(Stroke. 1998;29:2261-2267.)
© 1998 American Heart Association, Inc.
Original Contributions |
Increased Fibrinogen Levels and Acquired Hypofibrinolysis in Young Adults With Ischemic Stroke
From the Departments of Clinical Neuroscience (B.K., J.M.), Clinical Chemistry (T.K.N., J.H.), and Medicine (B.C., T.O.), University Hospital of Umeå (Sweden).
Correspondence to Bo Kristensen, MD, PhD, Department of Clinical Neuroscience, University Hospital, S-901 85 Umeå, Sweden. E-mail Bo.Kristensen{at}neuro.umu.se
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Abstract |
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Background and Purpose—Elevated fibrinogen levels and abnormalities in the fibrinolytic system are related to the occurrence of cardiovascular events. However, the role of these factors in the evolution of cerebrovascular disease has received less attention, in particular in young stroke patients. The aim of this study was to evaluate possible abnormalities in plasma fibrinogen levels and the state of the fibrinolytic system in young adults with a first-ever ischemic stroke.
Methods—This study is based on 102 consecutive patients aged 18
to 44 years admitted between January 1991 and May 1996 as a result of a
first ischemic stroke. Forty-one healthy controls were
recruited. Evaluations of anthropometric/metabolic
variables, plasma fibrinogen levels, and the fibrinolytic system
were undertaken 
3 months (mean, 5.4±2.0 months) after admission.
Results—Patients had lower tissue plasminogen activator activity and increased plasminogen activator inhibitor type 1 activity at baseline, as well as increased tissue plasminogen activator mass concentration both at baseline and after a venous occlusion test. Overall, there were no significant differences between the main etiologic subgroups regarding plasma fibrinogen levels and fibrinolytic variables. Baseline fibrinolytic variables were strongly correlated with body mass index, serum triglycerides, and cholesterol levels. After adjustments in multivariate models, fibrinogen levels and tissue plasminogen activator mass concentration both at baseline and after venous occlusion test remained significantly increased in patients. Logistic multiple regression analyses indicated that plasma fibrinogen was a strong predictor of ischemic stroke (odds ratio, 11.25; 95% CI, 3.27 to 38.69).
Conclusions—Increased fibrinogen levels and tissue plasminogen activator mass concentration are independently associated with ischemic stroke in young adults. Metabolic perturbations are closely interrelated with aberrations in tissue plasminogen activator and plasminogen activator inhibitor type 1 activity in these patients, findings consistent with an acquired hypofibrinolysis.
Key Words: fibrinogen • fibrinolysis • plasminogen activators • stroke, ischemic • young adults
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Introduction |
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An obvious cause for ischemic stroke among young adults is often not found.1 2 Furthermore, the pathogenetic importance of potential risk factors for stroke, including cardioembolic sources such as patent foramen ovale, has not been clearly established.3 Other causes for vascular thromboembolic occlusions in this patient group should therefore be investigated.
Plasma levels of fibrinogen and the profibrinolytic enzyme tissue plasminogen activator (tPA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), have emerged as strong predictors of myocardial infarction.4 5 6 7 8 9 10 In contrast, the role of these factors in cerebrovascular disease has received less attention, and only a few studies have considered these aspects of hemostasis in a young stroke population.11 12 13 14 15 Furthermore, there is a clear association between fibrinolytic factors and metabolic alteration such as obesity and hyperlipidemia.16 17 The aim of this study was therefore primarily to evaluate specific components of the fibrinolytic system and its possible interrelationship with other vascular risk factors in a large consecutive series of young adult patients with a first ischemic stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
This study is based on consecutive patients aged 18 to 44 years admitted to Umeå University Hospital between January 1991 and May 1996 as a result of a first ischemic stroke. The inclusion/exclusion criteria and diagnostic evaluation have been presented previously.18 Briefly, the diagnostic investigations included CT, MRI of the brain, and cerebral angiography. Furthermore, duplex ultrasonography of the cervical arteries and 24-hour electrocardiographic Holter recording were performed. Echocardiographic studies included both transthoracic echocardiographic and transesophageal echocardiographic investigations. In addition, a detailed laboratory study was performed.
