(Stroke. 2000;31:26.)
© 2000 American Heart Association, Inc.
Original Contributions |
Tissue Plasminogen Activator, Plasminogen Activator Inhibitor-1, and Tissue Plasminogen Activator/Plasminogen Activator Inhibitor-1 Complex as Risk Factors for the Development of a First Stroke
From the Department of Medicine, Skellefteå County Hospital (L.J., J-H.J., K.B.), and Departments of Clinical Chemistry (T.K.N.), Public Health and Clinical Medicine (B.S., G.H.), and the Medical Bank (G.H.), Umeå University Hospital (Sweden).
Correspondence to Lars Johansson, Department of Medicine, Skellefteå County Hospital, Skellefteå, S-931 86 Sweden. E-mail lars.johansson.ss{at}vll.se
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Abstract |
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Background and Purpose—Abnormalities in the fibrinolytic system have been associated with an increased risk for stroke in a few studies. This study was designed to test whether plasma levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and tPA/PAI-1 complex could predict a first-ever stroke.
Methods—The study was an incident case-control study nested within the Västerbotten Intervention Program and the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) cohorts. In this study 108 first-ever stroke cases were defined according to the MONICA classification, and 216 controls from the same cohort were randomly selected and matched for age, sex, sampling time, and geographic region.
Results—Stroke occurred on average 30 months after the blood sampling date. The mean plasma concentration of tPA/PAI-1 complex was higher for the stroke cases than for the controls (3.9 versus 3.0 µg/L). In univariate regression analysis, significantly higher odds ratios were found for the tPA/PAI-1 complex as continuous variable. When divided into quartiles, the odds ratio was 2.74 for the highest quartile compared with the lowest. In the multivariate model, the tPA/PAI-1 complex remained an independent predictor for stroke. Additionally, tPA mass concentration quartiles 3 and 4 showed a significant association with all stroke as outcome. No association was found, however, for PAI-1. In subgroup analysis of cerebral hemorrhage (n=18), the mean tPA/PAI-1 complex level was higher for the cases than for the controls (4.8 versus 3.0 µg/L), and in multivariate analysis including all controls (n=216), only tPA/PAI-1 complex remained significant.
Conclusions—This prospective study shows that tPA/PAI-1 complex, a novel fibrinolytic marker, is independently associated with the development of a first-ever stroke, especially hemorrhagic stroke. This finding supports the hypothesis that disturbances in fibrinolysis precede a cerebrovascular event.
Key Words: cerebral hemorrhage • cerebral infarction • fibrinolysis • risk factors
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Introduction |
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In the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Project, traditional cardiovascular risk factors such as hypertension, smoking, diabetes, hypercholesterolemia, and overweight have been reported.1 2 These risk factors may only explain part of the individual risk for cardiovascular events.3 4 In studies on patients with other atherosclerotic diseases, such as angina pectoris and myocardial infarction, the fibrinolytic factors plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) mass concentration have been shown to be independent predictors for atherothrombotic events,5 6 7 presented in both cross-sectional studies and later prospective cohort studies.8 9 10 11 12 13 The relation between stroke and the fibrinolytic variables has been less extensively studied. High levels of both tPA and PAI-1 have been observed in patients with a history of stroke,14 15 16 17 18 and in 2 prospective studies high levels of tPA predicted an increased risk for stroke.19 20
tPA is synthesized by endothelial cells. Increased levels of tPA mass concentrations are regarded to reflect decreased fibrinolytic activity, whereas increased levels of tPA activity represent increased fibrinolytic activity. High levels of tPA mass concentrations are also associated with atherosclerotic conditions such as carotid atherosclerosis and peripheral vascular disease.21 22 23 This may reflect the pathological process in the vessel wall and its endothelium.
