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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3321-3325.)
© 1997 American Heart Association, Inc.

Articles

Hemostatic Factors as Predictors of Ischemic Heart Disease and Stroke in the Edinburgh Artery Study

F. B. Smith; A. J. Lee; F. G. R. Fowkes; J. F. Price; A. Rumley; ; G. D. O. Lowe

From the Wolfson Unit for Prevention of Peripheral Vascular Diseases, Department of Public Health Sciences, University of Edinburgh, Medical School, Edinburgh, Scotland (F.B.S., A.J.L., F.G.R.F., J.F.P), and the Haemostasis, Thrombosis and Vascular Medicine Unit, University Department of Medicine, Glasgow Royal Infirmary, Glasgow, Scotland (A.R., G.D.O.L.).

Correspondence to Felicity B. Smith, Wolfson Unit for Prevention of Peripheral Vascular Diseases, Department of Public Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh EH8 9AG, Scotland, UK.

	Abstract

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Abstract Plasma fibrinogen is a consistent predictor of ischemic heart disease (IHD) in prospective studies, but there are fewer data relating other hemostatic variables to IHD and also to stroke. We therefore studied the relationships of plasma fibrinogen, von Willebrand factor antigen, tissue plasminogen activator (TPA) antigen, factor VII, and fibrin D-dimer to incidence of IHD and stroke and determined whether any associations could be explained by conventional risk factors and baseline heart disease. In the Edinburgh Artery study, 1592 men and women aged 55 to 74 years, randomly sampled from the general population, were followed prospectively over 5 years to detect fatal and nonfatal IHD and stroke events. During the 5 years, 268 new vascular events were identified. Baseline plasma fibrinogen was independently related to risk of stroke in multivariate analysis that adjusted for cigarette smoking, LDL-cholesterol, systolic blood pressure, and preexisting IHD (relative risk [RR] 1.52, 95% confidence interval [CI] 1.17,1.98). TPA antigen, and fibrin D-dimer were also independently associated with risk of stroke (RR 1.69, 95% CI 1.22,2.35 and RR 1.96, 95% CI 1.12,3.41, respectively). Significant relationships were found between TPA antigen and myocardial infarction (P.05). In older men and women, increased coagulation activity and disturbed fibrinolysis are predictors of future vascular events (both IHD and stroke).

Key Words: tissue plasminogen activator • fibrin D-dimer • ischemic heart disease • stroke

	Introduction

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In seven longitudinal cohort studies, elevated plasma fibrinogen has been shown to be a strong predictor of IHD and stroke independently of the main cardiovascular risk factors.^1–7 Impaired fibrinolytic function may also be important in increasing the risk of thrombotic vascular events. Elevated TPA antigen levels were associated with an increased risk of coronary events in patients with angina pectoris or previous myocardial infarction.^8–10 Also, TPA antigen was shown to predict future myocardial infarction, although this relationship was not independent of other risk factors.¹¹ There are few data, however, on hemostatic factors such as vWF, factor VII, and fibrin D-dimer^1,6 and the incidence of IHD in the general population. Also, few hemostatic factors, with the exception of fibrinogen^3,5 and TPA antigen,¹² have been examined prospectively in relation to the risk of stroke.

In the cross-sectional phase of the Edinburgh Artery Study, we reported that fibrinogen was associated with IHD.¹³ In this prospective phase, our aim was to determine whether baseline levels of a range of hemostatic factors were related to increased risks of future IHD and stroke events and whether these associations could be explained by interactions with conventional risk factors or baseline evidence of IHD. We have already reported the relationships of baseline rheologic factors to future IHD and stroke.¹⁴

	Methods

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Study Population
The Edinburgh Artery Study is a population-based cohort study comprising a baseline survey and follow-up period of 5 years. A total of 1592 men and women aged 55 to 74 years were initially recruited into the study during 1988. They were selected by age- and sex-stratified random sampling from 11 general practices distributed widely throughout the city to ensure that the catchment population was socioeconomically diverse. The response rate was 65% and follow-up of a 20% sample of nonparticipants showed no significant differences in medical history of heart attack, angina, and peripheral arterial disease compared with participants. Details of the study procedures have been described previously.¹⁵

Sample Size
The sample size in the original baseline survey was estimated on the basis of the number required to conduct a subsequent follow-up study with adequate power to detect differences in the incidence of vascular events. Power calculations were performed at the beginning of the study for plasma fibrinogen, total cholesterol, and diastolic blood pressure. For example, with 1500 subjects, a difference of 0.23 g/L in plasma fibrinogen could be detected with 95% power and the 5% significance level.