Hypertension was defined as systolic blood pressure 160
mm Hg and/or diastolic pressure 95 mm Hg on 2
different occasions measured in the acute phase of stroke or patients
who had been on antihypertensive drugs during the last 2 weeks before
recruitment. Diagnosis of diabetes mellitus was documented by medical
records or at recruitment according to World Health Organization
criteria.19 Current smoking was defined as
smoking 1 cigarettes a day for 2 months. Current oral contraceptive
use (OCU) was defined as OCU during the last 6 months. A modified
stroke subtype classification for the etiology of ischemic
stroke was used with the definitions based on the Trial of ORG 10172 in
Acute Stroke Treatment (TOAST) classification, accommodated and
validated for stroke in the young.18 20 A plasma
protein electrophoretic profile and immunoturbidimetric quantification
of 
1-antitrypsin, haptoglobin, and orosomucoid
were performed to assess possibly persistent acute-phase response; only
5 of the 102 patients had slight signs of inflammatory activity at the
time of investigation in the poststroke phase.
One hundred seven patients were clinically evaluated in the acute
phase. Fibrinolytic studies were undertaken in 102 patients (3 patients
died in the acute phase of the disease, and 2 patients were lost to
follow-up) at a follow-up visit 3 months after admission (mean,
5.4±2.0 months). At the time of blood sampling, 12 patients were on
treatment with oral anticoagulants. Ninety patients received a low dose
of aspirin as secondary prophylaxis.
Forty-one healthy control subjects were recruited by local announcement through the University Hospital of Northern Sweden faculty and staff and from the Umeå community at large. The healthy controls had no history of hypertension, diabetes mellitus, hyperlipidemia, malignancy, vascular disease, or any other major disease that might affect the vascular endothelium.
Blood Sampling and Laboratory Methods
Sampling took place in the early morning (7 to 9 AM)
after an overnight fast to eliminate circadian rhythm as a confounding
element. Coffee drinking or smoking was not allowed on the morning of
sampling. Venous blood samples were drawn from the antecubital vein
without stasis after 10 minutes of bed rest into evacuated glass tubes
(Venoject) containing 1/100 volume of 0.5 mol/L EDTA or, for the
fibrinolytic assays, into 1/10 volume of 0.45 mol/L of citrate, pH 4.4
(Stabilyte tubes, Biopool). If tPA activity is to be measured,
immediate acidification of the blood sample is necessary to prevent
PAI-1 from inactivating tPA. This can be achieved by a vacuum tube
(Stabilyte) prefilled with citrate to a lower pH than
usual.21
A venous occlusion (VO) test was performed on the opposite arm by inflating a blood pressure cuff to 100 mm Hg for 10 minutes. Blood was then collected in another Stabylite tube for measurement of tPA activity and tPA mass concentration after VO. Plasma and serum aliquots were prepared by centrifugation at 1500g for 15 minutes at room temperature and stored within 1 hour at -80°C until assayed. Plasma samples that were thawed only once were used.
Plasma levels of each hemostatic factor were determined with the use of the following assay systems. The mass concentration of tPA in plasma (in previous studies often termed tPA antigen) was determined with an enzyme-linked immunosorbent assay (Imulyse tPA) purchased from Biopool.22 The activities of tPA and PAI-1 were measured with chromogenic substrate assay based on the fibrin-stimulated, tPA-mediated, plasminogen-to-plasmin conversion.23 The reagent (Spectrolyse fibrin) was purchased from Biopool. vWF was measured with an enzyme-linked immunosorbent assay24 (DAKO). The values are expressed as percentage of the value obtained in a pool of normal subjects. Plasma fibrinogen was measured with a thrombin reaction time kit from BioMerieux. Serum total cholesterol and triglycerides were determined by enzymatic methods.
Statistical Methods
Means and proportions were computed for background
variables. Comparisons between patients and controls were made with
Student's t test for continuous variables. The
2 or Fisher's exact test was used for
proportions. Spearman correlation coefficients
(rs) were applied to test for correlation
between continuous variables. Medians and interquartile ranges
(25th and 75th percentiles) were computed for the fibrinolytic
variables (plasminogen, PAI-1, tPA activity, tPA mass
concentration) and fibrinogen because of skewed distribution of the
variables. Differences between patients and controls were tested
with the Mann-Whitney U test, and odds ratios with 95% CIs
were calculated.
