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(Stroke. 2000;31:1856.)
© 2000 American Heart Association, Inc.
Original Contributions |
Hemostatic Markers in Patients at Risk of Cerebral Ischemia
From the Divisions of Neurology (R.C., F.B.) and Hematology (S.S., J.R.L.), Montreal General Hospital, and Department of Epidemiology and Biostatistics (C.W., F.R.), McGill University, Montreal, and the Division of Neurology, Hôpital de l’Enfant Jésus, Laval University, Quebec City (A.M., D.S., B.L.), Canada.
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Abstract |
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Background—Increased levels of markers of hemostasis may assist in the determination of the extent of carotid occlusive disease and the identification of neurologically intact individuals at increased risk of ischemic events.
Methods—We conducted a prospective study of 304 subjects,
including 82 with a recent (
7 days) transient ischemic attack
(TIA), 157 asymptomatic individuals with a cervical bruit,
and 65 control subjects. Baseline evaluation included a neurological
assessment, ECG, cervical ultrasonography, and cerebral CT and/or MRI.
Levels of markers of coagulation and fibrinolytic activity were also
determined. Results were analyzed in relation to the degree of
carotid disease and the subsequent occurrence of cerebral and cardiac
ischemic events.
Results—Over a mean follow-up period of 2.8 years (SD, 1.3
years), 114 ischemic events occurred. Survival analyses
showed that prothrombin fragment 1.2 (F1.2) was a predictor
of time to cerebral and cardiac ischemic events in the combined
TIA and asymptomatic bruit group (relative risk [RR],
1.46; 95% CI, 1.18 to 1.81) as well as in the asymptomatic
bruit group separately (RR, 1.70; 95% CI, 1.14 to 2.53). In the TIA
group, both F1.2 (RR, 2.36; 95% CI, 1.19 to 4.68) and
severe (
80%) carotid stenosis (RR, 3.53; 95% CI, 1.19 to
10.51) were predictive of time to ischemic stroke, myocardial
infarction, or vascular death.
Conclusions—In patients with TIAs and in asymptomatic individuals with cervical bruits, F1.2 levels were found to be independent predictors of subsequent cerebral and cardiac ischemic events. Our results are consistent with an active role of the coagulation system through upregulation of thrombin in carotid disease progression and in the pathogenesis of ischemic events in patients at risk.
Key Words: : cerebral ischemia • diagnosis • hemostasis • prognosis • stenosis
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Altered hemostasis has been reported to occur in different clinical conditions, ranging from ischemic coronary disease and peripheral vascular insufficiency to acute ischemic stroke and reversible cerebral ischemia.1 2 3 4 5 6 7 8 9 10 11 To date, most studies reporting abnormalities of hemostasis in cerebrovascular conditions have focused on patients with ischemic strokes, a condition that may, in itself, lead to a spurious elevation of markers secondary to a breakdown of the blood-brain barrier and release of procoagulants from necrotic cerebral tissue.7 The precise role of these markers has yet to be clarified, especially in nondisabled individuals who are at higher risk of cerebral infarction or other serious vascular events. Current prognostic models that use traditional risk factors have limited potential and have not had a major practical impact at the individual level.12
In the present study, we examined the diagnostic and prognostic role of several of these markers that reflect either activation of the coagulation system or decreased activity of the fibrinolytic process in neurologically intact subjects at various risks for ischemic vascular events. This was justified by the fact that hemostatic markers play an active role in the atherothrombotic process, which, in most cases, leads to the occurrence of ischemic events. Individuals were grouped according to the presence of recognized vascular risk factors, the presence and degree of asymptomatic carotid disease, and the occurrence of recent transient ischemic attacks (TIAs). Abnormalities in hemostatic marker profiles reflecting increased thrombotic activity might allow identification of higher-risk subgroups, which may lead to investigational and therapeutic changes, ultimately decreasing their risk of disabling deficits. A similar approach has recently been suggested in other groups of patients at high risk for stroke and other cardiovascular events.13
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From July 1993 to September 1996, all patients seen at either the Montreal General Hospital or l’Enfant Jésus Hospital with a diagnosis of recent TIA (
7 days) in either the carotid or
vertebrobasilar territory were approached for participation. TIA was
defined as a sudden episode of focal neurological deficit believed to
be vascular in nature with complete resolution within <24
hours.14 During the same period, all neurologically
asymptomatic patients with a cervical bruit referred from
the community or recruited from specialty clinics were also approached
and formed the asymptomatic carotid bruit (ACB) group. A
healthy control group consisted of spouses of patients, patients with
nonneurovascular problems, or patients from other specialty clinics.
