© 2001 American Heart Association, Inc.
Thrombosis |
Prospective Study of Fibrinolytic Factors and Incident Coronary Heart Disease
The Atherosclerosis Risk in Communities (ARIC) Study
From the Division of Epidemiology (A.R.F.), School of Public Health, University of Minnesota, Minneapolis; the Division of Hematology (N.A., H.J., K.K.W.), University of Texas Medical School, Houston; the Biostatistics Department (E.P.), University of North Carolina, Collaborative Studies Coordinating Center, Chapel Hill; and the KTL-National Public Health Institute (V.S.), Department of Epidemiology, Helsinki, Finland.
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Abstract |
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Abstract—The fibrinolytic system may play a role in the pathogenesis of coronary heart disease (CHD), but existing prospective studies have not consistently shown an independent association between fibrinolytic factors and CHD. None has reported an association between plasminogen and CHD incidence. In the prospective Atherosclerosis Risk in Communities (ARIC) Study of middle-aged adults, we examined the association of incident CHD with several fibrinolytic factors: tissue plasminogen activator antigen, plasminogen activator inhibitor-1, plasminogen, and fibrin fragment D-dimer as well as a marker of coagulation activation (prothrombin fragment F1.2). We measured these in stored baseline plasma samples of 326 subjects who developed CHD and, for comparison, a stratified random sample of the entire cohort (n=720). Tissue plasminogen activator and plasminogen activator inhibitor-1 antigen levels were associated positively with CHD incidence in analyses adjusted for age, race, and sex but were not associated with CHD after adjustment for other risk factors. Plasminogen and D-dimer levels were associated positively and independently with CHD incidence; the multivariable-adjusted relative risks (95% CIs) for the highest versus lowest quintiles were 2.20 (1.2 to 4.2) for plasminogen and 4.21 (1.9 to 9.6) for D-dimer. F1.2 was not associated with CHD incidence. Our findings lend support for a link between fibrinolytic factors and CHD incidence. A positive association between plasminogen and CHD is seemingly opposite the direction expected but may reflect a compensatory response to impaired plasminogen activation in subjects prone to CHD.
Key Words: coronary disease • fibrinolysis • risk factors
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Introduction |
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Thrombosis of a disrupted atherosclerotic plaque triggers most ischemic cardiovascular events. Because thrombi are resolved through the action of the fibrinolytic system, researchers have hypothesized that impaired fibrinolytic function may be a risk factor for ischemic events. Fibrinolysis involves the action of tissue plasminogen activator (tPA) on plasminogen to produce plasmin, which, in turn, degrades cross-linked fibrin to D-dimer and other fibrin degradation products. Plasmin also activates matrix metalloproteinases that, in turn, degrade the extracellular matrix.1 Plasminogen activator inhibitor-1 (PAI-1) is a major plasma inhibitor of tPA.
Prospective studies have generally reported that the risk of
ischemic cardiovascular events is increased in
participants with coagulation activation or impaired fibrinolytic
function, reflected as increased levels of tPA antigen, PAI-1, fibrin
fragment D-dimer, or plasmin-antiplasmin complex or as delayed clot
lysis.2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
However, there are relatively few large prospective studies relating
fibrinolytic factors to first ischemic events in
population-based samples of healthy
subjects.9 10 11 12 13 14 15 16 17 18 19 20 21
These studies
(Table 1
) did not always find the association between
impaired fibrinolytic function and ischemic events to be
independent of other cardiovascular risk factors.
Furthermore, no prospective study, to our knowledge, has reported on
the association of plasma plasminogen concentration with
incident ischemic events. Therefore, we examined the
association of several plasma markers of fibrinolytic function (tPA
antigen, PAI-1 antigen, plasminogen, and D-dimer) and a
marker of coagulation activation (prothrombin fragment F1.2) with the
risk of incident coronary heart disease (CHD) in a cohort of
middle-aged adults.
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Methods |
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Study Population and Baseline Measurements
In 1987 through 1989, the Atherosclerosis Risk in Communities (ARIC) Study22 recruited a population-based cohort of persons aged 45 to 64 years from 4 US communities. A total of 15 792 participants completed a home interview and clinic examination. The ARIC Study reexamined the participants from 1990 to 1992 (93% return rate), 1993 to 1995 (86% return rate), and 1995 to 1997 (80% return rate).