For multivariate analysis, ANOVA with covariates was used with logarithmically transformed dependent variables. From the ANOVA models, adjusted geometric means were computed. When appropriate, a constant of 1.0 was added to all values before transformation to avoid problems with taking log of zero. Logistic regression was used to analyze the association between risk of stroke and independent variables. Because of a highly skewed distribution of the basal tPA activity variable, this variable was dichotomized (tPA activity below detection level was assigned to 0 and levels above to 1). Results are presented as odds ratios with 95% CIs. Kruskal-Wallis 1-way ANOVA was used for comparison of diagnostic subgroups and continuous variables without normal distribution. Two-tailed tests were used, and a value of P<0.05 was considered significant.
Informed verbal consent was obtained from all subjects. The study was approved by the Research Ethics Committee of Umeå University, and the data handling procedures were approved by the National Computer Data Inspection Board.
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Results |
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Etiology
The patient population included 63 men and 39 women (mean age, 36.1±6.1 years). Table 1
shows the etiology of ischemic stroke according to the main
diagnostic categories defined by the modified TOAST
classification. A cardioembolic etiology was presumed in 34 patients.
The most frequent abnormality was right-to-left cardiac shunts
consistent with patent foramen ovale, which became evident in
26 patients. Atrial septum aneurysm was detected in 9 patients
(isolated in 5 patients and associated with PFO in 4 patients). In 3
patients a major source of cardiac embolism was present (congenital
heart disease [n=2] and atrial septum defect with left atrial
thrombus [n=1]).
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The pathogenetic mechanism underlying nonatherosclerotic vasculopathy (n=18) was in all cases nontraumatic cervicocerebral arterial dissection. The carotid arteries were affected in 9 patients and the vertebral arteries in 9 patients. Regarding atherosclerotic vasculopathy (n=13), 9 patients had only discrete plaque formation in the carotid arteries without any signs of flow abnormalities, and in 4 patients an atherosclerotic stenosis of >50% was found. In addition, transesophageal echocardiography revealed a simple aortic arch atheroma in 3 patients. With respect to hematologic causes of stroke (n=7), 1 patient had an inherited protein S deficiency. Four patients had low positive readings for IgG anticardiolipin antibodies. A history of heavy alcohol ingestion within the preceding 24 hours could be elicited in 1 patient. Ischemic stroke occurred in the postpartum state in 1 patient. Four patients met the criteria for lacunar infarction, 1 fulfilled the criteria for a probable migraine-induced stroke, and in 3 patients OCU was the likely cause of stroke. The etiology of cerebral infarction was indeterminate in 22 patients. The evaluation was "truly negative" except for 1 patient who did not have an angiography and 1 patient who was unable to endure transesophageal echocardiography but had a normal transthoracic echocardiographic investigation.
Risk Factor Levels (Stroke Patients Versus Controls)
Table 2 summarizes the
basic clinical features, established cardiovascular
risk factors, OCU, and von Willebrand factor (vWF) levels among
patients and controls. Mean levels of body mass index, serum
cholesterol, and triglycerides were
significantly increased in patients. Twenty-five percent of the
patients had known or newly discovered hypertension. There was no
significant difference between patients and controls regarding age, sex
distribution, current smoking, vWF levels, and, among women, OCU.
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In the baseline samples, patients had significantly higher fibrinogen
levels, lowered tPA activity, and increased PAI-1 activity, as well as
increased tPA mass concentrations (Table 3). In samples drawn after
10 minutes of VO, the patients had higher mean levels of tPA activity
and tPA mass concentration. The interindividual spread was rather high
in postocclusion samples, however, and only the difference in tPA mass
concentration reached statistical significance. The values of tPA mass
concentration at baseline, plotted versus tPA mass concentration
obtained in the same subject after VO, are shown in the Figure
for both patients and controls. It is
seen that control subjects cluster in the quadrant
representing low values of tPA mass concentration both at
baseline and after VO, whereas patient values cluster in the quadrant
showing increased values of tPA mass concentration both at baseline and
after VO. In general, there was a good correlation between tPA mass
concentration values at baseline and after VO
(rs=0.51).
