© 1996 American Heart Association, Inc.
Articles |
Correlates of Thrombin Markers in an Elderly Cohort Free of Clinical Cardiovascular Disease
the Departments of Pathology (M.C., E.M., E.G.B., E.S.C., R.P.T.), Medicine (M.C.), and Biochemistry (R.P.T.), University of Vermont, Colchester; the Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (B.M.P.); and the Departments of Medicine and Epidemiology, University of Pittsburgh, Pa (L.H.K.).
Correspondence to Russell P. Tracy, PhD, University of Vermont, Aquatec Building, T205, 55A South Park Dr, Colchester, VT 05446. E-mail rtracy@moose.uvm.edu.
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Abstract |
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Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 µg/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.
Key Words: cardiovascular disease • fibrinopeptide A • blood coagulation factors • prothrombin fragment 1-2 • aged
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Introduction |
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The biochemical markers F1-2 and FPA reflect in vivo thrombin generation and activity, respectively.1 2 3 4 5 Levels of F1-2 or FPA are increased in acute coronary thrombosis,6 7 unstable angina,8 deep venous thrombosis,9 atrial fibrillation,10 and peripheral vascular disease.11 Levels of F1-2 increased with age in three studies of predominantly middle-aged subjects,12 13 14 and this increase may be related to increased atherosclerotic burden with age.12 Level of FPA was not associated with age in a cohort of middle-aged Finnish men.15
Thrombosis has a critical role not only in acute myocardial infarction but also in the progression of atherosclerotic lesions.16 17 18 19 20 21 22 Several coagulation and fibrinolysis factors are related to cardiovascular disease risk. Fibrinogen is the most widely studied.23 24 25 26 27 28 Since the importance of "traditional" cardiovascular risk factors may decline with aging, the thrombotic component of CVD may become more important with aging.29
Because markers of thrombin, such as F1-2 and FPA, reflect the procoagulant activity state, they may predict incident cardiovascular events. While prospective studies currently under way will estimate the associations of these markers to events, little is known about the relationships between thrombin markers and other cardiovascular risk factors.
The CHS is a cohort study of 5201 community-dwelling persons over 65 years of age.30 From this cohort, we identified 399 persons free of prevalent CVD at the baseline examination of the study. We report the cross-sectional correlates of F1-2 and FPA in this group. In particular, we determined the relationships of these factors to (1) traditional CVD risk factors, (2) newly recognized CVD risk factors, and (3) measures of subclinical CVD.
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Methods |
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CHS Design
The CHS cohort was recruited and the baseline examination performed over 1 year, beginning in May, 1989, at four field centers, located in Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pennsylvania. Each community sample was recruited from random samples of Medicare eligibility lists. Individuals with prevalent clinically diagnosed CVD were included in the sample. A detailed description of recruitment methods has been reported.31 Informed consent was obtained with protocols approved by institutional review committees at each center.
The baseline examination consisted of interview, physical examination, and comprehensive assessment of CVD status. Blood pressure, heart rate, anthropomorphic measurements, and medical and lifestyle histories were obtained, and phlebotomy was performed. Blood samples were analyzed at a central laboratory at the University of Vermont (Burlington). Data were transmitted to a coordinating center at the University of Washington (Seattle). Reports describing the study design, laboratory methods, and quality assurance procedures have been published.30 32 All subjects underwent duplex ultrasonography of the carotid arteries,33 echocardiographic examination,34 ankle-brachial blood pressure index, and resting twelve-lead electrocardiogram.35
Hypertension was defined as seated systolic blood pressure 
160 mm Hg or diastolic pressure 95 mm Hg or self-reported hypertension and use of anti-hypertensive medications. Borderline hypertension was defined as systolic pressure of 140 to 159 mm Hg or diastolic pressure of 90 to 94 mm Hg. Obesity was defined as >130% ideal body mass using the body-mass index. Smoking was categorized as never, former, or current use. Subclinical carotid atherosclerosis was measured as the maximum percent diameter stenosis in either internal carotid artery or the mean of multiple measurements of maximal intimal-medial thickness of the internal carotid artery.33 Abnormal ankle-brachial index was defined as <0.9.36 Major electrocardiogram abnormalities were defined as the presence of at least one of the following: ventricular conduction defect, major Q/QS-wave abnormalities, isolated major ST-T–wave abnormalities, atrial fibrillation, or first-degree atrioventricular block.35 A composite subclinical CVD variable was created identifying any subject with either carotid thickness >80th percentile, low ankle-brachial index, or major electrocardiogram abnormalities.