Technicians measured resting blood pressure 3 times with a random-zero sphygmomanometer and averaged the last 2 measurements for analysis. We expressed physical activity as a sports index ranging from 0 (low) to 5 (high).23 Technicians measured waist (umbilical level) and hips (maximum) to compute the waist-to-hip ratio. Technicians measured average carotid intima-media thickness (IMT) by using standardized B-mode ultrasonography.24 We defined prevalent CHD at baseline as a self-reported history of a physician-diagnosed heart attack, prior myocardial infarction (MI) by ECG, prior cardiovascular surgery, or prior coronary angioplasty. The ARIC Study also measured prior stroke or transient ischemic attack through a standardized interview.25
Using a standardized protocol,26 27 28 ARIC technicians drew fasting blood samples into vacuum tubes containing serum-separating gel, sodium citrate, EDTA, or a combination anticoagulant solution (D-Phe-L-Pro-D-Arg chloromethyl ketone, isobutylmethylxanthine, aprotinin, and EDTA). The technicians centrifuged samples at -4°C and filtered the plasma from the combination anticoagulant tube through a 0.45-m Millipore filter. They then froze samples at -70°C until analyzed.
At baseline, ARIC laboratories measured fasting serum
insulin, white blood cell count, plasma
fibrinogen,29 total
cholesterol,30
HDL
cholesterol,31
triglycerides,32
and Lp(a) and computed LDL
cholesterol.33 We
defined diabetes as fasting serum glucose 
126 mg/dL, nonfasting
glucose 200 mg/dL, or a physician diagnosis or pharmacological
treatment for diabetes.
Ascertainment and Classification of
Incident CHD Cases
The ARIC Study followed the cohort and ascertained
CHD events.22 34
For the present study, we included CHD events occurring between
ARIC visit 1 and December 31, 1993. The mean follow-up time was 4.3
years (maximum 7.1 years). We defined CHD incidence as (1) a definite
or probable MI,34 (2) a
silent MI between examinations by ECG, (3) a definite CHD
death,34 or (4) a
coronary
revascularization.
Cohort Sample
We used a case-cohort design for the present
study, in which information on plasma fibrinolytic factors was
determined for CHD cases and a stratified random sample of the entire
ARIC cohort of 15 792 participants. We first excluded participants in
Forsyth County who were not white or African American (n=21) and
participants in Minneapolis and Washington County who were not white
(n=82), because these race-center strata were too small for meaningful
sample weighting. We then excluded participants with prevalent CHD (or
unknown status) at baseline (n=1112), participants with a history of
stroke or transient ischemic attack at baseline (n=264), and
participants with missing sampling or event information (n=7). All
incident CHD cases were sampled (n=469). For the reference cohort
sample (n=986), we oversampled noncases with thin average carotid IMT
measurements at baseline (<30 percentile) and also stratified the
sampling by age and sex. Thirty-seven participants were selected
both as cases and into the reference cohort.
Laboratory Measurements
After the ARIC Study had identified the incident
cases and cohort sample (total number of participants=1418),
technicians attempted to retrieve these participants’ baseline
samples, frozen from 1987 to 1989. However, because of an interim
freezer meltdown and some other missing samples, we had complete
unthawed samples for only 1018 (326 cases, of which 28 were in the
cohort sample, and 692 noncases). Compared with those not included in
the analysis, those included were similar (within the case and
noncase groups) for 13 risk characteristics
(P>0.05); however, those
included had a somewhat lower mean carotid IMT (0.04 mm in cases,
0.03 mm in noncases) and a higher mean sports index (cases only)
and were less likely to be African American (cases only). These
differences were expected to have little effect on the present
study.
After the specimens were thawed (1997 to 1998), the ARIC Hemostasis Laboratory measured tPA antigen in citrated plasma with the use of an enzyme immunoassay (Asserachrom tPA kit, Diagnostica Stago).35 The laboratory measured PAI-1 antigen in citrated plasma by ELISA with use of an IMUBIND Plasma PAI-1 kit (American Diagnostica).36 This assay detects active and inactive forms of PAI-1 and complexes of tPA/PAI-1 and urokinase plasminogen activator/PAI-1, and its sensitivity level is <1 ng/mL. The laboratory measured plasminogen in citrated plasma by chromogenic assay with the use of an Actichrome PLG kit (American Diagnostica).37 It measured D-dimer in citrated plasma by an enzyme immunoassay procedure (Asserachrom D-Di kit, Diagnostica Stago).38 The laboratory measured F1.2 with a Thrombonostika F1.2 ELISA (Organon Teknika).39 It measured serum C-reactive protein (CRP) by an ELISA obtained from United Biotech Magiwel.40 The sensitivity of the assay is <1 µg/L, and the minimal detectable concentration of CRP is 0.35 µg/L. The laboratory used an enzyme immunoassay to measure soluble thrombomodulin in citrated plasma.41 We tested assay reliability by using blinded duplicate specimens from different tubes of single blood drawn (n=54 to 71 pairs). Pearson correlation coefficients were 0.76 for PAI-1, 0.91 for tPA antigen, 0.70 for plasminogen, 0.27 (0.80 after excluding outliers >1000 ng/mL) for D-dimer, and 0.50 (0.66 after excluding outliers >5 nmol/L) for F1.2. An earlier ARIC study involving fresh samples taken 3 times at 1- to 2-week intervals, to assess intraindividual variability, yielded reliability coefficients of 0.81 for tPA, 0.72 for PAI-1, and 0.72 for D-dimer.28
Data Analysis
The laboratory classified some samples (n=101) as
lipemic, as hemolyzed, or as having microprecipitates on thawing.