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) and 41 controls (
).In univariate regression analyses across the whole group (n=143), PAI-1 activity and baseline tPA mass concentration were inversely correlated with baseline tPA activity (rs=-0.54 and rs=-0.52, respectively; P<0.001). PAI-1 activity was positively correlated with baseline tPA mass concentration (rs=0.64, P<0.001) and inversely correlated with tPA activity release (the difference between the tPA activity after VO and that before the test) (rs=-0.42, P<0.001), whereas there was no significant correlation between PAI-1 activity and release of tPA mass concentration (rs=0.04, P=0.66).
Fibrinolytic Variables in Relation to Other Vascular Disease
Risk Factors
There were strong correlations between baseline fibrinolytic
variables and body mass index, serum triglycerides, and
cholesterol levels, as depicted in Table 4. Plasma fibrinogen levels
were weakly although significantly correlated to these factors.
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After adjustments for possible confounding factors in a
multivariate model, PAI-1 activity as well as
plasminogen did not differ between groups, whereas
fibrinogen levels, tPA activity, and tPA mass concentrations at
baseline and after VO remained significantly higher among patients
(Table 5).
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To assess the relative importance of possible explanatory variables
for ischemic stroke, a logistic regression analysis was
applied. The list of potential explanatory variables included
fibrinogen, fibrinolytic variables, and established
cardiovascular risk factors. Because the robustness of
the model was jeopardized by including tPA activity and mass
concentration after VO, these variables were omitted from the
model. The analysis indicated that plasma fibrinogen and serum
cholesterol were strongly associated with the presence of
ischemic stroke, whereas tPA mass concentration barely reached
significance (Table 6).
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Fibrinolysis and Etiology of Ischemic
Stroke
Fibrinogen, fibrinolytic activity, and vWF were analyzed
according to the 4 main diagnostic categories for
analysis of a possible diagnostic dependency. The
other diagnostic categories were excluded because of small
numbers. The diagnostic subgroups did not differ
significantly from each other except for tPA mass concentration after
VO, which was appreciably higher in the 3 diagnostic
subgroups with documented vasculopathies or cardioembolic source
(P=0.04).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study, the first to investigate plasma fibrinogen levels, tPA, PAI-1 activity, and tPA mass concentration in a substantial population of young adults with a first ischemic stroke, demonstrates that these patients have increased fibrinogen levels and an acquired hypofibrinolytic state, characterized by a lower level of tPA activity and higher levels of PAI-1 activity and of tPA mass concentrations in baseline samples compared with healthy controls (Table 2
). This may be an important contributing cause of vascular
occlusion. The results from the prospective Physicians' Health Study, in which a high plasma tPA mass concentration was found to be predictive of stroke in men aged 40 to 84 years,25 are in accordance with our finding that young stroke patients have an acquired hypofibrinolytic state, despite higher than normal tPA mass concentration levels. In elderly stroke populations, increased levels of tPA and PAI-1 mass concentration26 and PAI-1 activity27 measured in the acute phase remained stable and unchanged at follow-up examination in the convalescent phase. Thus, it is plausible that impaired fibrinolysis preexisted in our stroke patients and less likely that it represents a phenomenon secondary to the stroke event. Because tPA mass concentration correlated strongly with PAI-1 activity but inversely with tPA activity, it is conceivable that the elevation of tPA mass concentration to some extent is a reflection of elevated PAI-1, because tPA mass concentration assays do not distinguish free tPA from tPA that is complexed with PAI-1. Results pertaining to fibrinolytic variables in the various etiologic subgroups were quite similar; the only exception was a lower tPA mass concentration after VO in patients with an indeterminate etiology. Thus, a generalized abnormality of the fibrinolytic system seems to be present among these patients.