The fibrinolytic system is activated when tPA transforms plasminogen to plasmin. Only free tPA has fibrinolytic activity and is inhibited when PAI-1 and other inhibitors form an enzymatically inactive complex with tPA.24 When tPA mass concentration is analyzed with enzyme-linked immunosorbent assay, both free tPA and tPA in complex with its inhibitors are determined.25 Thus far, only tPA and PAI-1 have been evaluated clinically. Recently, a new assay has been developed that solely detects tPA in complex with PAI-1. This tPA/PAI-1 complex assay has been proposed as a new marker of the fibrinolytic system.26
The aim of this study was to determine whether changes in concentration of fibrinolytic factors (tPA, PAI-1, tPA/PAI-1 complex) preceded a first-ever stroke and to test whether these factors could predict subjects at risk better than established risk factors.
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Subjects and Methods |
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Study Cohort
In 1985, 2 population-based surveys started in northern Sweden. One, the Västerbotten Intervention Program (VIP), was a community intervention program on cardiovascular disease and diabetes prevention,27 28 and the other was the World Health Organization (WHO) MONICA Project conducted in the 2 northernmost counties in Sweden (Norrbotten and Västerbotten).29 30 The VIP survey was designed to fit the MONICA criteria so that it would be possible to refer to MONICA data when the community intervention program was evaluated. In the VIP study, all men and women were invited to a health survey at their local primary healthcare center the year they became aged 30, 40, 50, and 60 years. In the MONICA study, 3 population surveys were performed in 1986, 1990, and 1994. At each survey, 2000 individuals aged 25 to 64 years were invited. Participants in both surveys were requested to donate blood samples to be stored at the Northern Sweden Medical Research Bank for future research purposes. More than 91% donated blood samples. Participants were also asked to complete a questionnaire with items on, among other things, social background, smoking habits, medical history, and intake of drugs. All participants gave their informed consent. As of August 31, 1996, approximately 40 000 subjects had been screened in the VIP health survey and 4725 in the MONICA surveys.
In this study an incident case-control study nested within the MONICA and VIP studies was used. Cases with definite first-ever stroke were defined by the Northern Sweden MONICA incidence registry29 30 during the period January 1, 1985, to August 31, 1996, and the controls were randomly selected from the population-based health surveys in the VIP or MONICA screenings. Cases were excluded if they had been registered for a previous acute myocardial infarction or stroke according to the MONICA registry or cancer according to the Swedish National Cancer Registry. Of 129 cases who fulfilled the criteria, 108 had donated blood samples that were adequate for analysis. Eighteen were diagnosed as having intracerebral hemorrhage, 87 cerebral infarction, and 3 unspecified stroke. Controls were matched for sex, age (±2 years), date of health survey (±1 year), type of survey (VIP or MONICA), and geographic region. Two controls were matched for each case. Controls were excluded if they had died or if they had moved from the MONICA region before August 31, 1996. All subjects with a prior myocardial infarction or stroke according to the MONICA registry or cancer according to the Swedish National Cancer Registry were excluded. A questionnaire was sent to each control to confirm the absence of a prior stroke and/or acute myocardial infarction.
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.
Clinical Variables and End Points
Hypertension was defined as systolic blood pressure
160 mm Hg and/or diastolic blood pressure 90
mm Hg or on the basis of reported antihypertensive medication during a
period of 14 days before the health survey. Systolic and
diastolic blood pressures were categorized into quartiles
by the distribution of the controls. Smokers were divided into daily
smokers, ex-smokers, and nonsmokers. Previous smokers or occasional
smokers were classified as ex-smokers. Cholesterol was
divided into 4 clinically relevant groups: <5.2, 5.2 to 6.49, 6.5 to
7.79, and 7.8 mmol/L. Body mass index (BMI) was calculated as
weight (kg)/height (m)2 and divided into 4
groups: <25, 25 to 26.9, 27 to 29.9, and 30. A statement on presence
of diabetes was obtained from the questionnaire.
The diagnosis of stroke was according to WHO MONICA criteria.29 30 An acute stroke case was defined as "rapidly developing clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by surgery or death) with no apparent cause other than a vascular origin." The WHO criteria excluded all transient ischemic attacks, subdural hemorrhage, and acute stroke with concomitant brain tumor or severe blood disease. Stroke subtypes were divided into intracerebral hemorrhage (International Classification of Diseases, Ninth Revision [ICD-9] 431), cerebral infarction (ICD-9 434), and unspecified stroke (ICD-9 436). Hemorrhagic stroke was diagnosed through a positive finding on CT scan and/or autopsy; for cerebral infarction there was no sign of hemorrhage on CT scan or autopsy. Neither CT scan nor autopsy was performed for unspecified stroke. In this study the 3 cases with an unspecified stroke diagnosis were excluded in subgroup analysis. Cases diagnosed as subarachnoid hemorrhage were not included.
