention before the onset of the current stroke, and it was continued during the study. Twelve patients started with aspirin at the beginning of the study, of whom 11 received it in accordance with the IST and 1 after denying consent for randomization in the IST. In 2 patients who had received aspirin from the general practitioner and who denied consent for randomization in the IST, the medication was discontinued during the sampling period. Thus, a total of 17 patients were using antiplatelet medication before the start of the study, which was continued in 15 and stopped in 2, and 13 patients started with antiplatelet medication at the beginning of the study. No difference was found in excretion levels of both eicosanoids between patients who were on antiplatelet medication before the beginning of the study and patients who started on admission, nor was a difference found between patients on aspirin and patients on NSAIDs. Therefore, all patients using cyclooxygenase inhibitors before and/or during the sampling period were compared with patients without cyclooxygenase inhibitors.
Compared with thromboxane excretion levels of control subjects from our previous study (mean+2 SD=251 pmol/mmol creatinine),1 40 patients (65%) had at least one sample with an increased excretion rate of 11-dehydro-TXB2, while in 32 (52%) increased metabolite excretion was found repeatedly. For patients treated with cyclooxygenase inhibitors at the time of study, the corresponding percentages were 53% and 40%, respectively. In untreated patients these percentages were higher (P=.1), at 75% and 63%, respectively.
In 30 patients treated with cyclooxygenase
inhibitors (most of whom were taking 300 mg of aspirin
daily), 197 samples were obtained. Urinary 11-dehydro-TXB2
averaged 221±207 pmol/mmol creatinine (mean±SD;
range, 13 to 967) in these samples. In 186 samples of 32 untreated
patients, 11-dehydro-TXB2 averaged 392±392 (range, 26 to
2533). The difference was statistically significant
(P<.001). No statistically significant difference was found
in the levels of 8-epi-PGF2, with mean
values of 74±42 (range, 14 to 206) in patients on
cyclooxygenase inhibitors and 83±65
(range, 24 to 570) in untreated patients.
Values of 8-epi-PGF2 were only modestly
correlated with 11-dehydro-TXB2 excretion, with a
coefficient of .40 (P<.001). The correlation coefficient
was .35 in patients treated with cyclooxygenase
inhibitors and .41 (P<.001) in untreated
patients.
Fig 1
shows mean values and 95%
confidence intervals of both eicosanoids of all patients for each time
period. The level of 8-epi-PGF2 fluctuated
at approximately 80 pmol/mmol creatinine. No
consistent pattern was found in its excretion over time. In
contrast, excretion of 11-dehydro-TXB2 was increased in the
first period after stroke onset, with a subsequent decline thereafter.
When medication was taken into account, most of this decline could be
attributed to cyclooxygenase inhibition. As shown
in Fig 2, patients treated with
cyclooxygenase inhibitors had a swift
and constant decrease in 11-dehydro-TXB2 excretion to
normal values in the first 24 hours after stroke onset. Metabolite
excretion remained constant in the subsequent periods. In contrast,
patients without cyclooxygenase inhibition had
repeatedly increased values of 11-dehydro-TXB2 excretion.
No difference was found in 8-epi-PGF2
excretion between patients with and without
cyclooxygenase inhibitors.
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In a first approach to evaluate univariately the
relationship between baseline characteristics, risk factors, stroke
characteristics, and medication on the one hand and level of
eicosanoids on the other, we explored differences in peak eicosanoid
excretion. Table 1 shows the mean±SD
value of peak eicosanoid excretion for demographic characteristics and
cardiovascular risk factors. Higher values of
11-dehydro-TXB2 were found in patients with atrial
fibrillation and in patients with congestive heart failure. For
8-epi-PGF2 no differences in excretion rates
were found. Table 2 shows the mean±SD of
peak eicosanoid excretion for stroke characteristics and medication.
Patients with a cortical syndrome had higher peak values of
11-dehydro-TXB2 than patients with a lacunar stroke or a
stroke confined to the vertebrobasilar territory. Higher peak values of
11-dehydro-TXB2 were also found in patients with severe
strokes. Patients using cyclooxygenase-inhibiting
drugs had significantly lower peak values of
11-dehydro-TXB2. Again, for
8-epi-PGF2 no differences in excretion rate
were found.
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As a second step, we performed the time series analysis
described in "Subjects and Methods." In this analysis,
8-epi-PGF2 levels were found to be elevated
in patients with atrial fibrillation. Higher levels of
11-dehydro-TXB2 were found in patients with a history of
intermittent claudication, atrial fibrillation, cortical infarctions,
severe strokes, and poor stroke outcome and in patients with a urinary
catheter. Patients with a history of myocardial infarction and patients
using cyclooxygenase inhibitors had
lower values of 11-dehydro-TXB2. Because patients with a
urinary catheter had increased 11-dehydro-TXB2 levels, we
examined whether this could be explained by urinary tract damage with
subsequent hemorrhage and platelet activation. None of the
patients had macroscopic hematuria. Furthermore, no relationship was
found between level of microscopic hematuria and level of
11-dehydro-TXB2.
In a multiple logistic regression analysis, repeatedly increased 11-dehydro-TXB2 levels were related to severity of stroke on admission, presence of atrial fibrillation, and antiplatelet treatment. Coumarin and heparin treatment were not associated with repeatedly increased 11-dehydro-TXB2 levels.
