© 1999 American Heart Association, Inc.
Original Contributions |
Fibrinolytic Activation Markers Predict Myocardial Infarction in the Elderly
The Cardiovascular Health Study
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Abstract |
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Abstract—Coagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women
65 years of age who were enrolled from
1989 to 1990. Cases were 146 participants without baseline clinical
vascular disease who developed myocardial infarction, angina, or
coronary death during a follow-up of 2.4 years. Controls
remained free of cardiovascular events and were matched
1:1 to cases with respect to sex, duration of follow-up, and baseline
subclinical vascular disease status. With increasing quartile of
D-dimer and PAP levels but not of PAI-1, there was an
independent increased risk of myocardial infarction or coronary
death, but not of angina. The relative risk for D-dimer
above versus below the median value (120 µg/L) was 2.5 (95%
confidence interval, 1.1 to 5.9) and for PAP above the median (5.25
nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein
and fibrinogen concentrations. There were no differences in risk by sex
or presence of baseline subclinical disease. D-dimer and PAP, but not
PAI-1, predicted future myocardial infarction in men and women over age
65. Relationships were independent of other risk factors, including
inflammation markers. Results indicate a major role for these markers
in identifying a high risk of arterial disease in this
age group.
Key Words: blood coagulation • fibrinolysis • myocardial infarction • elderly • risk factors
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Introduction |
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Elderly persons have the highest incidence of myocardial infarction (MI).1 In older men and women without clinically apparent vascular disease, noninvasively assessed subclinical disease predicts subsequent clinical events.2 Because the endothelial damage that accompanies atherosclerosis provides a surface for cyclic thrombin production and reactive fibrinolysis,3 markers of fibrinolysis might predict clinical events in apparently healthy persons with subclinical disease.
D-dimer and plasmin-antiplasmin complex (PAP) are
hemostatic activation markers that assess the balance of procoagulant
and fibrinolytic reactions. Procoagulant reactions producing fibrin
activate fibrinolysis to produce plasmin, which
degrades fibrin to produce D-dimer. PAP is formed by avid
binding to and inactivation of free plasmin by its
inhibitor, 
2-antiplasmin, so the PAP level measures
recent plasmin production.4
Plasminogen activator inhibitor-1
(PAI-1) is the major fibrinolysis
inhibitor, with higher levels associated with the
acute-phase reaction5 and the insulin resistance
syndrome.6
D-dimer and tissue plasminogen activator (in an assay that included assessment of the tissue plasminogen activator/PAI-1 complex) predicted MI in male physicians,7 8 but these effects were not independent of lipid levels. The PAI-1 level predicted the short-term risk of recurrent MI in young men9 but did not predict in subjects with angina10 or in older men, some of whom had existing coronary disease.11 In the latter study D-dimer was associated with MI risk. The PAP level rose during acute MI and fibrinolytic therapy.12 However, to our knowledge, there are no prospective data for PAP.
Given the underlying hypotheses that hemostatic balance promotes progression of atherosclerosis and is increasingly important in the elderly,13 we completed a nested case-control study in the Cardiovascular Health Study (CHS). The specific hypotheses were that (1) higher baseline levels of D-dimer, PAP, and PAI-1, as indicators of fibrinolysis, would predict subsequent MI, angina, or coronary death in healthy older men and women and (2) the risks would be greatest in those with subclinical disease at baseline.
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Methods |
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CHS Design
Subjects were selected from the CHS, a cohort study of risk factors for cardiovascular disease in 5201 free-living men and women age 65 and over.14 Subjects were recruited from 1989 to 1990 from random samples of Medicare eligibility lists at 4 field centers: Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pennsylvania. Informed consent was obtained with methods approved by institutional review committees at each center.
The baseline examination included an interview, physical examination, phlebotomy, and assessment of clinical and subclinical vascular disease.14 To assess subclinical disease, subjects underwent duplex ultrasonography of the carotid arteries,15 echocardiography,16 measurement of ankle-brachial blood pressure index, and a resting 12-lead ECG,17 and they completed the Rose questionnaires for angina and claudication.