Statistical analyses that were run including and excluding
these samples were similar, so we included them. We excluded some
extreme outlying values: PAI-1383 ng/mL (n=2), CRP 36.5 mg/L
(n=11), F1.2 253 nmol/L (n=3), and D-dimer 15 000 ng/mL
(n=6).
We determined interrelations among hemostatic factors by using Pearson correlations in the cohort random sample after appropriate weighting for the stratified case-cohort sampling design. To test the study hypotheses, we first used weighted ANCOVA to compute age-, race-, and sex-adjusted mean values of fibrinolytic factors for CHD cases versus noncases. We used geometric means for several of the hemostatic variables that were right-skewed. Reported probability values are 2-sided.
To determine the relation of fibrinolytic factors with other variables, some of which may be confounders in this analysis, we categorized the cohort sample into quintiles for each fibrinolytic factor and used ANCOVA to compute age-, race-, and sex-adjusted mean levels or percentages of the other variables for each quintile.
We computed relative risks and 95% CIs of CHD in relation to categories of study variables by a weighted proportional hazards regression, accounting for the stratified random sampling, and the case-cohort design by Barlow’s method.42 We analyzed each hemostatic factor separately in 2 regression models. In the first model, we adjusted for age, sex, and race (black, white). In the second multivariate model, we adjusted for sex, age, race, and other major CHD risk factors: smoking status (never, former, current), total cholesterol, HDL cholesterol, systolic blood pressure, use of antihypertensive medication, and diabetes. We ran additional regression models, as needed, by using continuous variables or by examining subgroups to test the independence of observed associations.
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Results |
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Descriptive Characteristics
The final sample included 326 incident CHD cases (183 definite or probable MI, 19 silent MI, 34 definite fatal CHD, and 90 revascularization procedure) and a reference cohort sample of 720 (of whom 28 were also CHD cases). Twenty-two percent of the CHD case subjects were black, and 72% were men.
There were moderate correlations between tPA and PAI-1 (r=0.36) and between tPA and plasminogen (r=0.17) but not between PAI and plasminogen (r=-0.05). D-dimer and F1.2 were not correlated with other fibrinolytic variables.
Mean Differences in Fibrinolytic
Factors
Compared with participants who remained free of CHD,
those who developed CHD had higher age-, sex-, and race-adjusted mean
values of tPA antigen, PAI-1 antigen, and plasminogen (all
P<0.05,
Table 2). However, mean D-dimer and F1.2 were not
significantly different between incident cases and
noncases.
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Relations of Fibrinolytic Factors With
Other Risk Factors
PAI-1 values were higher in diabetic than nondiabetic
individuals; these values were associated positively with age, CRP,
fasting insulin, plasma triglycerides, waist-to-hip ratio,
fibrinogen, and soluble thrombomodulin and associated negatively with
the sports index and HDL cholesterol
(Table 3). tPA was similarly associated with these factors,
except for the sports index and soluble thrombomodulin, and, in
addition, was associated positively with systolic blood
pressure and total cholesterol and associated negatively
with current smoking. In contrast, plasminogen was
associated positively with only triglycerides and total
cholesterol and associated negatively with soluble
thrombomodulin. D-dimer (not shown) was associated positively and
linearly only with age (mean age was greater by 5 years across
quintiles of D-dimer) and fibrinogen (mean fibrinogen was greater by 52
mg/dL across quintiles of D-dimer). F1.2 (not shown) was not materially
associated with any risk factor.