Baseline Examination
Subjects attended a university clinic where they completed a questionnaire that included validated questions on medical history, angina, intermittent claudication, smoking history, and current medication. Systolic and diastolic (phase V) blood pressure values were measured in the right arm after 10 minutes of rest using a Hawksley random zero sphygmomanometer. A 12-lead ECG was also recorded using the Minnesota coding system,¹⁶ by two independent observers. A 20-mL fasting blood sample was taken for analysis of hemostatic factors and serum lipids. All samples were taken between 9 AM and 11 AM to minimize the effect of diurnal variation on hemostatic factor levels.

In the laboratory, serum total cholesterol, HDL-cholesterol, and serum triglyceride levels were estimated by a Cobas Bioanalyzer (Roche Products) using standard kits. Fibrinogen was measured in citrated plasma by a thrombin-clotting turbidometric method in a centrifugal analyzer.¹⁷ Fibrin D-dimer was measured using a commercial enzyme-linked immunosorbent assay supplied by AGEN. vWF was also estimated using an enzyme-linked immunosorbent assay (DAKO), as was TPA antigen (Biopool). Factor VII activity was measured using a chromogenic assay (Kabi Diagnostica).

Five Year Follow-up
Subjects were followed-up over 5 years to determine the incidence of fatal and nonfatal cardiovascular events. Notification of deaths was supplied by the United Kingdom National Health Service Central Registry. Information on nonfatal events was obtained from general practitioners, hospital registers, the Information and Statistics Division of the Scottish Home and Health Department, and annual questionnaires to the study participants. Confirmation of all reported cardiovascular events was sought from hospital or general practitioner records. In addition, subjects had a 5-year follow-up clinical examination during 1993 and 1994 during which they completed a self-administered questionnaire that included questions on smoking and new cardiovascular events and the World Health Organization angina and claudication questionnaires.¹⁸

Definition of Cardiovascular Events
Criteria used to define MI and stroke were adapted from the American Heart Association.¹⁹ These are described in detail elsewhere.²⁰ Four categories of disease were defined: angina pectoris, combined fatal and nonfatal MI, combined fatal and nonfatal stroke, and a total vascular event group (angina, MI, and stroke). Transient ischemic attack events were not included in the stroke category. Multiple events of the same type in a subject were recorded only once.

Statistical Analysis
Data were analyzed on the University of Edinburgh mainframe computer using SPSS-X and SAS statistical packages. A ² test and Student's t test were used to assess the significance of differences in the sex distribution and mean levels of conventional risk factors across each of the four event groups (angina pectoris, MI, stroke, and total vascular events) relative to those with no evidence of IHD or stroke at baseline. The Kolmogorov-Smirnov test was used to examine differences in the distribution of each hemostatic factor across the four categories of disease relative to the apparently healthy group. For subsequent analysis, due to positive skewness, square-root transformations were carried out on the values of TPA, vWF, and factor VII. Fibrin D-dimer levels were logarithmically transformed because the distribution was highly skewed. Cigarette smoking was calculated as packyears (number of years of smoking multiplied by the average number of packs smoked per day). The distribution of packyears was skewed with a few heavy smokers and so a square-root transformation was used. LDL-cholesterol was calculated from the formula:

Age- and sex-adjusted relative risks were estimated using multiple logistic regression for a SD increase in each hemostatic factor. Strokes were not differentiated by ischemic or hemorrhagic origin due to the small number (20%) of patients in whom computed tomographic brain scans or necropsy was performed. Relative risks were further adjusted for the conventional cardiovascular risk factors and for preexistent baseline IHD (angina and/or MI). Baseline angina was defined as a positive World Health Oranization questionnaire and either recall of a doctor's diagnosis or ECG ischemia and baseline MI as diagnosis recall and either a positive World Health Organization questionnaire or diagnostic ECG changes.

	Results

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Of the original 1592 subjects, 1156 attended for the follow-up examination, a further 131 subjects completed a questionnaire only, and there were 203 deaths. The remaining 102 subjects comprised those who were too ill to attend or did not want to take part in the follow-up examination or who could not be traced. However, during the 5-year follow-up, information was available for the majority of these 102 from annual questionnaires, general practitioners, hospital notes, or death certificates. A total of 1174 subjects had no evidence of angina, MI, or stroke at baseline or during follow-up. A total of 268 subjects with a fatal or nonfatal vascular event was identified. Of these, 92 subjects developed new angina, 166 had a MI, and 45 had a stroke, with several subjects (35) having more than one type of event. The remaining 150 subjects either died of a nonvascular cause or had incomplete data for the study criteria used to define cardiovascular status.

