(Stroke. 1999;30:7-11.)
© 1999 American Heart Association, Inc.
Original Contributions |
Elevated Tissue Plasminogen Activator Antigen and Stroke Risk
The Stroke Prevention in Young Women Study
From the Departments of Neurology (R.F.M., S.J.K., A.E., D.K.C., M.A.W., M.A.S., T.R.P.) and Epidemiology and Preventative Medicine (S.J.K., M.A.S., R.S., T.R.P., R.J.M., P.D.S.), the University of Maryland at Baltimore; the Geriatrics Research, Education, and Clinical Center (R.F.M.), Baltimore Department of Veterans Affairs Medical Center, Baltimore, MD; the Department of Neurology (D.W.B., C.J.E., C.J.J., R.J.W.), Johns Hopkins University, Baltimore, MD; and the Department of Neurology (B.J.S.), Emory University School of Medicine, Atlanta, Ga.
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Abstract |
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Background and Purpose—Abnormalities in endogenous fibrinolysis are associated with an increased risk for stroke in men and older adults. We tested the hypothesis that elevated plasma tissue plasminogen activator (tPA) antigen, a marker for impaired endogenous fibrinolysis, is an independent risk factor for stroke in young women.
Methods—Subjects were 59 nondiabetic females ages 15 to 44 years with cerebral infarction from the Baltimore-Washington area and 97 control subjects frequency-matched for age who were recruited by random-digit dialing from the same geographic area. A history of cerebrovascular disease risk factors was obtained by face-to-face interview. Plasma tPA antigen was measured by enzyme-linked immunosorbent assay.
Results—Mean plasma tPA antigen levels were significantly higher in stroke patients than control subjects (4.80±4.18 versus 3.23±3.67 ng/mL; P=0.015). After adjustment for age, hypertension, cigarette smoking, body mass index, and ischemic heart disease, there was a dose-response association between tPA antigen and stroke with a 3.9-fold odds ratio of stroke (95% CI, 1.2 to 12.4; P=0.03) for the upper quartile (>4.9 ng/mL) of tPA antigen compared with the lowest quartile. The dose-response relationship between tPA antigen and stroke was equally present in white and nonwhite women, and further adjustment for total and HDL cholesterol levels only modestly attenuated this association.
Conclusions—This population-based case-control study shows that elevated plasma tPA antigen level is independently associated with an increased risk for ischemic stroke in nondiabetic females 15 to 44 years of age. These findings support the hypothesis that impaired endogenous fibrinolysis is an important risk factor for stroke in young women.
Key Words: cerebral infarction • fibrinolysis • risk factors • young adults • women
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Abnormalities in endogenous fibrinolysis are increasingly recognized as independent predictors for increased risk of atherothrombotic events.1 2 In particular, elevations in tPA antigen have emerged as an important marker for impaired fibrinolysis associated with increased cerebral infarction risk in older populations.3 4 In a prospective study, Ridker et al found that elevated plasma tPA antigen levels were independently associated with an increased risk for stroke in adult males with a mean age of 62 years.5 Young adults, particularly women, are known to have better endogenous fibrinolysis profiles, lower atherosclerosis prevalence rates, and a more diverse profile of etiology for stroke than is typically found in older populations.6 7 8 The significance of impaired endogenous fibrinolysis as an independent predictor for increased risk of stroke in the young adult population, and in women in particular, has not been established.