For all subjects, enrollment was conditional on informed consent.
Information on medical history and vascular risk factors was obtained
directly from the individuals and review of hospital charts. All
participants underwent a complete neurological evaluation at baseline.
Determination of the presence of vascular risk factors was based on
previously published criteria.15 We excluded patients <50 years of age, those with an ischemic lesion on either CT or MRI of the brain, patients taking oral anticoagulants, and those with potential causes of TIA other than atherosclerosis or conditions that could affect hemostasis, such as liver disease, coagulopathy, congestive heart failure, or arrhythmia, including atrial fibrillation, venous thromboembolic disorders, malignancy, surgery, or any invasive procedure in the previous 3 months. In addition, patients with a recent myocardial infarction (<6 months) or angina (<2 weeks) were excluded because these conditions have been shown to be associated with abnormal marker levels.3
All groups had blood drawn at baseline for measurement of complete
blood count, platelets, prothrombin time, international normalized
ratio, partial thromboplastin time, and liver, renal, and lipid
profiles. Levels of the following markers were also determined:
fibrinopeptide A (FPA), thrombin-antithrombin complexes
(TAT), prothrombin fragment F 1.2(F1.2),
D-dimer, plasminogen activator
inhibitor-1 (PAI-1), and
plasmin-
2-antiplasmin complexes (PAP).
Venous blood was obtained atraumatically by 2 experienced nurses and collected in tubes with sodium citrate for measurement of D-dimer, TAT, F1.2, PAI-1, and PAP; blood was also collected into sodium citrate with added anticoagulants as supplied with the kit for measurement of FPA. Platelet-free plasma was obtained by centrifuging the blood immediately in a refrigerated centrifuge at 3000 rpm for 15 minutes. Plasma was placed in aliquots and kept at -70°C until testing. D-Dimer and FPA were quantified by ELISA with kits from Murex Diagnostics, Canada. The laboratory reference range for D-dimer is 33 to 341 ng/mL; for FPA, 0.5 to 1.7 ng/mL. F1.2, TAT, and PAP were measured by ELISA with kits from Behring Diagnostics Canada Inc. Laboratory reference ranges are as follows: F1.2, 0.2 to 2 nmol/L; TAT, 0.8 to 2.6 µ/L; and PAP, 161 to 503 µ/L. PAI-1 was assayed by ELISA with a kit from Biopool, Canada. All tests were carried out according to manufacturer’s suggestions. The PAI-1 reference range is 0 to 13.9 ng/mL.
Except for the control group, all individuals were scheduled for a 12-lead resting ECG and a cervical duplex ultrasound. The results of the ultrasound study were categorized as a reduction in luminal diameter in the following 6 categories: (1) no stenosis, (2) 1% to 15% stenosis, (3) 16% to 49% stenosis, (4) 50% to 79% stenosis, (5) 80% to 99% stenosis, and (6) occlusion. This method was validated previously at both institutions.16 In addition, all patients in the TIA group were scheduled for a CT scan of the brain within 1 month of the qualifying event and a cerebral MRI to exclude a recent cerebral infarction that could act as a trigger for a spurious increase in marker levels. The TIA patients were treated medically or surgically as judged appropriate and according to accepted standards of care.14 At initial assessment, 73% of the patients in the TIA group were already receiving either acetylsalicylic acid or another antiplatelet compared with only 32% (P=0.001) in the ACB group.
For patients who required anticoagulant therapy or surgery during the course of the study, only blood samples drawn before these interventions were included in the analysis; in addition, these patients were censored from further follow-up starting at the time of the intervention. All patients were assessed every 6 months in the neurovascular clinics to document any new or further vascular events, such as TIAs, stroke, new-onset angina, unstable angina, myocardial infarction, or vascular or nonvascular death. Clinical staff were blinded to the results of the hemostatic marker levels.