Blood Sampling and Laboratory Procedures
Venous blood samples for hemostatic assays were drawn without
stasis into evacuated glass tubes (Venoject) containing 1/100 volume of
0.5 mmol/L EDTA. Plasma was obtained by
centrifugation at 1500g for 15 minutes,
aliquoted, and stored frozen at -80°C until analysis. Blood
specimens from cases and controls were analyzed in triplets of
1 case and 2 controls; the position was varied at random within the
triplet to avoid systemic bias and interassay variability. The
investigators and laboratory staff had no knowledge of case and control
status. The mass concentrations of tPA, PAI-1, and tPA/PAI-1 complex
were determined with enzyme-linked immunosorbent
assays.26 The reagent kits used (Imulyse t-PA [for
tPA mass concentration], Imulyse PAI-1 [for PAI-1 mass
concentration], and TintElize tPA/PAI-1 [for tPA/PAI-1 complex mass
concentration]) were purchased from Biopool AB. For tPA mass
concentration, the coefficient of variation (CV) was 10%, for PAI-1
the CV was 9%, and for tPA/PAI-1 complex the CV at 6 µg/L was 6.6%,
all according to the manufacturer. Serum samples for lipid measurement
were obtained after a minimum of 4 hours of fasting. Total
cholesterol was measured by enzymatic methods with the use
of Reflotron bench-top analyzers (Boehringer Mannheim
GmbH Diagnostica) at each health survey center or by an
enzymatic method (Boehringer Mannheim GmbH
Diagnostica) at a hospital laboratory.
Statistical Analysis
Mean values and SDs for baseline cardiovascular
risk factors were calculated for cases and controls.
The data were analyzed by univariate and multivariate logistic regression with the conditional maximum likelihood method designed for matched analysis in the STATA 5.0 statistical package. To test the relation between increasing levels of risk factors and the risk of stroke, the variables were categorized into quartiles by the distribution of the control values or into defined levels, as for BMI and total cholesterol. Univariate logistic regression was performed on each of the variables to estimate odds ratios (ORs) and 95% CIs.
Multivariate logistic regression was performed to estimate the effects on different risk factors when controlling for other factors. Factors were excluded from the model if the univariate logistic regression resulted in a clearly nonsignificant OR (P>0.2). By backward elimination, the variable with the smallest partial correlation was removed from the model until only significant variables remained. A P value <0.05 was considered statistically significant.
Missing Values
The numbers of individuals with missing values per variable
were as follows: diabetes, 12; smoking, 7; cholesterol, 3;
BMI, 13; hypertension, 37; systolic and diastolic
blood pressure, 7; and tPA, PAI-1, and tPA/PAI-1 complex, 6. If
information about diastolic or systolic blood
pressure or antihypertensive medication was lacking, values were
categorized as missing in the hypertension variable. For
categorical variables, missing values were treated as a separate
category and omitted from tables. In the logistic regression
analysis, missing values for continuous variables were
replaced by the mean value of the controls to ensure a
conservative estimate.
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Results |
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Stroke occurred in 108 cases (41 women and 67 men; age, 30 to 70 years; mean age, 55.1 years) on average 30 months (median, 28 months) after the date of the health survey. There was no relation between sample storage time and the concentration of fibrinolytic variables. Baseline characteristics for controls, all stroke cases, and subgroups of cerebral infarction and cerebral hemorrhage are given in Table 1
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The conditional univariate logistic regression
analysis including all cases revealed that diabetes,
systolic and diastolic blood pressures,
hypertension, and tPA/PAI-1 complex were related to a first-ever
stroke, and after categorization into quartiles, BMI 30
kg/m2 (quartile 4) and tPA 10.8 µg/L
(quartiles 3 to 4) also showed significant associations with the
outcome (Table 2). No significant
association for PAI-1 mass concentration was found.