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Relative Risks Analyzed by
Proportional Hazards Regression
As shown in
Table 4 after adjustment for age, sex, and race (model 1),
there were moderately strong positive associations of CHD incidence
with tPA antigen, PAI-1, plasminogen, and D-dimer. The
relative risk of CHD for the highest quintile, compared with the lowest
quintile, was 2.05 for tPA, 2.32 for PAI-1, 2.38 for
plasminogen, and 1.89 for D-dimer. There was no association
of CHD with F1.2; relative to the lowest quintile, the relative risk
for the highest quintile was 0.67
(Table 4) and for the highest decile was 0.47 (not
shown).
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After adjustment for major CHD risk factors (model 2,
Table 4
), plasminogen remained significantly
and positively associated with CHD incidence, with a relative risk of
2.20 for the highest versus lowest quintile but little evidence of dose
response. Similar adjustment for other risk factors strengthened the
positive association between D-dimer and CHD, with a relative risk of
4.21 for the highest quintile
(Table 4). Using stepwise regression, we determined that the
adjusting covariate that most augmented the association of CHD with
D-dimer was diabetes, although each covariate contributed to the
augmentation. In contrast, multivariate adjustment
completely eliminated the associations of CHD incidence with tPA and
PAI-1. The covariates that had most attenuated the association of CHD
with tPA and PAI-1 were diabetes, HDL cholesterol,
systolic blood pressure, and antihypertensive medication use.
With adjustment for only age, race, sex, smoking status, and total
cholesterol, the relative risks of CHD for the highest
versus lowest quintiles were 1.80 (95% CI 0.94 to 3.4) for tPA and
2.01 (95% CI 1.1 to 3.7) for PAI-1.
We further explored the independence of the associations of
CHD with plasminogen and D-dimer by adding to model 2
(Table 4) other variables associated with these
fibrinolytic factors. After adjustments for the waist-to-hip ratio and
plasma triglycerides were also made, the relative risk of
CHD for the highest versus lowest quintile of plasminogen
was 2.20 (95% CI 1.2 to 4.2); further adjustment for fibrinogen, white
blood cell count, and thrombomodulin attenuated this relative risk to
1.25 (95% CI 0.6 to 2.7). Alternatively, adding CRP to model 2
attenuated the plasminogen relative risk <10%. Adding
fibrinogen to model 2
(Table 4) for D-dimer changed the relative risk of CHD for
the highest versus lowest quintile of D-dimer to 2.79 (95% CI 1.2 to
6.8). Finally, when we put plasminogen and D-dimer in model
2 simultaneously, both were significant predictors of CHD
incidence; the relative risks for highest versus lowest quintiles were
3.77 (95% CI 1.6 to 8.7) for D-dimer and 2.15 (95% CI 1.1 to 4.3) for
plasminogen.
Subgroup analyses for plasminogen and
D-dimer are shown in
Table 5. Elevated plasminogen was associated
with increased CHD in men and women, in participants with high and low
carotid IMT, and in participants with high but not low CRP. D-dimer was
associated positively with CHD in all strata, although not always
statistically significantly, given the reduced sample
sizes.
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Because some researchers have reported that fibrinolytic factors may be associated more strongly with earlier compared with later cardiovascular events,19 we repeated the regression analyses with follow-up stratified according to the median (4.7 years). For plasminogen, the model 2 relative risk for the highest versus lowest quintile was higher (relative risk 2.40) for earlier than for later (relative risk 1.20) follow-up. For D-dimer, the respective relative risks were 3.91 and 3.95, suggesting no diminution in association with longer follow-up. Sixty-one events occurred in the first year. When we instead calculated relative risks of CHD for <1 year versus >1 year of follow-up, the estimates were elevated more in the first year for plasminogen (relative risk 5.16 versus 1.85, respectively) and D-dimer (relative risk 4.28 versus 3.84, respectively).
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Discussion |
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The main findings of the present prospective study were that increased levels of several markers of fibrinolytic function were associated positively with the incidence of CHD. Specifically, tPA antigen, PAI antigen, plasminogen, and D-dimer were moderately strong risk factors for CHD. However, only the associations for plasminogen and D-dimer were statistically significant after adjustment for other major risk factors. We also found that F1.2 was not associated with incident CHD.
PAI-1 is associated particularly strongly with markers of
the insulin resistance syndrome
(Table 3), and not all previous studies have determined
whether PAI-1 is associated with CHD independently of these markers.