Abnormalities in fibrinolysis are now recognized in association with advancing age, male sex, and the extent of asymptomatic carotid atherosclerosis.7 8 9 10 Impaired fibrinolysis is also linked to selected cardiovascular disease (CVD) risk factors (including diabetes, hypertension, obesity, and dyslipidemia), elements of the insulin resistance syndrome that may elevate atherothrombotic risk by increasing plasminogen activator inhibitor-1 (PAI-1, the main circulating inhibitor for tPA).9 11 12 Prior case-control studies suggest that impaired fibrinolysis may be present in a substantial proportion of young stroke patients, including women.13 14 15 However, interpretation of these earlier studies is confounded by the nonspecific nature of fibrinolysis measures used and the limited covariate analysis for other CVD risk factors, which could also account for the impaired fibrinolysis findings. The present population-based study examined the hypothesis that elevated plasma tPA antigen is an independent risk factor for stroke in females aged 15 to 44 years.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Subjects
The Stroke Prevention in Young Women Study is a case-control study within the defined geographic region of Maryland (except the far western panhandle), Washington, DC, and southern portions of Pennsylvania and Delaware. Case subjects included females aged 15 to 44 years with a diagnosis of first cerebral infarction identified by discharge surveillance at the 59 participating hospitals or by direct referral by regional neurologists. Recruitment within 1 year of stroke was required for participation. Methods for discharge surveillance, chart abstraction, and case adjudication have been previously described.16 Control subjects for the Stroke Prevention in Young Women Study were females without a history of stroke, frequency matched by age and geographic region, and recruited at a 2:1 ratio to the case subjects. For the tPA antigen study, consecutive ischemic stroke case subjects with citrate anticoagulated plasma available for measurement of tPA antigen were included, whereas controls included those women enrolled during the same time period with archived plasma similarly available for tPA antigen measurement. Stroke case and control subjects with a history of diabetes mellitus were excluded because of the known association between insulin resistance and impaired fibrinolysis, and because too few diabetic case subjects (n=3) were present to adjust for this important confounding variable.11 12
A structured evaluation was used to characterize participant demographics, CVD risk factors, and other potential covariates affecting the relationship between tPA antigen and stroke. Hypertension, diabetes mellitus, and angina or myocardial infarction history were determined by asking study participants (or their proxy if participants could not answer) whether they had ever been diagnosed with such a condition or conditions by a physician. Smoking status was ascertained by determining whether participants had any cigarette usage in the 30 days preceding the index stroke, or before their interview for controls.
Hematologic Measures
Nonfasting blood samples for tPA antigen were collected by
antecubital venipuncture in citrate anticoagulated
evacuated tubes (Vacutainer; Becton-Dickinson), placed immediately on
ice, and transported to a central processing laboratory. Plasma was
prepared by centrifugation (1520g at 4°C
for 15 minutes) and stored at -70°C until measured in duplicate by
enzyme immunosorbent assay (American
Bioproducts).7 Total cholesterol and
HDL cholesterol levels were measured according to standard
practice17 ; high total cholesterol and HDL
cholesterol levels were defined as 
240 and 35 mg/dL,
respectively.
Statistical Analysis
t tests were used to compare the means between
groups. Fisher's exact test was used to compare clinical and
demographic features between patient and control populations.
Wilcoxon rank sum tests were used to analyze the
relationships between tPA antigen levels and selected clinical and
demographic factors in controls, because the distribution of tPA
antigen values was found to be skewed. For statistical
analysis, age was categorized as less than or greater than 35
years, and body mass index (BMI, kg/m2) was
evaluated by median split. Crude and adjusted odds ratios derived from
logistic regression were used to determine whether the upper quartiles
for tPA antigen were associated with an increased risk for stroke
compared with the lowest quartile. Odds ratios for stroke were
initially determined separately in white and nonwhite participants;
these groups were combined for subsequent models because there was no
effect modification by race.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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There were 59 stroke patients and 97 control subjects with blood samples available for tPA antigen determination. Clinical and demographic features of study participants are shown in Table 1
. There were no significant differences
in age, education level, or distribution by race between patients and
controls. Etiologic categories for stroke included 10 cardioembolic, 12
atherosclerotic, 1 small vessel (lacune), 15 indeterminate, and 21
"other" etiologies, based on the classification scheme previously
described. Prevalence rates for current smoking status and low HDL
cholesterol level (defined as <35 mg/dL) were higher among
stroke patients. There was a nonsignificant trend toward higher
proportions of hypertension and coronary artery disease history
among case subjects with stroke than control subjects.