Table 1 shows differences in age and sex distribution and mean risk factor levels of subjects within the different categories of vascular events. Subjects who had a stroke or MI were significantly older (stroke mean 68.3 years, MI mean 66.5 years) than those who had no cardiovascular event (P.001) and were more likely to be male. Mean systolic blood pressure was higher in all event categories compared with those having no event, even although a considerable proportion of subjects were taking antihypertensive medication: angina (20.7%), MI (21.1%), stroke (37.8%), total events (26.6%), and no events (8.9%). In contrast, only 4 subjects in each of the MI and stroke categories reported taking aspirin or warfarin on a regular basis. Lifetime smoking (packyear) levels were higher in all the disease groups and particularly in the stroke category. The proportion of subjects who had evidence of IHD at baseline varied from 3.3% in the angina group up to 30.1% in the MI group. By definition, the angina group was composed of those with no angina at baseline and first onset during follow-up, thus accounting for the angina group's low prevalence of IHD at baseline.

View this table: [in this window] [in a new window]   Table 1. Age, Sex, and Mean Risk Factor Values at Baseline According to Category of Vascular Events Occurring During Follow-up

Median levels and interquartile ranges of hemostatic factors across the categories of events are shown in Table 2. Baseline levels of all the factors except factor VII were highest in those who subsequently developed stroke. Factor VII levels were most elevated in the new angina group compared with the level in other disease categories. The levels of the hemostatic factors in those who remained healthy were lower compared with those who developed disease.

View this table: [in this window] [in a new window]   Table 2. Medians (Interquartile Ranges) of Hemostatic Factors at Baseline According to Category of Vascular Events Occurring During Follow-up

Table 3 shows the relative risks of each type of cardiovascular event for 1 unit (SD) increase in the level of each hemostatic factor after first adjusting for age and sex and then further adjusting for cardiovascular risk factors and the presence of baseline IHD. There was no significant association between factor VII or between vWF and the risk of any cardiovascular or cerebrovascular event. Fibrinogen no longer remained predictive of MI and angina when all risk factors were taken into account, although the significant relationship of fibrinogen with total events was maintained (P.05). TPA remained significantly related to an increased risk of MI (P.05). In contrast, the weak univariate association with MI became statistically nonsignificant for fibrin D-dimer. This was probably a reflection of stronger interactions between fibrin D-dimer and preexisting disease and the conventional risk factors in subjects with IHD than for subjects with stroke. Further analysis of those 55 subjects who died of MI revealed that the median levels of fibrinogen, vWF, TPA, and D-dimer were all significantly higher compared with the healthy group. The age- and sex-adjusted relative risks were significant for each of the four factors, although on multivariate analysis, none of the relative risks reached statistical significance (data not shown).

View this table: [in this window] [in a new window]   Table 3. Relative Risks (95% Confidence Intervals) of Vascular Events for Unit Increase in Hemostatic Factors and Adjusted for Cardiovascular Risk Factors and Baseline Disease

Fibrinogen, TPA, and fibrin D-dimer levels were each significantly related to the subsequent occurrence of stroke, although on multivariate analysis, the magnitude of the relative risk of fibrinogen with stroke increased slightly. This effect may have been partly due to the inverse correlation between fibrinogen levels and packyears, (r=-.22, P.01 (data not shown). The figure shows that the age- and sex-adjusted relative risks of stroke for each of the three hemostatic factors were stronger than those of cigarette smoking and LDL-cholesterol, whereas the association of systolic blood pressure with stroke was slightly stronger than that of fibrinogen. There was, however, considerable overlap between the 95% confidence intervals of each factor.

	Discussion

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The main finding in this study was that fibrinogen, TPA antigen, and fibrin D-dimer were strong predictors of stroke, independently of baseline IHD and conventional cardiovascular risk factors. These factors were also predictive of IHD (especially MI), although the relationships were weaker, and only TPA remained significantly related to MI on multivariate analyses.

These findings are consistent with other prospective studies relating fibrinogen to the incidence of stroke.^3,5 However, the true strength of the association between fibrinogen and ischemic stroke may be greater than observed in this study because we were unable to reliably exclude patients with stroke of hemorrhagic origin from the stroke category. Fibrinogen has also been found to be an independent risk factor for transient ischemic attacks and minor ischemic strokes²¹ and in ischemic stroke survivors, fibrinogen predicted a second cardiovascular event within 2 years.²² The observation that fibrinogen levels were elevated in a small sample of patients who suffered a transient ischemic attack and did not subsequently rise suggests that fibrinogen may have a causal role in promoting cerebrovascular events.²³ However, these findings have yet to be confirmed in other studies.