Definition of Variables
Hypertension was defined as absent, borderline, or
present.18 Diabetes was evaluated as absent, impaired
glucose tolerance, or diabetes by using data from the medical history
and glucose challenge.18 Body mass index was calculated as
the weight in kilograms divided by the square of height in meters.
Smoking was categorized as never, former, or current use. Alcohol use
was the reported number of drinks consumed per week.
Participants were classified as having subclinical disease2 if they possessed any 1 of the following: internal carotid wall thickness >80th percentile, common carotid wall thickness >80th percentile, carotid stenosis >25%, major ECG changes,17 abnormal ejection fraction or wall motion on the echocardiogram, Rose questionnaire–positive, or an ankle-brachial index <0.9.
Identification of Cases and Controls
Participants with cardiac, cerebral, or peripheral
arterial disease at baseline were excluded from the study.
To identify cases of MI, angina pectoris, and coronary heart
disease death, participants were evaluated twice annually by clinic
visits and telephone calls. Hospital and outpatient records were
reviewed by committee for International Classification of Disease codes
410 through 414, 427.4, 427.5, and 428 and any discharge summary when
there was a question of a cardiovascular
event.19
Of those remaining free of events, 1 control was matched to each case on the basis of sex, baseline subclinical disease status, and duration of follow-up. We previously reported the association of C-reactive protein level with incident disease in the same case-control group.20
Laboratory Analyses
The fibrinolytic markers were measured on plasma drawn at
baseline and stored at -70°C.21 Blood was collected in
the morning, with minimal stasis after an 8- to 12-hour fast, into
tubes containing either sodium citrate or 4.5 mmol/L EDTA, 0.15
KIU/L aprotinin, and 20 µmol/L
D-Phe-Pro-Arg-chloromethylketone
(SCAT-1 tube, Haematologic Technologies, Inc).
D-dimer was measured in SCAT-1 plasma by ELISA using 2
monoclonal antibodies directed against nonoverlapping antigenic
determinants. The assay detects D-dimer from cross-linked
fibrin but not D-monomer.22 The interassay
coefficient of variation (CV) was 7.0%. PAP was measured in SCAT-1
plasma by using a 2-site ELISA with murine monoclonal antibodies
specific for PAP complex.4 The CV was 3.6%. PAI-1 antigen
was measured in citrated plasma by a sandwich-type
ELISA23 24 that detects latent and active free PAI-1 but
not PAI-1 complexed with tissue plasminogen
activator. The CV was 10.5%. Lipids, fibrinogen, and
C-reactive protein were measured as described.20 21
Statistical Analyses
The SPSS version 6.1 was used for data
analysis on an updated CHS database with minor corrections
through June 1993. EGRET was used for conditional logistic
regression. Means or proportions for baseline characteristics were
determined in cases and controls. The distributions of the fibrinolytic
markers were divided into quartiles based on the control distributions.
The odds ratio (estimating relative risk) of incident MI, angina
pectoris, or coronary death was determined by conditional
logistic regression for each of the upper 3 quartiles compared with the
first quartile. Because angina is less likely to be associated with
acute thrombosis, risk of MI or coronary death was evaluated
separately. The following risk factors were assessed in
multivariable models and were not included in the final models in
the absence of confounding: body mass index, race (white, nonwhite),
smoking status, total cholesterol, LDL and HDL
cholesterol, triglycerides, diabetes,
hypertension, and alcohol use. Subgroup analyses were done
based on the matching factors, with each hemostatic variable
dichotomized at the median and using conditional logistic regression
models with interaction terms.