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In the multivariate conditional regression analysis with all stroke cases as end point, we included diabetes, total cholesterol, BMI, hypertension, and tPA/PAI-1 complex in the model. Backward elimination was performed, and diabetes (OR, 15.74; 95% CI, 1.97 to 125.63) and tPA/PAI-1 complex (OR, 1.08; 95% CI, 1.00 to 1.16) remained significant. To further test the importance of blood pressure, we exchanged hypertension with either systolic or diastolic blood pressure as continuous variable, and in both models diabetes, tPA/PAI-1 complex, and systolic or diastolic blood pressure remained significant after the elimination procedure.
In conditional univariate regression analysis of
the subgroup with cerebral infarction (n=87), diabetes,
systolic and diastolic blood pressure, and tPA
10.8 µg/L (quartiles 3 to 4) and tPA/PAI-1 complex 3.25 µg/L
(quartile 4) showed significant associations with the outcome.
In conditional multivariate regression analysis
of cerebral infarction, only diabetes remained significant.
In conditional univariate analysis with cerebral
hemorrhage (n=18) as end point, the continuous variable
tPA/PAI-1 complex showed a higher OR than in the analysis with
ischemic stroke as end point. When we divided the levels of the
tPA/PAI-1 complex into quartiles, an exponential increase in ORs was
found (Figure ); for the quartile with
the highest complex concentration, the OR was 11.43 (95% CI, 0.48 to
271.63) compared with the lowest. Nevertheless, these relations were
not statistically significant. Since the numbers of cases were few, we
used all 216 controls in the multivariate
analysis to increase the power. When we included
traditional risk factors (age, sex, diabetes, smoking,
cholesterol, BMI, and hypertension) and tPA/PAI-1 complex
as continuous variables, only the tPA/PAI-1 complex showed a
significant association with the outcome (OR, 1.13; 95% CI, 1.01 to
1.27).
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Discussion |
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High mass concentrations of tPA and tPA/PAI-1 complex were associated with an increased risk for a first-ever stroke. Moreover, this association remained significant for the tPA/PAI-1 complex even when adjusted for traditional risk factors. The finding of an association between both tPA and tPA/PAI-1 complex and ischemic stroke, when subgroup analyses were performed, was also noteworthy. A new finding was that for hemorrhagic stroke there was a strong association with the tPA/PAI-1 complex but no relation to the tPA mass concentration. No differences were observed between cases and controls regarding PAI-1 (Table 2
). These results suggest that
determining the tPA/PAI-1 complex is not just another way of measuring
tPA and PAI-1 mass concentrations. The tPA/PAI-1 complex may therefore
provide new information on pathogenesis and is also a possible new
marker for prediction of stroke. It is well known from earlier studies that high tPA levels are linked to an increased risk for myocardial infarction and cardiovascular mortality.8 9 10 12 13 Likewise, our finding that PAI-1 was not predictive is in accordance with the failure to relate PAI-1 to the cardiovascular end points described in some of the aforementioned studies.9 10 12
The question of whether fibrinolytic factors play any role in the
pathogenesis of stroke has recently been addressed in a number of
case-control studies.14 15 16 17 18 Some of these have suggested a
potential role of both tPA mass concentration and PAI-1, since these
factors were found to be higher in patients than in control subjects.
However, case-control data remain hypothesis generating because of the
possible effect of the stroke event on both tPA and PAI-1
variables. The present population-based prospective study
demonstrates that elevated tPA and tPA/PAI-1 complex mass
concentrations are related to an increased risk of developing a future
stroke event. Two previous prospective studies have examined
associations between tPA and risk of stroke, and our results are
consistent with these studies.19 20 In the
Physicians’ Health Study, Ridker et al19 found almost all
of the excess risk of stroke among cases with the highest tPA levels,
with a similar pattern for cases with clearly thromboembolic stroke. In
our study there was a stepwise increase in ORs for each quartile of
both tPA and tPA/PAI-1 complex, with significant ORs in quartiles 3 and
4 for tPA and quartile 4 for tPA/PAI-1 complex, among cases with
ischemic stroke (Figure). Whether the risk is continuously
increasing with these fibrinolytic variables or whether a cutoff
level with a stepwise risk increase is present has not yet been
determined. A larger and more powerful study is needed to answer this
question.
