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(Circulation. 2004;109:1343-1348.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Endothelial Cell Markers and the Risk of Coronary Heart Disease

The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study

P.E. Morange, MD, PhD; C. Simon, MD, PhD; M.C. Alessi, MD, PhD; G. Luc, MD; D. Arveiler, MD; J. Ferrieres, MD, MSc; P. Amouyel, MD, PhD; A. Evans, MD, FRCP; P. Ducimetiere, PhD; I. Juhan-Vague, MD, PhD, on behalf of the PRIME Study Group

From the Department of Hematology, Faculty of Medicine, INSERM U626, Marseilles (P.E.M., M.C.A., I.J.-V.); Nutrition Study Group, Faculty of Medicine (C.S.), and the Strasbourg MONICA Project, Department of Epidemiology and Public Health, Faculty of Medicine (D.A.), Strasbourg; Department of Atherosclerosis, INSERM UR545 (G.L.), and the Lille MONICA Project, INSERM U508 (P.A.), Institut Pasteur de Lille, Lille; the Toulouse MONICA Project, INSERM U558, Department of Epidemiology, Paul Sabatier-Toulouse Purpan University, Toulouse (J.F.); and INSERM U258, Hôpital Paul Brousse, Villejuif (P.D.), France; and the Department of Epidemiology and Public Health, Queen’s University of Belfast, Belfast, Northern Ireland (A.E.).

Correspondence to I. Juhan-Vague, Laboratory of Haematology, CHU Timone, 13385 Marseilles cedex 5, France. E-mail irene.juhan{at}ap-hm.fr

Received July 15, 2003; de novo received September 23, 2003; revision received December 17, 2003; accepted December 30, 2003.

	Abstract

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Background— Tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), and thrombomodulin (TM) are 3 major hemostatic regulatory molecules synthesized by endothelium. Data from epidemiological studies aiming to evaluate the relation between plasma levels of these molecules and the development of coronary heart disease (CHD) are sparse or contradictory.

Methods and Results— We examined the association between these endothelial-cell markers and the incidence of fatal or nonfatal myocardial infarction (hard CHD) and stable or unstable angina (angina pectoris) in a prospective cohort (the PRIME Study) of nearly 10 000 healthy men recruited in France and Northern Ireland. We measured baseline plasma concentration of the free form of TFPI (f-TFPI), vWF, and the soluble form of TM (sTM) among 296 participants who subsequently developed CHD over the 5-year follow-up (158 with hard CHD and 142 with angina pectoris) and in 563 control subjects by use of a nested case-control design. Individuals with plasma vWF levels in the highest quartile showed a 3.04-fold increase in the risk of hard CHD compared with those in the lowest quartile (95% CI, 1.59 to 5.80). Individuals with f-TFPI levels below the 10th percentile had a 2.13-fold increased risk of hard CHD compared with those with levels above it (95% CI, 1.08 to 4.18). The risk for both molecules persisted after control for inflammatory parameters. Individuals with vWF levels in the highest quartile and f-TFPI levels below the 10th percentile presented a 6.9-fold increased risk of hard CHD compared with those with vWF levels in the lowest quartile and f-TFPI levels above the 10th percentile (95% CI, 1.3 to 37.8).

Conclusions— vWF and f-TFPI plasma levels were independent risk factors for hard CHD events.

Key Words: endothelium-derived factors • epidemiology • coronary disease • von Willebrand factor

	Introduction

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The endothelium is pivotal in the control of hemostasis and thrombosis because it is the primary source of many of the major hemostatic regulatory molecules, such as von Willebrand factor (vWF), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM).¹ vWF mediates platelet adhesion and plays a role in thrombus formation.¹ TFPI is the main physiological inhibitor of tissue factor (TF)–induced coagulation.² Intravascular TFPI exists in several pools.³ The free form of TFPI in plasma (f-TFPI) generally reflects the level of endothelial cell–associated TFPI and displays a potent anticoagulant activity, whereas lipid-bound TFPI seems to have only a small or no anticoagulant function.^4–6 TM is an endothelial cell–surface receptor for thrombin that functions as an anticoagulant by greatly accelerating thrombin-induced activation of protein C.⁷ A soluble truncated form of TM (sTM) circulates in plasma; until now, its physiological role has been unknown.⁸