Finally, repeatedly increased thromboxane metabolite excretion was not a statistically significant independent prognostic factor for outcome when added to stroke syndrome or stroke severity in a multiple logistic regression model, probably because of the rather small size of this study.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study, 65% of patients with acute ischemic stroke had at least one period of enhanced thromboxane biosynthesis, while in half of the patients this occurred repeatedly. This is slightly less than the 85% and 61%, respectively, we found in our previous study.2 However, in the current study almost half of the patients received cyclooxygenase inhibitors. For untreated patients the results were in accordance with our previous findings.
In contrast, levels of 8-epi-PGF2 seemed
rather low, with an average of approximately 80 pmol/mmol
creatinine. Although no control subjects were used in this
study, normal values of 8-epi-PGF2 of
50.7±5.7 and 70.5±33.9 pmol/mmol creatinine were
reported in other studies.16 29 We found only a weak
correlation between levels of 11-dehydro-TXB2 and
8-epi-PGF2. Whereas levels of
11-dehydro-TXB2 decreased in time in patients with
cyclooxygenase-inhibiting drugs, no changes in
urinary 8-epi-PGF2 excretion were found in
these patients. Although some studies suggest that
8-epi-PGF2 can be formed in a
cyclooxygenase-dependent fashion from human
platelets,16 18 our results indicate that in a
clinical condition in which platelets are clearly
activated, there are no concurrent changes in
8-epi-PGF2 formation and excretion.
Moreover, no significant differences in
8-epi-PGF2 were found between patients with
and without cyclooxygenase-inhibiting drugs, again
indicating that levels of 8-epi-PGF2 found
in patients with acute ischemic stroke are probably not
produced in a cyclooxygenase-dependent fashion. In
univariate analysis, no factors that were found to
be associated with 11-dehydro-TXB2 production were
also related to 8-epi-PGF2 excretion. Only
in patients with atrial fibrillation was
8-epi-PGF2 found increased in two
consecutive periods in the time series analysis.
Increased levels of 8-epi-PGF2 excretion
were found after thrombolytic therapy in patients with
acute myocardial infarction.16 These findings suggest that
the source of 8-epi-PGF2 under these
conditions is free radical–catalyzed lipid peroxidation associated
with occlusion/reperfusion. Enhanced formation of
8-epi-PGF2 might be expected in patients
with acute stroke, a condition in which formation of free radicals
occurs. However, in our patients no evident peaks of
8-epi-PGF2 excretion could be detected. In
stroke patients it is difficult to predict if and when reperfusion
occurs. Still, we should have detected significant changes in
8-epi-PGF2 excretion if they occurred, since
we collected 6-hour samples of urine during the time in which
reperfusion might be expected in the majority of
patients.31 Alternatively, increased oxidant stress might
occur as an early transient event, largely missed by the timing of our
urine sampling, or else the signal-to-noise ratio might be too small to
be detected at a distance from its source.
Increased 11-dehydro-TXB2 excretion was univariately associated with a history of intermittent claudication or atrial fibrillation, the presence of a urinary catheter, cortical infarctions, severe strokes, and worse outcome. A urinary catheter may induce urinary tract damage with subsequent hemorrhage and possibly platelet activation. In our study a urinary catheter was indeed associated with enhanced 11-dehydro-TXB2 level but also with stroke severity and outcome. In our ward, patients with severe strokes are always given a urinary catheter, which explains the relation to severity and outcome. None of the patients had macroscopic hematuria, and no association was found between the level of microscopic hematuria and the level of urinary 11-dehydro-TXB2. Therefore, it is unlikely that urinary 11-dehydro-TXB2 levels were the result of urinary tract damage. Data on the number of leukocytes and epithelial cells in the urine were incomplete, and therefore the contribution of these cells to urinary 11-dehydro-TXB2 could not be evaluated.
The other factors associated with increased thromboxane production—ie, atrial fibrillation, large subcortical and cortical infarctions, stroke severity and outcome, and the absence of cyclooxygenase inhibitors—may reflect the fact that atrial fibrillation is more likely to cause large cortical infarctions that are mostly severe. Moreover, patients with atrial fibrillation usually receive heparin and coumarin treatment and not cyclooxygenase inhibitors. However, in a multiple logistic regression analysis, atrial fibrillation, stroke severity, and cyclooxygenase inhibition were independently related to the level of urinary 11-dehydro-TXB2.
An important remaining question is whether a causal relationship exists between the extent and duration of platelet activation, as reflected by the level of 11-dehydro-TXB2 excretion, and stroke severity and outcome. In this study repeatedly increased thromboxane production was not a statistically significant independent prognostic factor for outcome when added to stroke syndrome or stroke severity in a multiple logistic regression model, probably because of the rather small size of our study. However, the results of trials that evaluate the value of antiplatelet therapy in acute ischemic stroke, of which the IST26 and the Chinese Acute Stroke Trial32 are by far the largest, may contribute to define the role of platelet activation in this setting. Preliminary results of these studies indicate that aspirin has a beneficial effect, albeit small, in acute ischemic stroke.32 33
We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in F2-isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) F2-isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the European Union (BMH1-CT93-1533) and by a grant from The Netherlands program for research on aging, NESTOR, funded by the Ministry of Education, Culture, and Sciences and the Ministry of Health, Welfare, and Sports. The expert assistance on data handling of the late Dr Anet van Latum and the assistance of Annemarie Wijnhoud are gratefully acknowledged.
Received January 6, 1997; revision received May 12, 1997; accepted May 12, 1997.
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