Statistical Analysis
In the first step, the clinical and demographic characteristics
of the patient groups were compared with the use of ANOVA for age and
marker levels. Multiple comparisons of means, adjusting the probability
value for the number of comparisons, were done using Tukey’s
Studentized Range Test. We used 
2 tests to
compare groups on categorical variables (eg, sex, presence of
diabetes mellitus). All analyses were performed with SAS
software.17 For some analyses, marker
concentrations were categorized into terciles and quartiles. To assess
the impact of inclusion of extreme values of FPA, which may reflect a
traumatic puncture18 (ie, FPA >22 ng/mL),
analyses were performed with all subjects and subjects with FPA
levels 22 ng/mL. Results were similar with both approaches.
The diagnostic potential of the markers was investigated
through logistic regression, in which the outcome was defined as
membership in the TIA group versus membership in the ACB group,
excluding control subjects (n=239), and degree of carotid
stenosis defined as 50% or 80%. The prognostic value of
markers and clinical variables to predict future events was
assessed in the TIA/ACB groups combined, as well as for a higher-risk
group that consisted of the TIA group and those patients from the ACB
group with >50% stenosis in 1 carotid. This was done with
logistic regression and survival analysis using the Cox
proportional-hazards model.19 Adjusted odds ratios (ORs)
and 95% CIs are reported for the logistic regression models; adjusted
relative risks (RRs) and 95% CIs are reported for the Cox
proportional-hazards models.
Two additional outcomes were defined: time to first ischemic event (ie, TIA, stroke, myocardial infarction, new-onset angina, and vascular death) and time to first serious vascular event (ie, myocardial infarction, stroke, and vascular death). Survival analysis was used for both types of outcomes, and for the first outcome, subjects who had not experienced any of these ischemic events by the end of follow-up were considered censored at their last date of follow-up. Similarly, for the second, more restrictive outcome, those subjects who had not experienced a myocardial infarction or stroke or had died from vascular causes were considered censored at the date of the last follow-up. Annualized rates of these 2 outcomes were also obtained for the TIA/ACB and high-risk groups. A value of P<0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Levels of markers were determined in 304 subjects, 82 presenting with an acute TIA, 157 from the ACB group, and 65 control subjects. Table 1
displays
the distribution of the demographic characteristics and the vascular
risk factors across groups. Age and sex were not significantly
different between groups; however, hypertension and heart disease were
more common in the TIA and ACB groups, as expected. Table 2 shows the mean levels of the markers
across groups. The mean levels of both D-dimer and PAP were
significantly higher in the TIA group compared with the control group
(P<0.01 for both comparisons). The mean levels of
F1.2 were also slightly higher in the TIA group
compared with control subjects but did not reach statistical
significance (0.05<P<0.1). In comparisons of the ACB and
control groups, significant differences were also found, with higher
mean levels in the ACB group for D-dimer
(P<0.01), PAI-1 (P<0.01), and PAP
(P<0.05). No significant differences in marker levels were
found between the TIA and ACB groups.
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Logistic regression analyses were performed to determine which
variables were predictive of either group membership (TIA or ACB)
or degree of carotid stenosis. Analyses categorizing
FPA above or below the 75th percentile (FPA 2.7 versus <2.7 ng/mL)
yielded a significant association between higher values of FPA and
membership in the TIA group after adjustment for other variables
(OR, 2.02; 95% CI, 1.04 to 3.92).
Results of cervical ultrasonography were available for all 82 patients
in the TIA group and for 155 patients (99%) in the ACB group. The
proportion of patients with 1 carotid stenosis 50% was
significantly higher in the ACB group (56%) than in the TIA group
(41%) (P=0.032). Logistic regression analyses of
the combined TIA/ACB group showed that upper quartile values of
F1.2 (OR, 2.04; 95% CI, 1.10 to 3.78), presence
of ischemic heart disease (OR, 2.04; 95% CI, 1.14 to 3.64),
and hypercholesterolemia (OR, 1.92; 95% CI,
1.11 to 3.32) were all predictors of carotid stenosis (50%)
on ultrasonography. In addition, the presence of peripheral
vascular disease was found to be a strong predictor of severe (80%)
carotid stenosis (OR, 2.74; 95% CI, 1.41 to 5.33). In the TIA
group only, upper quartile levels of F1.2 (OR,
4.26; 95% CI, 1.44 to 12.61) and presence of ischemic heart
disease (OR, 3.12; 95% CI, 1.09 to 8.98) remained predictors of severe
(80%) carotid stenosis.