The plasma levels of these molecules have been shown to increase with endothelial damage, suggesting that they could be reliable markers of endothelial dysfunction.^8–10 Furthermore, an alteration in the production of these molecules by the endothelium could directly contribute to atherothrombotic disease. However, epidemiological data aiming to evaluate the association between plasma levels and the risk of coronary heart disease (CHD) are sparse or contradictory. Several prospective studies of vWF conducted in healthy individuals are available but have produced mixed results.^11–15 Only a few data are available for TFPI in humans: f-TFPI levels are elevated in patients with unstable angina and increase the risk of a poor outcome.¹⁶ Very recently, a case-control study indicated that low levels of f-TFPI were a risk factor for deep vein thrombosis.¹⁷ Interestingly, mean TFPI levels were not lower in patients with deep vein thrombosis, but f-TFPI levels below the 10th percentile proved to be a risk factor. This finding supported the hypothesis of a threshold effect in which low levels of TFPI increased the risk of thrombosis. To the best of our knowledge, no prospective study data on healthy adults are available concerning associations between plasma f-TFPI and incidence of CHD. For sTM, a large prospective case-cohort study, showed that decreased plasma levels of TM were associated with an increased risk of myocardial infarction (MI).¹⁸

Given the lack of homogeneity of the results of these epidemiological studies, we aimed to simultaneously analyze these 3 markers in the same cohort to determine the most predictive ones and their relation with inflammatory markers on risk. We used a nested case-control study design within the Prospective Epidemiological Study of Myocardial Infarction (PRIME) prospective cohort. The PRIME Study is a large multicenter cohort study of men age 50 to 59 years at baseline with a 5-year follow-up, which aimed to investigate the association of different markers and the development of CHD in France and Northern Ireland. Its design afforded us the opportunity to study the predictive ability of parameters for both hard CHD (MI and coronary death) and angina pectoris.

	Methods

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The PRIME Study has been described in detail.¹⁹ It was set up to investigate risk factors in ischemic heart disease and to identify those explaining the difference in CHD incidence between France and Northern Ireland. From 1991 to 1994, 9758 men age 50 to 59 years with no previous CHD events, living in the area of Lille, Strasbourg, Toulouse, and Belfast, were recruited and followed up over a period of 5 years. At entry, venous blood (9 volumes) was collected between 9 and 10 AM after a 12-hour fast into siliconized vacuum tubes (Vacutainer, Becton Dickinson) containing 0.11 mol/L trisodium citrate (1 volume). Platelet-poor plasma was obtained by centrifugation at 4500g and 20°C for 15 minutes. Without delay, aliquots of plasma were transferred into plastic tubes and frozen on-site to -80°C and were then sent weekly to the central laboratory at the Pasteur Institute of Lille, where they were stored in liquid nitrogen until analysis.

For subjects reporting a possible clinical event, clinical information was sought directly from the hospital or general practitioners’ files. All details of ECG, hospital admissions, enzymes, surgical operations, angioplasty, treatment, etc, were collected and classified according to MONICA criteria.²⁰ Death certificates were also used to complete information on the cause of death. A medical committee provided independent validation and classification of coronary events. CHD categories retained for analysis were nonfatal MI or coronary death (grouped as hard coronary event), unstable angina pectoris, and effort angina (grouped as angina pectoris).²¹

A total of 335 subjects had a confirmed coronary event during follow-up. Each was matched with 2 control subjects (controls). Matched controls were study participants recruited in the same center at approximately the same day (±3 days) and with the same age as the corresponding case subject (case) and free of CHD on the date of the ischemic event of the case.