Subjects were classified as having prevalent cardiovascular disease or not at study entry.37 Coronary heart disease was defined by (1) self-reported myocardial infarction, angina, or use of nitroglycerin, (2) definite myocardial infarction on resting ECG by the Minnesota code38 , or (3) self-reported history of coronary angioplasty or coronary artery bypass surgery. Cerebrovascular disease was defined as self-reported stroke, transient ischemic attack, or carotid endarterectomy. Peripheral vascular disease was defined as self-reported intermittent claudication or history of peripheral artery angioplasty or bypass surgery.
Included in this analysis were 399 subjects randomly selected from all participants in the CHS who were free of prevalent cardiovascular disease at the baseline examination (n=3352). They were evenly distributed by sex and were among five age strata: 65 to 69, 70 to 74, 75 to 79, 80 to 84, and 85+ years. Four subjects receiving warfarin therapy were excluded. Four were excluded for inadequate blood sample volume to complete coagulation assays.
Blood Collection and Analysis
Blood collection methods have been reported.32 Blood was collected in a fasting state, with minimal stasis, and one drawing tube was a "special" coagulation tube designed to avoid in vitro coagulation activation. This tube (SCAT-1, Haematologic Technologies, Inc), at final concentrations, contained 4.5 mmol/L EDTA, 0.15 KIU/L aprotinin, and 20 µmol/L D-Phe-Pro-Arg chloromethyl ketone (a potent serine protease inhibitor).39 F1-2 was measured with an enzyme-linked immunosorbent assay (Baxter-Dade). The interassay CV was 8.5%. This assay has excellent correlation with another F1-2 assay (Behring Diagnostics, Inc), with a Pearson coefficient of .92 (P<.0001). FPA was measured on fibrinogen-free plasma, by a double antibody competition radioimmunoassay (Byk-Sangtec Diagnostica). Fibrinogen was extracted with bentonite.40 The postbentonite CV was 12.4% at 1.5 µg/L and 8.4% at 7.7 µg/L. In our experience, including the bentonite step increases the overall CV by twofold to threefold.41 The fibrin fragment D-dimer was measured by enzyme-linked immunosorbent assay (antibody kindly provided by Dr D. Collen, Belgium).42 The CV for control samples in the normal or high range was 7.0%. Fibrinogen, factor VII, and factor VIII were measured by using 3.2% citrate plasma as previously described.32 The marker of inflammation, CRP, was measured by in-house colorimetric competitive immunoassay (antibodies and antigens from Calbiochem), with a CV of 8.9%. Apolipoprotein(a) was measured by enzyme-linked immunosorbent assay (antibodies from Genentech, Inc), with a CV of 7.5%.43 Complete blood counts were performed at a designated local laboratory near each field center site. Lipid assays and general chemistries were done using 4.5 mmol/L EDTA plasma and serum, respectively, as previously reported.32
Statistical Analysis
SPSS for Windows44 was used for the analysis. Mean values for F1-2 and FPA were determined and distributions examined, and these were both skewed right. High values of F1-2 and FPA may be caused by traumatic phlebotomy or other preanalytical factors.3 45 46 Since the distributions included unusually high values, we used the highest 2.5% of values for either FPA or F1-2 to define subjects for exclusion as outliers from the analysis (n=13). We could have removed even more of the high values but chose not to, since little is known about the actual range of these analytes in the elderly. Bivariate analyses were completed with and without the exclusions to examine the effect of removing outliers on results.
F1-2, FPA, and other nonnormally distributed variables were natural log transformed so that parametric statistical tests could be applied. The effects of age and sex on plasma levels of the two factors were determined by ANOVA, with five age strata, and analyzed for linear trend. Bivariate associations of F1-2 and FPA with cardiac risk factors and laboratory measures were determined by Pearson correlation coefficients for continuous independent variables and ANOVA (with age adjustment) for discrete independent variables. The level of significance was defined as P
.05. Variables significantly related to F1-2 and FPA were entered in multivariable linear models with ln F1-2 or ln FPA as the dependent variable, for tests of significance. The predicted difference in F1-2 or FPA for a specified change of each independent variable in these models was determined using models without log transformation of dependent variables. The specified change for continuous independent variables usually represented a 1-SD change. Conventional units were transformed to SI units for analytes after statistical analysis.