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Results |
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There were 150 study events, with a mean follow-up of 2.4 years: 61% men, 74% with baseline subclinical disease. There were 146 cases with baseline plasma samples: 64 with MI, 73 with angina, and 9 coronary deaths. In cases and controls, the range of values for the analytes were as follows: D-dimer, 21 µg/L to 4578 µg/L; PAP, 2.20 nmol/L to 24.06 nmol/L; and PAI-1, 6 µg/L to 293 µg/L. No phlebotomy or processing difficulties were reported for participants with the highest values. Baseline characteristics are shown in Table 1
. Except
for D-dimer and PAI-1, hemostasis variables and
C-reactive protein were intercorrelated, as shown in Table 2.
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There were no relationships between PAI-1 and the occurrence of any
event (Table 3). After event types
were combined, the relative risk of any event increased with increasing
quartile of D-dimer, but not of PAP (Tables 4 and 5). Adjustment for
cardiovascular risk factors did not appreciably change
the results. When event types were separated, there were no
relationships between either analyte and the risk of angina. However,
there was a graded increase in the risk of MI or coronary death
with increasing D-dimer and PAP, with crude risks greater than 2-fold
for D-dimer or PAP above their respective median values (Table 6). Relative risks were higher in
adjusted models. To provide additional control for residual confounding
by subclinical disease beyond that afforded by the matched design,
there was no effect of further adjustment by ankle-arm index.
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Risks of MI or coronary death associated with D-dimer or PAP
above the median were unchanged by adjustment for PAI-1, fibrinogen,
C-reactive protein, or the effect of each marker for the other (Table 6
). Compared with participants with levels of
D-dimer and PAP below the median, those with both values
above the median had a crude risk of MI or coronary death of
2.7 (95% confidence interval, 1.1 to 6.7), with no effect of
adjustment for other risk factors. In subgroup analyses, there
were no differences in risk for D-dimer or PAP by the
matching factors of sex or subclinical disease status at baseline (data
not shown). However, the markers appeared to be better predictors of MI
or coronary death earlier in the follow-up period (Table 7).
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Discussion |
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The primary finding of this study was that levels of D-dimer and PAP, but not of PAI-1, predicted the first MI or coronary death, but not angina, in healthy persons over age 65. Estimated relative risks for D-dimer and PAP were substantial, with a 2.5-fold increased risk for D-dimer above the median (
120 µg/L) and a
3.1-fold increased risk for PAP above the median (5.25 nmol/L).
Relationships were independent of traditional risk factors, PAI-1, and
a recently studied inflammation marker, C-reactive
protein.20 25 D-dimer and PAP appeared to be
better predictors of events early in the follow-up period. The results suggest a significant role for fibrinolytic activation in the prediction of MI and extend the 4 previous reports of D-dimer in subjects with and without preexisting vascular disease.7 11 26 27 The 4 prospective studies included mainly middle-aged men, and we studied an elderly population of men and women. Our analyses related to subclinical disease provide important new information. We predicted that relationships of D-dimer and PAP to future events would be largest in those with subclinical disease, as we observed for C-reactive protein,20 but this was not the case. Additionally, we controlled for possible confounding by subclinical disease by using a matched design and further adjustment for ankle-arm index, a correlate of PAP.28 The findings suggest that even if the damaged endothelial surface increases the levels of these markers, it is less likely that the markers simply reflect the degree of underlying preclinical disease as we currently assess it.
High levels of PAI-1 antigen or activity mark the risk for ischemic events in those with existing vascular disease,9 10 27 but these relationships disappeared after adjustment for insulin resistance syndrome components in the study by Juhan-Vague and colleagues.10 Our null findings for PAI-1 antigen agree with a recent study of PAI-1 activity level in middle-aged men.11 Taken together, studies to date suggest that PAI-1 concentration may assess different aspects of risk, such as those associated with the insulin resistance syndrome, depending on the presence of baseline disease and characteristics of the population studied. Because PAI-1 is the major fibrinolytic inhibitor and downregulates PAP,29 the observed association between PAP and cardiovascular events suggests that the PAP assay reflects ongoing fibrin formation better than it reflects regulation by PAI-1 in this healthy, older population. To support this concept, in the CHS PAP is more strongly related to the procoagulant marker fibrinogen than it is to PAI-1, whereas PAI-1 is more strongly related to insulin level than it is to inflammation and procoagulation markers.28
Several factors might underlie the lack of relationships of the fibrinolysis markers to angina. Misclassification of angina may have occurred, because angina is largely a clinical diagnosis. Also, angina events included both stable (which are most likely not thrombosis related) and unstable (may consist of either spasm or thrombosis) angina. All of these factors would bias results toward the null hypothesis.