Stored plasma obtained at baseline from 296 cases (158 with hard CHD and 142 with angina pectoris, 4 presenting both types of event during follow-up) and 563 control subjects were sent from the central plasma bank on dry ice to the Laboratory of Hemostasis of La Timone Hospital in Marseilles, France. vWF, f-TFPI, and sTM antigens were determined with commercially available ELISAs from Diagnostica Stago. Blood specimens were analyzed in blinded pairs, with the position of the case specimen varied at random within pairs to reduce the possibility of systematic bias and minimize interassay variability. Interassay variation coefficients were 8%, 10%, and 10% for vWF, f-TFPI, and sTM, respectively. The methods used to evaluate baseline lipid parameters, fibrinogen, C-reactive protein (CRP), and interleukin (IL)-6 have been described elsewhere.^21,22 Tumor necrosis factor (TNF)- was measured by ELISA (R&D Systems) according to the instructions available from the supplier.

Statistical Analysis
Continuous variables are presented as mean±SD and qualitative variables as percentages. Because of skewed distributions, vWF, f-TFPI, and sTM were categorized before further analyses. Quartiles were used for vWF, f-TFPI, and sTM, whereas f-TFPI was also categorized according to the 10th percentile of the distribution in controls, as previously suggested.¹⁷ A conditional regression analysis suitable for a nested case-control design was performed to identify discriminating predictive parameters. The same analysis was used to determine the relative risk of future CHD events after control for different sets of variables: (1) body mass index (BMI), total cholesterol, HDL cholesterol, systolic blood pressure, smoking, alcohol, and diabetes; (2) further adjustment for CRP, TNF-, IL-6, and fibrinogen. The final model included all the above variables and vWF, f-TFPI, and TM. Estimated relative risks are presented with 95% CIs.

Associations of endothelial-cell markers with anthropometric characteristics, metabolic parameters, and inflammatory markers were tested by means of Pearson’s correlation coefficient in the control group. The statistical analyses were performed with SAS software (Version 8, SAS Institute). All tests were considered as significant at the 0.05 level.

	Results

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Table 1 shows the baseline clinical characteristics of the study participants. As expected, initially healthy men who subsequently developed CHD (cases) were more likely at baseline to have a history of hypertension, smoking, hyperlipidemia, or diabetes compared with men who remained free of reported disease (controls). The effect of these conventional cardiovascular risk factors was similar in France and Northern Ireland. Levels of inflammatory markers such as fibrinogen, CRP, and IL-6 were higher in cases than in controls.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Patient Characteristics (Mean±SD or Percentage) of Study Participants: The PRIME Study

Associations between the different parameters studied were tested in the control subjects. Among these, f-TFPI values were associated positively with BMI (r=0.14; P<10^-3), waist/hip ratio (r=0.11; P<0.01), triglycerides (r=0.15; P<10^-3), and total cholesterol (r=0.11; P<0.01) and negatively with HDL cholesterol (r=-0.10; P<0.01) but not with CRP, IL-6, or fibrinogen. sTM was associated negatively only with HDL cholesterol (r=-0.16; P<10^-4) and vWF with CRP(r=0.14; P<10^-3). Endothelial-cell markers correlated strongly with one another. f-TFPI correlated strongly with TM (r=0.53; P<10^-4) and to a lesser extent with vWF (r=0.12; P<0.01). vWF correlated with TM (r=0.12; P<0.01).

The mean levels of endothelial-cell markers across the categories of events are shown in Table 2. Baseline levels of vWF were higher in individuals who subsequently developed hard CHD but not angina pectoris. Mean f-TFPI and sTM did not differ significantly between cases and controls irrespective of the type of event. Because it was recently shown that f-TFPI levels below the 10th percentile were a risk factor for venous thrombosis,¹⁷ supporting a threshold effect, we performed a similar analysis in the present study. Of the individuals with hard CHD, 13.3% presented values below the cutoff, compared with 8.3% of the controls (P=0.07).