Our finding of no association for PAI-1 after
multivariate adjustment is nevertheless
consistent with most previous studies of healthy subjects
(Table 1). In contrast to PAI-1, a number of studies have
suggested that tPA antigen may be an independent risk for CHD
(Table 1). Nevertheless, we found tPA antigen to be
moderately correlated with many CHD risk factors and PAI antigen;
therefore, it was not an independent risk factor for CHD. Yet, even the
univariate associations of PAI-1 or tPA antigen with CHD
should not be dismissed, because they still could reflect an important
role of these factors in the pathogenesis of CHD events. An earlier
ARIC publication reported PAI-1 and tPA to be associated positively and
independently with carotid
IMT.43 Yet, the present
results suggest that measuring PAI-1 or tPA would have little
additional benefit beyond traditional risk factors in predicting
CHD.
Plasminogen level was associated negatively with soluble thrombomodulin. Soluble thrombomodulin has been shown to activate plasma thrombin-activable fibrinolysis inhibitor (TAFI), which inhibits fibrinolysis by several biochemical mechanisms.44 It is possible that the inverse relationship between plasminogen and soluble thrombomodulin may be related to TAFI, but the exact mechanism remains unclear and requires further investigation.
To our knowledge, there have not been previous reports on the association of plasminogen with risk of incident CHD. We found a plasminogen level in the highest quintile to be associated with increased CHD incidence even after adjustment for major CHD risk factors. This result is somewhat unexpected and seemingly contrary to our understanding of the role of fibrinolysis in arterial thrombosis. However, a positive association between plasminogen and CHD may be analogous to the positive association between tPA antigen and CHD, in which plasma tPA levels reflect tPA-PAI complexes and not free tPA levels on fibrin at the thrombotic site. Plasminogen also binds to fibrin, on which it is converted to plasmin by tPA, and the generated plasmin degrades the surrounding fibrin. It is unclear whether the quantity of plasminogen bound to fibrin is directly correlated with plasma plasminogen levels. Our results suggest that the plasma plasminogen level is not correlated with the available plasminogen on fibrin. Plasminogen activation on fibrin is reduced by TAFI.45 TAFI levels may be a CHD risk factor, which could explain a positive association of plasminogen and tPA with CHD. Work is underway to determine the association of TAFI with incident CHD and the correlation of TAFI with tPA and plasminogen levels.
Alternatively, elevated plasminogen could reflect the inflammation and acute-phase reaction of subclinical atherosclerosis in participants who later developed CHD, because plasminogen transcription has been shown to be increased in response to interleukin-6.46 47 However, plasminogen was not correlated with CRP and was correlated only weakly with fibrinogen in the present study. On the other hand, the plasma plasminogen level may merely reflect the association of plasminogen with lipoproteins, which would limit the availability of plasminogen for in situ fibrinolysis.
D-dimer is a major product of fibrin degradation by plasmin. Its production depends on the presence of fibrin and plasmin; therefore, it is a marker of coagulation activation and fibrinolysis. The level of D-dimer is considered to reflect the overall activity of clot formation and lysis. Because D-dimer is not artificially generated in vitro during blood collection, its measurement more consistently reflects in vivo hemostatic activity than do other assays for coagulation or fibrinolytic activities, ie, F1.2 or fibrinogen degradation products that may be activated in vitro. D-dimer levels are increased in venous thromboembolism and arterial thrombosis. Our data confirm 4 previous prospective studies15 16 18 19 reporting that D-dimer is associated positively with CHD incidence or recurrence.7
Strengths of the present study were its prospective population-based design and relatively large numbers of events. Limitations included missing plasma samples for some subjects; this situation was primarily due to a freezer failure. We made only single measures of the fibrinolytic factors, and assays had only moderate precision; these measurement errors should have led to an underestimate of the strength of association between impaired fibrinolytic function and CHD. Finally, it could be that the associations observed are not causal but, instead, reflect underlying processes in the arterial wall in subclinical atherosclerosis.
In conclusion, this population-based prospective study identified for the first time that plasma plasminogen may be an independent risk factor for CHD and provides further evidence of a positive association between D-dimer and risk of CHD.
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Acknowledgments |
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The ARIC Study was funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the US National Heart, Lung, and Blood Institute. The authors thank the staff and participants of the ARIC Study for their valuable contributions over many years.
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Footnotes |
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Reprint requests to Aaron R. Folsom, MD, Division of Epidemiology, School of Public Health, University of Minnesota, Suite 300, 1300 South Second St, Minneapolis, MN 55454-1015.
Received January 3, 2001; accepted January 10, 2001.
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