Adjusted mean tPA activity after stimulation of the fibrinolytic system
by VO was significantly increased in the patient group. This
discrepancy between reduced tPA activity at baseline but increased tPA
activity after VO, compared with control subjects, could indicate a
differential impact of the tPA inhibitor PAI-1 on
activities of tPA at baseline and after VO. In agreement with a
previously postulated hypothesis,28 tPA activity
among patients may be suppressed at baseline since patients have a
higher baseline PAI-1 activity than the controls. However, after VO,
the impact of PAI-1 on net tPA activity diminishes because the patient
group releases more tPA into the blood during VO than do the control
subjects, as clearly seen from the Figure. A similar pattern of
abnormalities in the fibrinolytic system has also recently been
reported in patients with borderline
hypertension.29
A few case-control studies have previously provided more detailed
information with respect to components of the fibrinolytic system in
younger stroke patients, with contradictory
results.11 12 13 14 15 Clearly, different subsettings of
young stroke patients have been evaluated in earlier studies, and a
selection bias due to different referral patterns and inclusion
criteria is possible. Our series of young stroke patients was
consecutive and represents 
80% of all cases in our
catchment area.18 The use of various assay
methods may also have contributed earlier published
inconsistent findings. Time of sampling is crucial, and the
results in several studies pertaining to tPA activity and PAI-1
activity may have been unduly influenced by the diurnal circadian
rhythm of tPA and PAI-1 levels. Thus, tPA activity doubles from early
morning until afternoon because of greatly decreased PAI-1
activity.30
All patients in this study were on medication with either aspirin (90%) or anticoagulant treatment. However, most earlier studies indicate that daily aspirin does not affect baseline levels of fibrinolytic activity31 32 33 but does appear to blunt the fibrinolytic response to VO.31 33 Oral anticoagulant therapy may increase the fibrinolytic activity in blood34; this clearly does not invalidate our results.
A well-known confounder affecting studies of the fibrinolytic system is that some of the variables are covariates with features of insulin resistance syndrome or syndrome X,35 36 particularly body mass index, and serum lipid levels, especially triglycerides.16 17 37 38 Adjustment of baseline tPA and PAI-1 activities for body mass index, cholesterol, and triglyceride levels tended to level out the differences between patients and controls. This strongly suggests that the hypofibrinolytic state in young ischemic stroke patients is acquired and is largely due to an unfavorable body composition and hyperlipidemia, ie, changes mimicking those found in insulin resistance syndrome. However, evidence is now accumulating for a genetic control of circulating PAI-1. PAI-1 promotor polymorphism has been associated with myocardial infarction at a young age.39 However, this and other polymorphisms were not found to be associated with an increased risk of stroke in an elderly stroke population27 or with important determinants of PAI-1 levels in a healthy population.40
In contrast to the reduced baseline tPA activity, the difference in tPA mass concentration, both at baseline and after VO, between patients and controls did not disappear when we adjusted for confounding factors. This suggests, in agreement with previous cardiovascular studies,29 41 that contrary to the tPA and PAI-1 activities, the tPA mass concentration does not just mirror the presence of an insulin resistance syndrome. tPA is secreted into the blood stream solely from the endothelial cells, in contrast to PAI-1, which is also secreted from vascular smooth muscle cells, hepatocytes, and adipocytes.42 Thus, increased tPA mass concentration in individuals predisposed to cerebrovascular disease may reflect a fundamental difference related to vascular integrity and/or function between patients and control groups.
After correction for other possible cerebrovascular risk factors in a
logistic regression model, plasma fibrinogen levels still differed
significantly between stroke patients and controls. Thus, in all
likelihood fibrinogen is an independent marker of increased risk of
ischemic stroke in young adults and may be a major contributor
to a prothrombotic state in these patients. Two prospective
observational studies43 44 and several
case-control studies45 46 have suggested that
fibrinogen is an independent risk factor for stroke in the elderly
population, but the role of high plasma fibrinogen levels as a risk
factor for ischemic stroke in young adults has not been studied
in detail. Fibrinogen levels are known to be elevated immediately after
stroke, and this has been attributed to the acute-phase response
resulting from brain ischemia and
necrosis.47 It seems very unlikely that sustained
effects from the acute phase have influenced our results in view of the
fact that all patients had blood taken 3 months after the stroke and
that an acute-phase reaction was ruled out in 95% of the patients by
analysis of the plasma protein electrophoretic profile.
In conclusion, elevated plasma fibrinogen levels and an acquired hypofibrinolysis in conjunction with metabolic perturbations may be important contributors to an increased stroke risk among young adults. Whether a genetic basis exists for parts of these abnormalities remains to be studied.
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Acknowledgments |
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This study was supported by the Swedish Medical Research Council (grant No. K97–19X-12237–01A to Dr Olsson), Karl-Oskar Hansson's Foundation, the Swedish Society of Neurologically Disabled (NHR), Norrlandsfonden, and the Swedish Heart and Lung Foundation. We thank Mats Eliasson for constructive criticism.
Received March 17, 1998; revision received July 28, 1998; accepted July 28, 1998.
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