View this table: [in this window] [in a new window]   TABLE 2. Baseline Plasma Concentrations of Endothelial Cell Markers According to Case and Control Status: The PRIME Study

The relative risks of CHD during follow-up according to plasma levels of endothelial-cell markers were assessed (Table 3). After adjustment for conventional cardiovascular risk factors, hard CHD incidence was higher in individuals with plasma concentrations of vWF in the highest quartile than in those in the lowest quartile (RR=3.04; 95% CI, 1.59 to 5.80; Table 3, model A). The association remained after further adjustment for inflammatory parameters (Table 3, model B). Individuals with plasma concentrations of f-TFPI below the 10th percentile presented an increased risk of hard CHD compared with those above the 10th percentile (RR=2.13; 95% CI, 1.08 to 4.18; Table 3, model A). As with vWF, the association remained significant after further adjustment for inflammation parameters (Table 3, model B). A decreasing trend, albeit not significant, of the risk of hard CHD in the 2 highest quartiles of f-TFPI was observed. No association was observed between incident hard CHD and sTM, whichever model was used. After inclusion of the 3 endothelial-cell markers in the same model (Table 4), both plasma levels of vWF in the highest quartile and f-TFPI above the 10th percentile remained independently associated with the risk of hard CHD.

View this table: [in this window] [in a new window]   TABLE 3. Adjusted Relative Risks of Hard CHD During Follow-Up According to Successive Plasma Levels of Each Endothelial Cell Marker: The PRIME Study

View this table: [in this window] [in a new window]   TABLE 4. Relative Risks of Hard CHD During Follow-Up According to Plasma Levels of Endothelial Cell Markers: The PRIME Study

Given the prothrombotic and antithrombotic properties of endothelial cells, a combined analysis of vWF and f-TFPI on risk was performed (Figure). Individuals with vWF levels in the highest quartile and f-TFPI levels below the 10th percentile exhibited a 6.9-fold increased risk of hard CHD compared with those with vWF levels in the lowest tertile and f-TFPI levels above the 10th percentile (95% CI, 1.3 to 37.8).

View larger version (19K): [in this window] [in a new window]   Adjusted relative risks of hard CHD among apparently healthy men according to baseline levels of vWF and f-TFPI. Values above bars are RRs and 95% CIs. Variables included in models were BMI, total cholesterol, HDL cholesterol, systolic blood pressure, smoking, alcohol, diabetes, fibrinogen, CRP, TNF-, IL-6, vWF, f-TFPI, and TM.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix: The PRIME Study... References

 
The main findings of this study are that f-TFPI and vWF plasma levels are independent predictors of hard CHD but not angina pectoris. Individuals with both f-TFPI below the 10th percentile and vWF in the highest quartile presented a 6.9-fold increase in the risk of hard CHD. sTM plasma levels were not associated with CHD whatever the cardiovascular end point studied.

Thompson et al²³ reported that plasma vWF antigen was an independent predictor of subsequent MI or sudden death from CHD in the ECAT study. In individuals healthy at baseline, a recent meta-analysis yielded a combined odds ratio of 1.5 (95% CI, 1.1 to 2.0).²⁴ However, among the studies included in this analysis, the predictive ability of vWF depends strongly on the variables controlled for.^11–15,24 The precise mechanism by which vWF is associated with cardiovascular risk is unclear. vWF, an acute-phase reactant, could be only a marker of the inflammatory process, which is known to play a major role in CHD. Accordingly, the ECAT study showed in subjects with angina pectoris that the independent relative risk of cardiovascular mortality associated with vWF disappeared after adjustment for variables related to inflammation, ie, CRP and/or fibrinogen.²³ In contrast, the Hoorn study found that the dual adjustment of vWF and CRP did not alter the risk estimate of coronary death.²⁵ In the PRIME Study, incident hard CHD was significantly associated with CRP, IL-6, and fibrinogen, but only IL-6 remained significantly associated with hard CHD when the 3 inflammatory markers were included in the same model.²² In our analysis, we have included these 3 inflammatory markers and TNF- to confirm that the contribution of vWF to CHD risk is independent of any inflammatory effect. After adjustment for these inflammatory variables, high vWF plasma levels remained a risk factor for hard CHD, suggesting different pathways through which vWF and inflammation determine hard CHD risk.