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Results |
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The characteristics of the cohort are shown in Table 1
. A significant number of these subjects without prevalent CVD had subclinical CVD. For example, 28% of men and 16% of women had major electrocardiogram abnormalities in the absence of clinical CVD, and 47% of men and 37% of women had some degree of subclinical CVD, as defined by the composite subclinical disease variable. Only 10% of men and 7% of women were current smokers. Fourteen percent of women used postmenopausal estrogen replacement.
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The range of F1-2 was 0.12 to 6.88 nmol/L, and the range of FPA was 0.9 to 496 µg/L. After exclusion of outliers, the range of F1-2 was 0.12 to 0.85 nmol/L, and the range of FPA was 0.9 to 44.1 µg/L (Fig 1). It is possible that some of the highest FPA values represent phlebotomy artifact.12 46 Women had higher mean F1-2 and FPA levels than men (F1-2, 0.39 nmol/L versus 0.33 nmol/L, P<.001; FPA, 4.6 µg/L versus 3.7 µg/L, P=.005). There was a significant linear increase in F1-2 with increasing age quintiles for women and men (P=.0001) (Fig 2). For FPA, the same relationship was observed in men (P=.002). In women, the age and FPA relationship was not apparent (P=.54) unless women with FPA >25 µg/L (n=3) were excluded (P=.015).
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Table 2 shows sex-specific Pearson coefficients for ln F1-2 and ln FPA, with continuous independent variables. In both sexes, the significant associations of F1-2 were age (+), glucose (-), creatinine (+), and D-dimer (+). In men only, ankle-brachial index (-) and CRP (+) were significant. In women only, systolic blood pressure (+) and triglyceride (+) were significant. In men, there were significant associations of FPA with age (+), total and LDL cholesterol (-), triglyceride (-), apolipoprotein(a) (+), CRP (+), leukocyte count (+), and D-dimer (+). In women, there were associations with ankle-brachial index (-) and D-dimer (+). If the sexes were combined, there was an association between F1-2 and factor VII (r=.11, P=.03); however, this was not the case for FPA and factor VII (r=.04, P=.45) or for any other factor nonsignificant in bivariate analysis.
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Women smokers had higher age-adjusted F1-2 than never or former smokers (0.48 nmol/L versus 0.37 nmol/L, P=.007). Age-adjusted F1-2 was lower in women with major electrocardiogram abnormalities than in those without major abnormalities (0.33 nmol/L versus 0.41 nmol/L, P=.001). For women, there was an increase of age-adjusted FPA from normal or borderline to hypertensive (3.9 µg/L versus 3.6 µg/L versus 5.9 µg/L, P=.007). There was no association with systolic or diastolic blood pressure as continuous variables. There were no significant associations in either sex for F1-2 or FPA with field center site, race, composite subclinical CVD variable, tertiles of weekly alcohol use, diabetes, obesity, or estrogen use (in women). For men, composite subclinical CVD was associated with higher F1-2 when age was not considered as a covariate (0.31 nmol/L without subclinical CVD versus 0.34 nmol/L with subclinical CVD, P=.04).
All bivariate associations were similar in analyses that included the 2.5% of subjects we previously excluded as outliers, with the exception that hypertension was not associated with FPA in women (P=.22). The variance in each of the three groups (normal, borderline, and hypertension) was very large, and more of the subjects with the highest values for FPA were in the normal and borderline groups than in the hypertension group.
Age, female sex, creatinine, triglyceride level, lower glucose, CRP, systolic blood pressure, and current smoking were associated with higher F1-2 levels, adjusting simultaneously for variables significant in bivariate analysis for both sexes (Table 3). Sex, age, and smoking had the largest association with F1-2 level. Since there were significant bivariate associations of age with creatinine and ankle-brachial index, age was excluded from the model to explore confounding. In this model, the ankle-brachial index was significant and the coefficient for creatinine increased. With ankle-brachial index or creatinine excluded from the model, the coefficient for age did not change.