There were differences between our results and others. First, D-dimer appears to be a more sensitive indicator of risk in an aged or atherosclerotic population. D-dimer levels over the median predicted MI in our study, whereas in male physicians this association was observed for levels above the 95th percentile only.7 Our findings were similar to 2 studies that included younger subjects with vascular diagnoses at baseline.11 26 The differences may be related to age; D-dimer increases with age,30 and older persons may be similar to younger subjects with diffuse atherosclerosis. Second, associations in our study and in 2 other studies11 26 were not attenuated by adjustment for lipid levels, in contrast to findings in male physicians.7 Third, because our results were similar in elderly men and women, inclusion of women does not explain the differences between our study and others composed largely of men.
Levels of C-reactive protein or fibrinogen did not confound the associations of D-dimer and PAP with MI and coronary death. Because these analytes have cross-sectional and biochemical associations with each other, our prospective results suggest that (1) the inflammatory response and fibrinolytic activation may have independent roles in atherogenesis; (2) because their predictive capacities are independent of each other, D-dimer and PAP appear to measure different aspects of fibrinolysis; and (3) measurement of inflammation and fibrinolysis might yield additive information in predicting a high risk for MI.
A mechanistic explanation for our findings related to D-dimer and PAP cannot be provided with the current study design. However, we suggest the following hypothesis. Although the findings seem to be independent of a single determination of subclinical atherosclerosis (cases and controls were matched on subclinical disease), because the markers predicted early events better than they did later events, it is possible that higher concentrations of PAP reflect ongoing cyclic subclinical atherothrombosis (plaque destabilization) occurring in proximity to arterial occlusive events in this elderly population. To test this hypothesis, we are currently studying longitudinal changes in D-dimer and PAP in relation to changes in subclinical disease and risk prediction of clinical events.
The strengths of our study were prospective follow-up, reliable event ascertainment, ability to determine independence of relationships, and matched design, allowing efficient control for important confounders, particularly subclinical disease. Inclusion of persons over age 65 allowed study of the highest-risk population.
The main limitation of the study was the relatively small number of events; estimates of relative risk require confirmation. Owing to the entry criteria, the CHS represented a healthy portion of the older population, so findings may not be fully generalizable. While subclinical disease categorization is a sensitive indicator of atherosclerosis,31 it is not a quantitative measure, so the magnitude of subclinical disease may not have been fully assessed as a confounder or effect modifier, even with further adjustment for ankle-arm index. Finally, imprecision of the fibrinolytic assays may affect interpretation of the relationships observed; however, in our laboratory, these assays have acceptable precision, with the index of individuality for all 3 assays identical at 0.68, compared with 0.48 for cholesterol.32
Measurement of PAP or D-dimer may be useful in identifying individuals at risk of MI and who might benefit from primary prevention with aspirin, lipid-lowering therapies with favorable hemostatic effects, or anticoagulants.33 In the CHS, the risk of cardiac disease was 2-fold in those with subclinical disease (37.2% of the cohort), 2.5-fold with C-reactive protein in the highest quartile, and 2.5-fold with D-dimer above the median. The annual incidence of coronary disease was 3.8% for those with subclinical disease and 1.5% for those without subclinical disease. If one assumes independent risks with D-dimer above the median and C-reactive protein in the top quartile, these incidence rates rise to 23.8% and 9.4%, respectively, so use of these markers might identify a large number of individuals for intervention. Before these markers may be used in patients, other studies are needed to further clarify the relationship of ongoing inflammation and fibrinolysis to clinical events in this age group and to determine whether interventions related to inflammation and fibrinolysis are beneficial.