Several reports have demonstrated the colocalization of TFPI and TF in atherosclerotic plaques, suggesting a significant role for TFPI in the regulation of TF activity.^26,27 Several studies in mice have shown that TFPI, through the inhibition of tissue factor activity, may influence plaque thrombogenicity.^28–31 In humans, epidemiological data concerning the association between CHD and TFPI are sparse and based on retrospective studies. Plasma f-TFPI is elevated in patients with unstable angina and increases the risk of an unfavorable outcome.¹⁶ To the best of our knowledge, this is the first prospective study on the association of CHD and f-TFPI. Individuals with f-TFPI levels below the 10th percentile have a 2.13-fold increased risk of hard CHD. Mean f-TFPI level, however, was not lower in patients with hard CHD, supporting the hypothesis of a threshold effect in which moderately reduced f-TFPI level may slightly increase the risk of hard CHD, as previously suggested for venous thrombosis.¹⁷ In the ARIC study, high sTM levels were found to be protective against CHD.¹⁸ The present study did not find the same association between sTM levels and any type of CHD events. The explanation for these different results is not clear but may be because of ethnic or age differences between the 2 populations. The proportion of black people tended to decline with increasing quintile of sTM, and sTM was positively related to age in the ARIC Study. Moreover, for CHD incidence, a significant interaction was found between plasma sTM concentration and age in this latter [The age range at inclusion was larger in the ARIC study (45 to 65 years) than in the PRIME Study (50 to 59 years)].

Endothelium synthesizes both procoagulant (vWF) and anticoagulant (f-TFPI and sTM) factors, suggesting the need for a combined analysis of prothrombotic and antithrombotic factors to provide a more precise estimation of the risk. This is underlined by the strong correlations observed between the different endothelial-cell markers in the present study. After inclusion of f-TFPI, vWF, and sTM in the same model, f-TFPI below the 10th percentile and vWF in the highest quartile remained independently associated with hard CHD. When these risk factors where considered together, individuals with both f-TFPI below the 10th percentile and vWF in the highest quartile presented a 6.9-fold increased risk of hard CHD. It should be noted that the small number of cases with hard disease constituted a limitation to the analyses of the interaction between these 2 endothelial markers and hard CHD. One of the aims of the PRIME Study is to explain the differences in risk of CHD between France and Northern Ireland. When analyses were performed separately for France and Northern Ireland, the relationships of endothelial-cell markers with hard CHD were similar, although statistical significance was lost because of the smaller number of subjects in each group.

In addition to the clinical manifestations of thrombosis, the contribution of platelets and the coagulation system to the progression of atheroma itself is recognized. However, in the present study, no association was observed between f-TFPI or vWF plasma levels and the risk of angina pectoris. This lack of association could be explained by the fact that the PRIME Study, after 5 years of follow-up, does not yet have sufficient power to detect a modest effect.

We conclude that plasma f-TFPI below the 10th percentile and vWF in the highest quartile are independently associated with the risk of hard CHD. Combined analysis of the 2 factors could provide a more precise estimation of the risk.

	Appendix: The PRIME Study Group

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The PRIME study is organized under an agreement between INSERM and the Merck, Sharpe and Dohme-Chibret Laboratory, with the following participating laboratories:

The Strasbourg MONICA Project, Department of Epidemiology and Public Health, Faculty of Medicine, Strasbourg, France (D. Arveiler, B. Haas).

The Toulouse MONICA Project, INSERM U558, Department of Epidemiology, Paul Sabatier-Toulouse Purpan University, Toulouse, France (J. Ferrières, J.B. Ruidavets).