We also found that TPA antigen was strongly predictive of stroke as well as MI, independently of baseline IHD and established cardiovascular risk factors. To date, only one other prospective study has examined possible associations between TPA and risk of stroke,¹² although the population was limited to a selected group of male physicians. In that study, exclusion of hemorrhagic events from multivariate analysis had no substantial effect on the magnitude of relative risk. Increases in TPA antigen levels in both the acute and chronic phases of ischemic stroke have been reported²⁴ and TPA antigen has also been found to be a strong discriminator of subjects with and without a history of cerebrovascular events.²⁵ These findings suggest that abnormal fibrinolytic activity may identify those at risk of cerebrovascular events.

A strong long-term association between high levels of TPA and the incidence of IHD has been reported in several studies.^10,26 However, Ridker et al¹¹ suggested that high TPA may represent a secondary response to the progression of atherosclerosis, because adjusting for atherosclerotic risk factors reduced the association between TPA and MI (but not stroke) to nonsignificance. The stronger relationship observed between TPA and stroke than for MI may reflect differences in risk factor associations between the two disease groups.

TPA antigen levels reflect inactive TPA/PAI complexes rather than free active TPA^27,28 and thus raised levels may indicate elevated PAI activity and impaired fibrinolytic activity. TPA has recently been discovered to be mitogenic for smooth muscle cells, which suggests that overexpression may contribute to atherogenesis.²⁹ Furthermore, plasmin, which is formed by the action of TPA on plasminogen, may also contribute to thrombogenesis through its ability to activate proteases, such as metalloproteases, which may weaken plaques and predispose them to rupture.³⁰

We report for the first time that fibrin D-dimer was independently related to the risk of stroke. Data are sparse concerning the relationship between D-dimer and cerebrovascular disease. In one cross-sectional study, D-dimer was linked to the extent of atherosclerosis within the cerebral arteries.³¹ Takano et al³² showed that fibrin D-dimer levels were strongly associated with re-embolization after acute ischemic stroke. This implies that high fibrin turnover may contribute to a prothrombotic state, which may be critical for progression of disease within the cerebral arteries.

In the present study, D-dimer was a predictor of myocardial infarction on univariate, but not multivariate, analyses. This finding agrees with a case-control study,³³ but not with two prospective studies, which observed D-dimer to be an independent predictor of IHD events.^34,35 Fibrin D-dimer is an index of ongoing degradation of cross-linked fibrin, which may occur in response to thrombus formation. It may also be directly involved in atherogenesis.³³ D-dimer is present in arterial lesions, stimulates smooth muscle cell proliferation, and is chemotactic for monocytes.³⁶ It may also increase the synthesis of fibrinogen by stimulating the release of interleukin-6 from monocytes, which in turn stimulates fibrinogen synthesis in the liver.³⁷

We could not confirm reports that factor VII is a predictor of IHD,^1,6 nor did it appear to be a predictor of stroke. We also found that there was no independent relationship between vWF and risk of MI or stroke, in contrast with two studies which observed that vWF was independently related to incidence of IHD.^35,38

In conclusion, our results indicate that hemostatic factors may have important etiologic roles in the development of cardiovascular and cerebrovascular events. In particular, measurement of both fibrinogen, TPA, and D-dimer levels may help to identify those at high risk of future stroke. Because our findings are based on a relatively low number of vascular events, further larger studies are needed to confirm these associations. If this occurs, controlled trials of reduction of fibrinogen and of oral anticoagulation, which lowers raised D-dimer levels,³⁹ may be warranted in stroke and IHD prophylaxis.

	Selected Abbreviations and Acronyms

 

IHD = ischemic heart disease MI = myocardial infarction TPA = tissue plasminogen activator vWF = von Willebrand factor

View larger version (10K): [in this window] [in a new window]   Figure 1. Relative risks (95% confidence intervals) or 1 U on a logarithmic scale adjusted for age and sex of stroke patients for 1 SD increase in conventional risk factors and hemostatic factors. BP, blood pressure. See Table 3 for units of 1 SD.

	Acknowledgments

 
We thank the British Heart Foundation for financial support.

Received February 21, 1997; accepted July 5, 1997.