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Acknowledgments |
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The study was supported by National Institutes of Health (Bethesda, Md) contract NO1-HC-85079–85086 and grant RO1-HL-46696 (Dr Tracy). Dr Cushman was supported by US Public Health Service Hemostasis Training grant T3207594 and K08-HL-03618. We are grateful to Drs P. DeClerck and D. Collen for providing D-dimer and PAP reagents and to our colleagues at the participating institutions of the Cardiovascular Health Study: Forsyth County, NC-Bowman Gray School of Medicine of Wake ForestUniversity: Gregory L. Burke, Sharon Jackson, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Gerardo Heiss, Dalane Kitzman, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Cathy Nunn, Ward Riley, John Chen, and Beverly Tucker; EKG Reading Center-Bowman Gray School of Medicine: Farida Rautaharju and Pentti Rautaharju; Sacramento County, Calif-University of California, Davis: William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Lawrence Laslett, Marshall Lee, John Robbins, and Richard White; Washington County, Md-Johns HopkinsUniversity: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Adrian Dobs, 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, and Melvyn Tockman; MRI Reading Center-Johns Hopkins University: R. Nick Bryan, Norman Beauchamp, Carolyn C. Meltzer, Naiyer Iman, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Cynthia Quinn, Earl P. Steinberg, Scott Wells, Linda Wilkins, and Nancy C. Yue; Allegheny County, Pa-University of Pittsburgh: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, and Sidney K Wolfson; Echocardiography Reading Center (Baseline)-Universityof California, Irvine: Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, and Nathan Wong; Echocardiography Reading Center (Follow-Up)-Georgetown Medical Center: John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, and Retha Webb; Ultrasound Reading Center-Geisinger Medical Center: Daniel H. O'Leary, Joseph F. Polak, and Laurie Funk; CentralBlood Analysis Laboratory-University of Vermont: Edwin Bovill and Elaine Cornell; 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, David S. Siscovick, Lynn Shemanski, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Maryann McBurnie, Chuck Spiekerman, Scott Emerson, Cathy Tangen, and Priscilla Velentgas; NHLBI ProjectOffice: Diane E. Bild, Robin Boineau, Teri A. Manolio, Peter J. Savage, and Patricia Smith.
Received June 9, 1998; accepted July 28, 1998.
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 M. Kremen, R. Krishnan, I. Emery, J. H. Hu, K. I. Slezicki, A. Wu, K. Qian, L. Du, A. Plawman, A. Stempien-Otero, et al. Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice PNAS, November 4, 2008; 105(44): 17109 - 17114. [Abstract] [Full Text] [PDF]
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 I. Tzoulaki, G. D. Murray, A. J. Lee, A. Rumley, G. D.O. Lowe, and F. G. R. Fowkes Relative Value of Inflammatory, Hemostatic, and Rheological Factors for Incident Myocardial Infarction and Stroke: The Edinburgh Artery Study Circulation, April 24, 2007; 115(16): 2119 - 2127. [Abstract] [Full Text] [PDF]
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 I. Tzoulaki, G. D. Murray, A. J. Lee, A. Rumley, G. D.O. Lowe, and F. G. R. Fowkes Inflammatory, haemostatic, and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study Eur. Heart J., February 1, 2007; 28(3): 354 - 362. [Abstract] [Full Text] [PDF]
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 T. J. Wang, P. Gona, M. G. Larson, G. H. Tofler, D. Levy, C. Newton-Cheh, P. F. Jacques, N. Rifai, J. Selhub, S. J. Robins, et al. Multiple Biomarkers for the Prediction of First Major Cardiovascular Events and Death N. Engl. J. Med., December 21, 2006; 355(25): 2631 - 2639. [Abstract] [Full Text] [PDF]