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The mean plasma tPA antigen levels were 4.80±4.18 ng/mL in cases and
3.23±3.67 ng/mL in controls, for a mean difference of 1.57
(P=0.015). Plasma tPA antigen levels measured in stroke
patients from the acute period <2 weeks after index cerebral
infarction were not significantly different from those measured 2
weeks after index stroke (5.28±4.7 [n=14] versus 4.66±4.08 ng/mL
[n=44]); P=0.64). Univariate relationships
between selected conventional CVD risk factors, demographic factors,
and plasma tPA antigen levels in controls are shown in Table 2. As expected, tPA antigen levels were
higher in participants >35 years in age, in those with a history of
ischemic heart disease, and in those with greater BMI by median
split analysis. There was a nonsignificant trend toward higher
tPA antigen levels in participants with elevated total
cholesterol levels.
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The odds ratios for stroke by increasing quartiles of tPA antigen
are shown in Table 3. Overall, there was
an unadjusted 4.4-fold increased risk for stroke associated with the
upper quartile of tPA antigen values; this included crude odds ratios
for stroke of 4.9 (95% CI, 1.4 to 17.4; P=0.014) in white
women and 5.0 (95% CI, 0.8 to 29.6; P=0.076) in nonwhite
women. After adjustment for age group, BMI by median split,
hypertension, smoking status, and ischemic heart disease, there
remained a strong dose-response association between tPA antigen and
risk for cerebral infarction (Table 3). Lipoprotein lipid
profiles were measured in 57 stroke patients and 96 control subjects.
In these participants, the upper quartile of tPA antigen was associated
with a 3.2-fold increased risk for stroke (95% CI, 0.097 to 10.7;
P=0.055), even after further adjustment for total and HDL
cholesterol levels.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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There are few hematologic factors that independently predict an increased risk for cerebral infarction in the young. Although factors such as elevated fibrinogen and impaired fibrinolysis are strongly associated with stroke, they also occur with advancing age and have been convincingly linked to stroke risk typically only in older stroke cohorts.5 7 18 In this population-based case-control study, we report an independent association between elevated plasma tPA antigen levels and risk for cerebral infarction in young women. The upper quartile of tPA antigen levels remained associated with an increased risk for stroke even after adjusting for age, BMI, history of angina or myocardial infarction, and conventional CVD risk factors, including total and HDL cholesterol levels. These findings provide the first evidence that impaired endogenous fibrinolysis is an independent predictor for increased risk of stroke in young women.
Some early studies suggest that impaired fibrinolytic capacity is present in young and middle-aged adults with stroke.13 14 15 Reduced fibrinolytic capacity determined with the fibrin plate method was reported in 70% of patients <55 years of age with a history of cerebral ischemia.15 Mettinger and Egberg13 later reported that "plasminogen antiactivator" levels indexed by a peptide substrate method were lower in young women (<40 years of age) with a history of cerebral ischemia but not in men. Defective vessel wall fibrinolytic response or reduced euglobulin clot lysis time after a venous occlusion test was found in 38% of young adults (<45 years of age) with cerebral ischemia.14 In contrast, Sharma et al reported finding no abnormalities in resting euglobulin clot lysis time in young patients (mean age, 33 years) with a history of thromboembolic stroke.19 These studies are limited by their use of nonspecific fibrinolysis laboratory measures and inadequate consideration of other conventional CVD risk factors now recognized in association with impaired fibrinolytic capacity.9 11 12
Recent case-control studies further support a relation between impaired fibrinolysis, indicated by elevated plasma tPA antigen, and increased risk for stroke in selected populations. In older men and women attending a metabolic ward, elevated plasma tPA antigen levels were a strong predictor of ischemic stroke status, more reliable than plasma PAI-1 antigen levels.4 Jeppeson et al found that there were elevated plasma tPA antigen levels in older women with ischemic stroke (mean age, 76 years) but not older men and that tPA levels were related to stroke severity and infarct size only in women.20 In the only prior study of fibrinolysis and stroke in young adults, Chancellor et al reported that tPA antigen levels were not elevated in male and female patients (mean age, 27 years) with stroke of undetermined etiology.21 Taken together, these studies suggest that sex- and age-specific differences may exist for the significance of fibrinolytic markers as predictors of increased stroke risk.