The mean follow-up period for the combined TIA and ACB group was 2.83
years (SD, 1.35 years); during this time, a total of 128 clinical
events occurred, of which 89% were vascular. As expected, the
proportion who experienced 1 event in the TIA group (48.7%) was
significantly higher than the proportion in the ACB group (24.4%)
(P=0.001). The mean follow-up in the former group was 2.51
years (SD, 1.26 years) compared with 2.99 years (SD, 1.36 years) in the
ACB group (P=0.01). For both groups, most events were
neurological and occurred primarily in the first 2 years of follow-up.
Table 3 lists the first clinical events
for both groups.
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We also focused on patients who experienced a greater number of
ischemic events during follow-up by grouping those patients
from the TIA and ACB groups who had 2 ischemic events (n=27)
and comparing them with patients with either no or only 1
ischemic event (n=207). The 2 groups were comparable with
respect to age, sex, length of follow-up, and presence of known
vascular risk factors. Significant increases in the mean levels of 2 of
the markers in the multiple event group, F1.2
(2.3 versus 1.7 nmol/L, P=0.0002) and TAT (42.9 versus 5.5
µ/L, P=0.0056), were identified.
Using Cox proportional hazards analyses, we assessed the
relationship between vascular risk factors, marker levels, and the time
to occurrence of clinical events in all patients.
F1.2 was found to be an independent predictor for
all ischemic events, including TIA, ischemic stroke,
new-onset angina, myocardial infarction, and vascular death, in the
combined group of TIA and ACB patients (RR, 1.46; 95% CI, 1.18 to
1.81), as well as in the ACB group only (RR, 1.70; 95% CI, 1.14 to
2.53). In the TIA group, F1.2 (RR, 2.36; 95% CI,
1.19 to 4.68) and severe degree (80%) of carotid stenosis
(RR, 3.53; 95% CI, 1.19 to 10.51) were independently predictive of
more serious vascular events, such as myocardial infarction,
ischemic stroke, and vascular death.
Prognostic survival analyses were also performed in the group
of patients (n=171) composed of the TIA group and subjects from the ACB
group with a carotid stenosis of 50%,
representing a higher-risk subgroup.20 21 In
this group, both F1.2 (RR, 1.46; 95% CI, 1.16 to
1.85) and peripheral vascular disease (RR, 2.06; 95% CI,
1.15 to 3.71) were independent predictors for any ischemic
event. F1.2 remained an independent predictor
(RR, 1.70; 95% CI, 1.29 to 2.23) of myocardial infarction,
ischemic stroke, and vascular death.
Table 4 shows the estimated RRs for
different vascular events in 3 subgroups of F1.2,
defined by terciles, both in the combined TIA/ACB group and in the
high-risk group. With the lowest tercile as the reference group, RR
increases with increasing levels of F1.2.
Annualized event rates for all vascular events were estimated on the
basis of the lower and upper terciles for both the TIA/ACB combined
group and the high-risk group. In the TIA/ACB group, the annual event
rate was 5.12% in the lower F1.2 tercile
compared with 17.01% in the upper tercile (P<0.01). In the
high-risk group, the annual rates were 7.54% for the lower tercile
compared with 21.37% in the upper tercile (P<0.01).
Figures 1 and 2 show the relationship between time to
first ischemic event and F1.2 levels in
relation to carotid stenosis (Figure 1) and
peripheral vascular disease (Figure 2). In the
combined TIA/ACB group, subjects with F1.2 levels
below the 33rd percentile were more likely to be event free by the end
of follow-up regardless of the level of carotid stenosis. In a
similar vein, a lower level of F1.2 in the
high-risk group was predictive of being event free during follow-up
regardless of the presence or absence of peripheral
vascular disease.
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Indicates stenosis <80% and F1.2
below 33rd percentile; 
, stenosis <80% and
F1.2 above 33rd percentile; •, stenosis 
, stenosis
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study was designed to assess both the diagnostic and prognostic potential of selected markers of hemostasis in individuals at increased risk for cerebral and cardiac ischemic events. FPA proved to be directly and independently correlated with the recent occurrence of a TIA. F1.2 was correlated with a more severe degree of carotid stenosis and was found to be a predictor of future ischemic events.