	References

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				T. N. Bongers, M. P.M. de Maat, M.-L. P.J. van Goor, V. Bhagwanbali, H. H.D.M. van Vliet, E. B. Gomez Garcia, D. W.J. Dippel, and F. W.G. Leebeek High von Willebrand Factor Levels Increase the Risk of First Ischemic Stroke: Influence of ADAMTS13, Inflammation, and Genetic Variability Stroke, November 1, 2006; 37(11): 2672 - 2677. [Abstract] [Full Text] [PDF]

				H. S. Al-Barjas, R. Ariens, P. Grant, and J. A. Scott Raised Plasma Fibrinogen Concentration in Patients With Abdominal Aortic Aneurysm Angiology, October 1, 2006; 57(5): 607 - 614. [Abstract] [PDF]

				I. Tzoulaki, G. D. Murray, J. F. Price, F. B. Smith, A. J. Lee, A. Rumley, G. D. O. Lowe, and F. G. R. Fowkes Hemostatic Factors, Inflammatory Markers, and Progressive Peripheral Atherosclerosis: The Edinburgh Artery Study Am. J. Epidemiol., February 15, 2006; 163(4): 334 - 341. [Abstract] [Full Text] [PDF]

				A. Smith, C. Patterson, J. Yarnell, A. Rumley, Y. Ben-Shlomo, and G. Lowe Which Hemostatic Markers Add to the Predictive Value of Conventional Risk Factors for Coronary Heart Disease and Ischemic Stroke?: The Caerphilly Study Circulation, November 15, 2005; 112(20): 3080 - 3087. [Abstract] [Full Text] [PDF]

				Fibrinogen Studies Collaboration* Plasma Fibrinogen Level and the Risk of Major Cardiovascular Diseases and Nonvascular Mortality: An Individual Participant Meta-analysis JAMA, October 12, 2005; 294(14): 1799 - 1809. [Abstract] [Full Text] [PDF]

				D. Feinbloom and K. A. Bauer Assessment of Hemostatic Risk Factors in Predicting Arterial Thrombotic Events Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2043 - 2053. [Abstract] [Full Text] [PDF]

				M. Woodward, G. D.O. Lowe, D. J. Campbell, S. Colman, A. Rumley, J. Chalmers, B. C. Neal, A. Patel, A. J. Jenkins, B. E. Kemp, et al. Associations of Inflammatory and Hemostatic Variables With the Risk of Recurrent Stroke Stroke, October 1, 2005; 36(10): 2143 - 2147. [Abstract] [Full Text] [PDF]

				P. M. Rothwell, S. C. Howard, D. A. Power, S. A. Gutnikov, A. Algra, J. van Gijn, T. G. Clark, M. F.G. Murphy, C. P. Warlow, and for the Cerebrovascular Cohort Studies Collaborati Fibrinogen Concentration and Risk of Ischemic Stroke and Acute Coronary Events in 5113 Patients With Transient Ischemic Attack and Minor Ischemic Stroke Stroke, October 1, 2004; 35(10): 2300 - 2305. [Abstract] [Full Text] [PDF]

				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]

				J. A. Ambrose and R. S. Barua The pathophysiology of cigarette smoking and cardiovascular disease: An update J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1731 - 1737. [Abstract] [Full Text] [PDF]

				L. Johansson, J.-H. Jansson, B. Stegmayr, T. K. Nilsson, G. Hallmans, and K. Boman Hemostatic Factors as Risk Markers for Intracerebral Hemorrhage: A Prospective Incident Case-Referent Study Stroke, April 1, 2004; 35(4): 826 - 830. [Abstract] [Full Text] [PDF]

				P.E. Morange, C. Simon, M.C. Alessi, G. Luc, D. Arveiler, J. Ferrieres, P. Amouyel, A. Evans, P. Ducimetiere, I. Juhan-Vague, et al. Endothelial Cell Markers and the Risk of Coronary Heart Disease: The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study Circulation, March 23, 2004; 109(11): 1343 - 1348. [Abstract] [Full Text] [PDF]

				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]

				B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]

				M. Roest and J. D. Banga Editorial Comment-- Genetic Make-Up for Increased PAI-1 Expression Protects Against Stroke Stroke, December 1, 2003; 34(12): 2828 - 2829. [Full Text] [PDF]

				K. W. Lee and G. Y. H. Lip Effects of Lifestyle on Hemostasis, Fibrinolysis, and Platelet Reactivity: A Systematic Review Arch Intern Med, October 27, 2003; 163(19): 2368 - 2392. [Abstract] [Full Text] [PDF]

				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]

				S.C. Kofoed, H.H. Wittrup, H. Sillesen, and B.G. Nordestgaard Fibrinogen predicts ischaemic stroke and advanced atherosclerosis but not echolucent, rupture-prone carotid plaques: The Copenhagen City Heart Study Eur. Heart J., March 2, 2003; 24(6): 567 - 576. [Abstract] [Full Text] [PDF]

				M. Naruszewicz, M.-L. Johansson, D. Zapolska-Downar, and H. Bukowska Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1249 - 1255. [Abstract] [Full Text] [PDF]