In a prospective study, Ridker et al found that plasma tPA antigen levels elevated beyond the 95th percentile (>19.7 ng/mL) were independently associated with a fourfold increased relative risk for thromboembolic stroke in adult males (mean age, 62 years).5 Similarly, we observed a dose-response relationship between the tPA antigen level and the adjusted odds ratio for thromboembolic stroke in young women, with the upper quartile of tPA antigen levels associated with a 3.8-fold increased risk. Furthermore, the odds ratios for stroke were of similar magnitude in white and nonwhite women. The mechanisms underlying cerebral infarction in young adults are diverse and fundamentally differ from those in older populations by virtue of reduced atherosclerosis rates.6 Thus, it is remarkable that we observed the same dose-response relationship between tPA antigen and stroke risk in young women as that described in older men by Ridker and colleagues.5 These results extend the hypothesis that impaired endogenous fibrinolysis is an important mechanism underlying increased risk for cerebral infarction across gender, race, and a broad age range.
Plasma tPA antigen levels constituting the upper quartile in young women (>4.9 ng/mL) were much lower than those in older stroke cohorts.3 4 5 This is consistent with studies showing reduced fibrinolytic capacity in men and with studies of advancing age.7 8 9 Results of this study indicate that even these low levels of tPA antigen are associated with an increased risk for stroke in young women. A number of conventional CVD risk factors that have been linked to the insulin resistance syndrome and those in which prevalence increases with advancing age are also related to impaired fibrinolysis.9 11 12 To account for these potential covariates we excluded diabetic patients, adjusted for age, BMI, and other conventional CVD risk factors in a multiple regression model. This analysis may underestimate the true importance of fibrinolysis abnormalities to stroke risk, because these factors may foster atherothrombosis in part by impairing fibrinolysis.9 11 12 That further adjustment for cholesterol levels modestly attenuates the association between tPA antigen level and stroke risk is consistent with this hypothesis. These results underscore a need for age-sex dependent adjustment and consideration of other CVD risk factors as covariates when interpreting the clinical significance of fibrinolytic markers.
Our results are limited by the retrospective study design. We cannot rule out the possibility that elevated tPA antigen was a consequence rather than a precursor to stroke. However, it is unlikely that the elevated tPA antigen levels were due to an acute phase response after stroke. There were no significant differences in mean plasma tPA antigen levels between those women whose blood was sampled before and those sampled >2 weeks after index stroke. These findings corroborate observations in older stroke patients that tPA antigen levels are similar in acute and convalescent phases.3 Plasma tPA antigen is a measure of inactive and free-active tPA; the majority is bound to PAI-1 as an inactive circulating complex.7 22 Findings of elevated tPA antigen are interpreted as reduced net fibrinolytic capacity with relative excess in PAI-1.22 23 24 Because we did not directly measure tPA and PAI enzyme activities, we cannot distinguish whether the elevated tPA antigen is a marker for premature atherosclerosis, impaired fibrinolysis, or both.
In summary, our findings suggest that elevated plasma tPA antigen level is an independent risk factor for cerebral infarction in young women, supporting the hypothesis that impaired endogenous fibrinolysis is an important predictor for increased risk of stroke across gender and a broad age range.4 5 20 This relationship is similar in white and black women and persists in a dose-response fashion even after adjustment for age and conventional CVD risk factors. The magnitude of increased risk, a 3.9-fold adjusted odds ratio for stroke with the upper quartile of tPA antigen levels, was more robust than those observed for hypertension and smoking. Further studies are needed to differentiate genetic from environmental determinants of elevated tPA antigen level and to investigate the potential health benefits of interventions aimed at improving endogenous fibrinolysis in high-risk populations.25 26 27
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Acknowledgments |
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This work was supported by a Clinical Stroke Research Center Award from the National Institute of Neurological Disorders and Stroke (NS16332-11 to Drs Kittner, Sloan, and Price); The Baltimore Veterans Administration Geriatrics Research, Education, and Clinical Center; and a Veterans Health Administration Research Advisory Group Grant (12A7A to Dr Macko). We thank the following members of the research team for their dedication: Mary Keiser, Ann Maher, Jennifer Rohr, Mary J. Seipp, Susan Snyder, Mary J. Sparks, and Nancy Zappala.