As expected, several indicators of arterial disease, including severity of carotid stenosis, and the presence of peripheral vascular disease were also found to be independently related to outcome, and others, such as heart disease and hypercholesterolemia, were positively associated with the extent of carotid disease. Higher concentrations of F1.2 were significantly associated with more severe carotid stenosis in the combined TIA/ACB group. Previous studies in different populations22 23 24 have also reported a positive association between hemostatic factors and degree of carotid disease. In the present study, 2 of the markers that reflect thrombin generation, namely F1.2 and TAT, were significantly elevated at baseline in patients who suffered multiple ischemic events during their follow-up. This suggests an active pathophysiological role for thrombin in the recurrence of ischemic events in these patients. These results are in keeping with pathological findings that support a role for plaque instability and thrombus formation in symptomatic cerebral and cardiac disease.25 26 27
Although several studies have reported hemostatic abnormalities in the context of ischemic coronary syndromes1 2 3 and cerebral infarction,7 8 9 10 few have prospectively studied the potential value of these hemostatic factors in neurologically intact individuals harboring various degrees of carotid atheroma.28 29 Our results are in accordance with these previous reports that showed a correlation between marker levels and outcome. The diagnostic and prognostic value of F1.2 is also supported by 2 recent studies; the first reported that high levels of F1.2 were independent predictors of myocardial infarction in asymptomatic hypertensive men,30 and the second showed that F1.2 was positively associated with the extent of coronary atherosclerosis in patients with established cardiac disease.31
We found that concentrations of F1.2 identified
different levels of risk for vascular events, as shown in Table 4
, similar to what has been reported for other markers of
coagulation in patients with angina.1 The up-to-5–fold
increase in risk of ischemic events with increasing
concentrations of F1.2 suggests that increased
thrombin generation precedes vascular events in our population. The
magnitude of risk might actually be underestimated because a
substantial proportion of patients at baseline were taking aspirin,
which can itself decrease levels of F1.2.32
For both the TIA/ACB and high-risk groups, annual ischemic event rates were >3 times higher in patients with F1.2 levels in the upper tercile compared with those in the lower tercile. We also found that higher levels of FPA, a marker of thrombin-mediated conversion of fibrinogen to fibrin, were positively correlated with the TIA group, consistent with previous reports showing similar results in patients with either acute TIAs11 or acute reversible coronary syndromes.3 4
Elevated levels of hemostatic markers have also been reported in patients with nonvalvular atrial fibrillation33 34 35 and are thought to reflect activation of the coagulation system, which contributes to the increased risk of ischemic stroke seen in this condition. To the best of our knowledge, no previous studies have reported on a potential role for activation of the coagulation system in individuals at risk for ischemic cerebral events in the absence of an established cardioembolic source. Some patients who present with higher levels of markers, such as F1.2, may be at increased risk for ischemic events and may respond better to anticoagulants rather than to antiplatelet therapy because treatment with warfarin decreases the levels of F1.2 more markedly than does aspirin.36 37 An approach that suggests the use of biological markers as therapeutic indicators has already been proposed, with determination of F1.2 levels to monitor anticoagulant treatment and response to therapy in patients with nonvalvular atrial fibrillation.38 39 A substudy of an ongoing randomized trial40 is also currently looking at the potential value of F1.2 as a guide to the use of antithrombotic therapy, which may include either aspirin or warfarin in the prevention of stroke recurrence after a first noncardiogenic cerebral infarction.
Our results suggest that F1.2 may identify patients with TIA or asymptomatic carotid disease who are at increased risk for stroke and other ischemic events. This could accelerate patient investigation and may lead to more effective therapeutic interventions. Further studies, however, are needed to confirm these results, and ultimately only randomized clinical trials will be able to establish the precise value of F1.2 and other markers in the selection of more optimal preventive strategies in these patients.
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Acknowledgments |
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This work was supported by the Quebec Heart and Stroke Foundation. We wish to thank Sandy Lavigne for her excellent secretarial work.
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Footnotes |
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Reprint requests to Dr Robert Côté, Montreal General Hospital, 1650 Cedar Ave, Room L7-408, Montreal, Quebec, Canada H3G 1A4.
Received March 26, 2000; revision received May 23, 2000; accepted May 23, 2000.
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