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Age, sex, apolipoprotein(a), and CRP were significant correlates of FPA, after adjustment for other variables significant in bivariate analysis (Table 4). Hypertension, ankle-brachial index, and age are related variables, so models were constructed to assess confounding. With ankle-brachial index removed from the model, hypertension became a stronger correlate (FPA 0.90 ng/mL higher with hypertension versus none, P=.07) and there was no change in the coefficient for age. With age or hypertension removed, ankle-brachial index became significant (FPA higher by 0.49 µg/L for a 1-SD decrease in ankle-brachial index).
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Discussion |
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These cross-sectional analyses from a cohort of men and women over age 65 and free of prevalent CVD suggest several relationships between thrombin action and CVD risk factors. Based on our findings, we hypothesize interrelationships between coagulation, inflammation, and fibrinolysis in the pathogenesis of CVD. An inflammatory response to factors such as repetitive subclinical plaque rupture47 may deregulate the normal coagulant balance48 and contribute to the progression of CVD.49
Strengths of our study include minimized influence of prevalent clinical CVD as a confounder of the relationships examined, carefully collected and processed blood samples, and control for confounding in the multivariable analyses.
The main weakness of our study is that interpretation of our findings is restricted by the cross-sectional analysis. A prospective study currently under way will increase our understanding of the relationships of F1-2 and FPA to clinical CVD in this age group. Generalizability of our results may be limited because inclusion required participants to be free of clinical CVD. Relationships of F1-2 and FPA to the factors studied may be different than in the general elderly population. The large number of statistical comparisons made must be considered in interpretation of results; the results are best considered as hypothesis-generating data. Also, many of the independent variables are interrelated, so that some associations described may not be observed in other populations, especially those comprised of younger subjects.
Sex and Age
F1-2 and FPA increased with age in men and were higher overall in women than men. In women, FPA increased with age after exclusion of those with unusually high FPA values. Three studies showed that F1-2 increased with age starting in middle age,12 13 14 and our findings confirm and extend this to older age. Our results disagree with one study of Finnish men.15 One might speculate that the increase of F1-2 and FPA with age may contribute to the increased risk of CVD in older people; however, a causal or temporal relationship cannot be determined with existing data.
Increased thrombin action with age may be related to several factors. Subclinical CVD may increase with age, which may cause increased thrombin generation and activity through provision of damaged endothelial surface. In addition, unknown genetic or environmental factors closely related to age may cause increased thrombin action by an unknown mechanism. For F1-2, at least in men, this relationship is not due to decreased clearance of F1-2 with age.12
A sex difference in F1-2 was not found in a younger cohort.14 Higher F1-2 in CHS women compared with men may be related to hormonal factors, although a mechanism is not known. Women may have a decrease in clearance of F1-2 and FPA compared with men. Elderly women are known to have higher factor VII levels than men,50 and increased thrombin action may partly explain their increased CVD risk.
Smoking
We observed a positive relationship between current smoking and F1-2 level. Another study found a weak relationship, but extent of the effect was not reported.14 Increased thrombin action in smokers may be related to increased endothelial damage, reduced fibrinolysis, or increased platelet activation, but the mechanism at this time is unclear.
Subclinical Disease
We did not find independent correlations of F1-2 or FPA with subclinical disease when age was included in our models. We believe the bivariate associations of F1-2 and FPA with ankle-brachial index were partly explained by correlation between ankle-brachial index and age. A possible causal pathway is that decreasing ankle-brachial index reflects increased atherosclerosis with age, which results in inflammation and endothelial damage, leading to increased F1-2 and FPA with age. Our findings extend a previous finding of increased F1-2 in clinically evident peripheral vascular disease11 to subclinical disease. The same conclusion concerning age and subclinical CVD may be drawn regarding the relationship of F1-2 to the composite subclinical disease variable in men.
Relationships of F1-2 and FPA with subclinical disease may have been underestimated for several reasons. The relatively healthy group we studied may not have had severe enough subclinical disease. The sample size with any given subclinical disease was relatively small, which might limit the power to detect relationships; however, there were no independent relationships with a composite subclinical CVD variable. Methods we used to measure subclinical disease may not be sensitive enough to detect relationships. For example, there was a trend of association of FPA with hypertension, and it is possible that individuals with hypertension have a greater degree of subclinical atherosclerosis, which was not measured by the methods we used. Any increase in thrombin generation or action observed in clinical CVD6 8 11 may occur at a later time in the development of the disease. Prospective studies may help shed light on this issue.