Stroke is a heterogeneous entity including different types of both ischemic and hemorrhagic pathological mechanisms. In another study on acute stroke, no differences in the relation between fibrinolytic factors and stroke subtypes were found.14 In our study a high tPA/PAI-1 complex concentration was predictive of future cerebral infarction, and this correlation was even more pronounced in cases of intracerebral hemorrhage, with an OR of 11 for quartile 4. A possible explanation is that the risk for future intracerebral hemorrhage, reflected through elevated tPA/PAI-1 complex levels, represents a more severe form of endothelial dysfunction caused by a more advanced form of atherosclerotic disease prone to hemorrhagic rather than thrombotic complications. Thus, high levels of tPA mass concentrations and tPA/PAI-1 complex in individuals predisposed to cerebrovascular events could be a risk marker for the severity of the atherosclerotic process. It is known that several factors, such as age, sex, diabetes, BMI, and hypertension, influence the fibrinolytic variables in a hypofibrinolytic manner.31 32 33 34 Our study shows, however, that the novel fibrinolytic marker tPA/PAI-1 complex remained significantly associated with end points even after adjustment for these possible confounders.
Another speculative explanation is that the fibrinolytic differences are due to genetic variations in the population. However, even though evidence for an association of the insertion/deletion polymorphism in the tPA gene and nonfatal myocardial infarction has been found,35 such studies are not consistent.36 PAI-1 promotor polymorphism has been associated with myocardial infarction37 but not with an increased risk of stroke.38
The interrelations between plasma concentrations of tPA and its inhibitors in plasma have been elucidated through a number of observations. The turnover time of physiological levels of injected radiolabeled active tPA in vivo was reported to be 2 to 3 minutes because of a rapid uptake in the liver.39 Measurements of the plasma concentrations of tPA/PAI-1, tPA/C1 inhibitor, and tPA/antiplasmin complexes40 41 showed that the tPA/PAI-1 complex mass concentration in plasma correlated moderately with plasma PAI-1 mass concentrations or activity, whereas the correlation with tPA mass concentration was excellent. Turnover studies using supranormal (pharmacological) tPA loading doses showed that tPA/PAI-1 complex is cleared from the circulation more slowly than free active tPA but more rapidly than active PAI-1.42 Taken together, these findings suggest that tPA/PAI-1 complex concentration is a variable of the fibrinolytic system in its own right, which cannot be said to be just another way of measuring either PAI-1 or tPA mass concentrations. As recently stated by Nordenhem and Wiman,41 "The good correlation between tPA antigen and tPA/PAI-1 complex . . . raises the question whether the concentration of tPA/PAI-1 complex in plasma would correlate more strongly with thrombotic events than tPA antigen. Indeed, this must be confirmed by including this kind of assay in forthcoming epidemiological studies of fibrinolytic function in connection with thrombotic disease." The present prospective study provides a step in that direction.
In summary, our study suggests that elevated tPA and tPA/PAI-1 complex concentrations predict an increased risk for a first-ever stroke. When stroke was divided into hemorrhagic and ischemic subtypes, high tPA/PAI-1 complex levels showed a positive association with both groups. This association seemed to be stronger for hemorrhagic strokes, although the total number of hemorrhagic strokes was limited. For tPA mass concentrations, an association was observed only with ischemic strokes. These results support the hypothesis that abnormalities in the fibrinolytic system occur before the cerebrovascular event. Whether this is an expression of preexisting cerebrovascular disease or due to genetic variances in the population remains to be elucidated.
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Acknowledgments |
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This study was supported by grants from the Swedish Medical Research Council (K.98.27I.12692-01, K.98.27X.12692-019, 27P-12314, 27X-013077), County Council of Västerbotten, Foundation of Swedish Stroke Association, and Foundation of Medical Research in Skellefteå. We also thank the County Council of Västerbotten for its persistence in maintaining the community care program and thereby creating and guaranteeing the study base.
Received July 19, 1999; revision received October 7, 1999; accepted October 7, 1999.
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