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 P.E. Morange, C. Bickel, V. Nicaud, R. Schnabel, H.J. Rupprecht, D. Peetz, K.J. Lackner, F. Cambien, S. Blankenberg, L. Tiret, et al. Haemostatic Factors and the Risk of Cardiovascular Death in Patients With Coronary Artery Disease: The AtheroGene Study Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2793 - 2799. [Abstract] [Full Text] [PDF]
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 R. von Kanel, J. E. Dimsdale, P. J. Mills, S. Ancoli-Israel, T. L. Patterson, B. T. Mausbach, and I. Grant Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and d-dimer. J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2006; 61(9): 963 - 969. [Abstract] [Full Text] [PDF]
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 E. Paffen and M. P.M. deMaat C-reactive protein in atherosclerosis: A causal factor? Cardiovasc Res, July 1, 2006; 71(1): 30 - 39. [Abstract] [Full Text] [PDF]
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M. M. McDermott, K. Liu, J. M. Guralnik, L. Ferrucci, D. Green, P. Greenland, L. Tian, M. H. Criqui, C. Lo, N. Rifai, et al. Functional decline in patients with and without peripheral arterial disease: predictive value of annual changes in levels of C-reactive protein and d-dimer. J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 374 - 379. [Abstract] [Full Text] [PDF]
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 E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw Biochemical risk markers: a novel area for better prediction of renal risk? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508. [Full Text] [PDF]
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G. D.O. Lowe, A. Rumley, A. D. McMahon, I. Ford, D. St. J. O'Reilly, C. J. Packard, and for the West of Scotland Coronary Prevention Study Interleukin-6, Fibrin D-Dimer, and Coagulation Factors VII and XIIa in Prediction of Coronary Heart Disease Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1529 - 1534. [Abstract] [Full Text] [PDF]
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A. D. Pradhan, A. Z. LaCroix, R. D. Langer, M. Trevisan, C. E. Lewis, J. A. Hsia, A. Oberman, J. M. Kotchen, and P. M Ridker Tissue Plasminogen Activator Antigen and D-Dimer as Markers for Atherothrombotic Risk Among Healthy Postmenopausal Women Circulation, July 20, 2004; 110(3): 292 - 300. [Abstract] [Full Text] [PDF]
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G.D.O. Lowe, J. Danesh, S. Lewington, M. Walker, L. Lennon, A. Thomson, A. Rumley, and P.H. Whincup Tissue plasminogen activator antigen and coronary heart disease: Prospective study and meta-analysis Eur. Heart J., February 1, 2004; 25(3): 252 - 259. [Abstract] [Full Text] [PDF]
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 T. Hoekstra, J. M. Geleijnse, C. Kluft, E. J. Giltay, F. J. Kok, and E. G. Schouten 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly Stroke, December 1, 2003; 34(12): 2822 - 2828. [Abstract] [Full Text] [PDF]
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 M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita The clinical implications of endothelial dysfunction J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1149 - 1160. [Abstract] [Full Text] [PDF]
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 R. P. Tracy Thrombin, Inflammation, and Cardiovascular Disease: An Epidemiologic Perspective Chest, September 1, 2003; 124(3_suppl): 49S - 57S. [Abstract] [Full Text] [PDF]
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 A Wakai, A Gleeson, and D Winter Role of fibrin D-dimer testing in emergency medicine Emerg. Med. J., July 1, 2003; 20(4): 319 - 325. [Abstract] [Full Text] [PDF]
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 M. Cushman, A. R. Folsom, L. Wang, N. Aleksic, W. D. Rosamond, R. P. Tracy, and S. R. Heckbert Fibrin fragment D-dimer and the risk of future venous thrombosis Blood, February 15, 2003; 101(4): 1243 - 1248. [Abstract] [Full Text] [PDF]
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M. G. Shlipak, L. F. Fried, C. Crump, A. J. Bleyer, T. A. Manolio, R. P. Tracy, C. D. Furberg, and B. M. Psaty Elevations of Inflammatory and Procoagulant Biomarkers in Elderly Persons With Renal Insufficiency Circulation, January 7, 2003; 107(1): 87 - 92. [Abstract] [Full Text] [PDF]