Lipids
Triglyceride level was associated with higher F1-2, and apolipoprotein(a) was positively associated with FPA. Triglyceride level is also associated with higher factor VII levels,51 and a study of gemfibrozil therapy showed that lipid lowering was associated with decreased F1-2.52 Apolipoprotein(a) is hypothesized to be a fibrinolytic inhibitor,53 and therefore, the positive relationship we observed was not unexpected. The regulatory events leading to this relationship are not understood at this time.
Fibrinogen and Inflammation
The coagulation factor fibrinogen, also a marker of inflammation, is an independent risk factor for CVD,54 but F1-2 and FPA were not correlated with fibrinogen. We found a strong relationship between CRP and thrombin action, indicating potentially complex interrelationships between inflammation and procoagulation. Fibrinogen may not be related to CVD solely by its role in coagulation.
Our findings suggest that regulation of fibrinogen level may occur by a mechanism at least partly independent of procoagulation. Other mechanisms, such as inflammation, may explain part of the association of fibrinogen with CVD. Contrary to our findings, a recent study of Italian middle-aged subjects identified a positive association between F1-2 and fibrinogen.55 The investigators in that study proposed that F1-2 modulates the production of fibrinogen by the liver, although this effect has not been directly demonstrated.
We have identified correlates of thrombin generation and activity. The relationship of F1-2 with age, sex, triglyceride, smoking, and CRP and the relationship of FPA with age, sex, CRP, apolipoprotein(a), and subclinical peripheral vascular disease should be considered in the design and analysis of similar cross-sectional and prospective studies. We have proposed several hypotheses of the interrelationships between risk factors, thrombin action, and progression of atherosclerosis. Prospective clinical studies and basic research will further define the role of F1-2 and FPA in the pathogenesis of CVD.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute contracts NO1-HC-85079 through NO1-HC-85086; by US Public Health Service grant T3207594; and by National Heart, Lung, and Blood Institute grant RO1-HL-46696. We gratefully acknowledge P. DeClerck and D. Collen for D-dimer reagents, and W.L. Wong for apolipoprotein(a) reagents. We thank the staff members of the CHS field centers and central laboratory and all our CHS colleagues, whose names appear in the "Appendix."
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Appendix |
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Field Centers
Forsyth County, North Carolina
Bowman Gray School of Medicine of Wake Forest University—Gregory L. Burke, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Edward Haponik, Gerardo Heiss, Dalane Kitzman, H. Sidney Klopfenstein, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Maurice B. Mittelmark, Cathy Nunn, Ward Riley, Grethe S. Tell, James F. Toole, Beverly Tucker
Bowman Gray School of Medicine-EKG Reading Center—Kris Calhoun, Harry Calhoun, Farida Rautaharju, Pentti Rautaharju, Loralee Robertson
Sacramento County, California
University of California, Davis—William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Paul Kellerman, Lawrence Laslett, Marshall Lee, Virginia Poirier, John Robbins, Marc Schenker, Nemat Borhani
Washington County, Maryland
The Johns Hopkins University—M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman
MRI Reading Center, The Johns Hopkins University—R. Nick Bryan, Carolyn C. Meltzer, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Earl P. Steinberg, Scott Wells, Linda Wilkins, Nancy C. Yue
Allegheny County, Pennsylvania
University of Pittsburgh—Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson
CHS Support
Echocardiography Reading Center (Baseline)
University of California, Irvine—Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, Nathan Wong
Echocardiography Reading Center (Follow-up)
Georgetown Medical Center—John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb
Ultrasound Reading Center
Geisinger Medical Center—Daniel H. O'Leary, Joseph F. Polak, Laurie Funk
Respiratory Sciences
University of Arizona, Tucson—Paul Enright
Coordinating Center
University of Washington, Seattle—Alice Arnold, Annette L. Fitzpatrick, Bonnie K. Lind, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Lynn Shemanski, Lloyd Fisher, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Maryann McBurnie
National Heart, Lung, and Blood Institute
Project Office, Bethesda, Maryland—Diane E. Bild, Teri A. Manolio, Peter J. Savage, Patricia Smith, Rachel Solomon
Received February 16, 1996;
revision received June 5, 1996;
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