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Footnotes |
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Corresponding to Richard Macko, Department of Neurology, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD 21201.
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Appendix 1 |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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The authors would like to acknowledge the assistance of the following individuals who have sponsored the Stroke Prevention in Young Women Study at their institutions: Frank Anderson, MD; Clifford Andrew, MD, PhD; Christopher Bever, MD; Nicholas Buendia, MD; Young Ja Cho, MD; James Christensen, MD; Remzi Demir, MD; Terry Detrich, MD; John Eckholdt, MD; Nirmala Fernback, MD; Jerold Fleishman, MD; Benjamin Frishberg, MD; Stuart Goodman, MD, PhD; Norman Hershkowitz, MD, PhD; Luke Kao, MD, PhD; Mehrullah Khan, MD; Ramesh Khurana, MD; John Kurtzke, MD; William Leahy, MD; William Lightfoote II, MD; Bruce Lobar, MD; Michael Miller, MD, PhD; Harshad Mody, MBBS; Marvin Mordes, MD; Seth Morgan, MD; Howard Moses, MD; Sivarama Nandipati, MD; Mark Ozer, MD; Roger Packer, MD; Thaddeus Pula, MD; Philip Pulaski, MD; Naghbushan Rao, MD; Marc Raphaelson, MD; Solomon Robbins, MD; David Satinsky, MD; Elijah Saunders, MD; Michael Sellman, MD, PhD; Arthur Siebens, MD (deceased); Harold Stevens, MD, PhD; Dean Tippett, MD; Roger Weir, MD; Michael Weinrich, MD; Richard Weisman, MD; Don Wood, MD (deceased); and Mohammed Yaseen, MD.
In addition, the study could not have been completed without the support from the administration and medical records staff at the following institutions: in Maryland, Anne Arundel Medical Center, Atlantic General Hospital, Bon Secours Hospital, Calvert Memorial Hospital, Carroll County General, Church Hospital Corporation, Doctors Community Hospital, Fallston General Hospital, Franklin Square Hospital Center, Frederick Memorial Hospital, The Good Samaritan Hospital of Maryland, Inc., Greater Baltimore Medical Center, Harbor Hospital Center, Harford Memorial Hospital, Holy Cross Hospital, Johns Hopkins Bayview Inc, the Johns Hopkins Hospital, Howard County General Hospital, Inc, Kennedy Krieger Institute, Kent and Queen Anne Hospital, Laurel Regional Hospital, Liberty Medical Center, Inc, Maryland General Hospital, McCready Memorial Hospital, Memorial Hospital at Easton, Mercy Medical Center, Montebello Rehabilitation Hospital, Montgomery General Hospital, North Arundel Hospital, Northwest Hospital Center, Peninsula Regional Medical Center, Physician's Memorial Hospital, Prince George's Hospital Center, Saint Agnes Hospital, Saint Joseph Hospital, Saint Mary's Hospital, Shady Grove Adventist Hospital, Sinai Hospital of Baltimore, Southern Maryland Hospital Center, Suburban Hospital, The Union Memorial Hospital, University of Maryland Medical System, Department of Veterans Affairs Medical Center in Baltimore, Washington Adventist Hospital, and Washington County Hospital; in Washington, DC, Children's National Medical Center, District of Columbia General Hospital, The George Washington University Medical Center, Georgetown University Hospital, Greater Southeast Community Hospital, Hadley Memorial Hospital, Howard University Hospital, National Rehabilitation Hospital, Providence Hospital, Sibley Memorial Hospital, Veterans Affairs Medical Center, and The Washington Hospital Center; in Pennsylvania, Gettysburg Hospital and Hanover General Hospital.
Received August 20, 1998; revision received October 8, 1998; accepted October 8, 1998.
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