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 R. von Kanel, J. E. Dimsdale, T. L. Patterson, and I. Grant Association of Negative Life Event Stress With Coagulation Activity in Elderly Alzheimer Caregivers Psychosom Med, January 1, 2003; 65(1): 145 - 150. [Abstract] [Full Text] [PDF]
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 P. Greenland, S. S Gidding, and R. P Tracy Commentary: Lifelong prevention of atherosclerosis: the critical importance of major risk factor exposures Int. J. Epidemiol., December 1, 2002; 31(6): 1129 - 1134. [Full Text]
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W. Koenig, D. Rothenbacher, A. Hoffmeister, M. Griesshammer, and H. Brenner Plasma Fibrin D-Dimer Levels and Risk of Stable Coronary Artery Disease: Results of a Large Case-Control Study Arterioscler. Thromb. Vasc. Biol., October 1, 2001; 21(10): 1701 - 1705. [Abstract] [Full Text] [PDF]
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 M. Oya, Y. Akiyama, T. Okuyama, and H. Ishikawa High Preoperative Plasma D-dimer Level is Associated with Advanced Tumor Stage and Short Survival After Curative Resection in Patients with Colorectal Cancer Jpn. J. Clin. Oncol., August 1, 2001; 31(8): 388 - 394. [Abstract] [Full Text] [PDF]
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R. von Kanel, P. J. Mills, C. Fainman, and J. E. Dimsdale Effects of Psychological Stress and Psychiatric Disorders on Blood Coagulation and Fibrinolysis: A Biobehavioral Pathway to Coronary Artery Disease? Psychosom Med, July 1, 2001; 63(4): 531 - 544. [Abstract] [Full Text] [PDF]
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J. Danesh, P. Whincup, M. Walker, L. Lennon, A. Thomson, P. Appleby, A. Rumley, and G. D.O. Lowe Fibrin D-Dimer and Coronary Heart Disease : Prospective Study and Meta-Analysis Circulation, May 15, 2001; 103(19): 2323 - 2327. [Abstract] [Full Text] [PDF]
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G. D. O. Lowe, J. W. G. Yarnell, A. Rumley, D. Bainton, and P. M. Sweetnam C-Reactive Protein, Fibrin D-Dimer, and Incident Ischemic Heart Disease in the Speedwell Study : Are Inflammation and Fibrin Turnover Linked in Pathogenesis? Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 603 - 610. [Abstract] [Full Text] [PDF]
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A. R. Folsom, N. Aleksic, E. Park, V. Salomaa, H. Juneja, and K. K. Wu Prospective Study of Fibrinolytic Factors and Incident Coronary Heart Disease : The Atherosclerosis Risk in Communities (ARIC) Study Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 611 - 617. [Abstract] [Full Text] [PDF]
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 R. Chadarevian, E. Bruckert, L. Leenhardt, P. Giral, A. Ankri, and G. Turpin Components of the Fibrinolytic System Are Differently Altered in Moderate and Severe Hypothyroidism J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 732 - 737. [Abstract] [Full Text]
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H. J. Cohen Editorial: In Search of the Underlying Mechanisms of Frailty J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2000; 55(12): 706M - 708. [Full Text]
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R. P. Tracy, A. M. Arnold, W. Ettinger, L. Fried, E. Meilahn, and P. Savage The Relationship of Fibrinogen and Factors VII and VIII to Incident Cardiovascular Disease and Death in the Elderly : Results From the Cardiovascular Health Study Arterioscler. Thromb. Vasc. Biol., July 1, 1999; 19(7): 1776 - 1783. [Abstract] [Full Text] [PDF]
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P. A. Sakkinen, M. Cushman, B. M. Psaty, B. Rodriguez, R. Boineau, L. H. Kuller, and R. P. Tracy Relationship of Plasmin Generation to Cardiovascular Disease Risk Factors in Elderly Men and Women Arterioscler. Thromb. Vasc. Biol., March 1, 1999; 19(3): 499 - 504. [Abstract] [Full Text] [PDF]
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