The Lille MONICA Project, INSERM U508, Institut Pasteur de Lille, France (P. Amouyel, M. Montaye).

The Department of Epidemiology and Public Health, Queen’s University Belfast, Northern Ireland (A. Evans, J. Yarnell).

The Department of Atherosclerosis, INSERM UR545, Lille, France (G. Luc, J.M. Bard, L. Elkhalil, J.C. Fruchart).

The Department of Hematology, Hôpital de la Timone, Marseilles, France (I. Juhan-Vague).

The Laboratory of Endocrinology, INSERM U326, Toulouse, France (B. Perret).

The Vitamin Research Unit, The University of Bern, Bern, Switzerland (F. Gey).

The Trace Element Laboratory, Department of Medicine, Queen’s University Belfast, Northern Ireland (D. McMaster, Jayne Woodside, Ian Young).

The DNA Bank, INSERM U525, Paris, France (F. Cambien).

The Coordinating Center, INSERM U258, Paris-Villejuif, France (P. Ducimetière, A. Bingham).

	Acknowledgments

 
This work was supported by a grant from the Fondation de France. We are indebted to J. Ansaldi, A. Bescond, and M. Billerey for their technical assistance with this project. We thank the Centre d’Investigation Clinique of Marseille for statistical advices. We thank the following organizations, which allowed the recruitment of the PRIME subjects: the health screening centers organized by the Social Security of Lille (Institut Pasteur), Strasbourg, Toulouse, and Tourcoing; Occupational Medicine Services of Haute-Garonne, of the Urban Community of Strasbourg; the association Inter-entreprises des Services Médicaux du Travail de Lille et environs; the Comité pour le Développement de la Médecine du Travail; the Mutuelle Générale des PTTT du Bas-Rhin; the Laboratoire d’Analyses de l’Institut de Chimie Biologique de la Faculté de Médecine de Strasbourg; and the Department of Health (NI) and the Northern Ireland Chest Heart and Stroke Association.

	References

Top Abstract Introduction Methods Results Discussion Appendix: The PRIME Study... References

 

1. Cines DB, Pollak ES, Buck CA, et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998; 91: 3527–3561.[Free Full Text]
   
2. Broze GJ Jr, Girard TJ, Novotny WF. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry. 1990; 29: 7539–7546.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Sandset PM. Tissue factor pathway inhibitor (TFPI): an update. Haemostasis. 1996; 26 (suppl 4): 154–165.[Medline] [Order article via Infotrieve]
   
4. Kokawa T, Enjyoji K, Kumeda K, et al. Measurement of the free form of TFPI antigen in hyperlipidemia: relationship between free and endothelial cell-associated forms of TFPI. Arterioscler Thromb Vasc Biol. 1996; 16: 802–808.[Abstract/Free Full Text]
   
5. Kawaguchi A, Miyao Y, Noguchi T, et al. Intravascular free tissue factor pathway inhibitor is inversely correlated with HDL cholesterol and postheparin lipoprotein lipase but proportional to apolipoprotein A-II. Arterioscler Thromb Vasc Biol. 2000; 20: 251–258.[Abstract/Free Full Text]
   
6. Bridey F, Lacombe C, Sustendal L, et al. Development of a method to separate lipoprotein-bound and lipoprotein-depleted tissue factor pathway inhibitor: measurement of free tissue factor pathway inhibitor activity. Blood Coagul Fibrinolysis. 1998; 9: 637–643.[Medline] [Order article via Infotrieve]
   
7. Sadler JE. Thrombomodulin structure and function. Thromb Haemost. 1997; 78: 392–395.[Medline] [Order article via Infotrieve]
   
8. Ishii H, Uchiyama H, Kazama M. Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost. 1991; 65: 618–623.[Medline] [Order article via Infotrieve]
   
9. Blann AD, McCollum CN, Lip GY. Relationship between plasma markers of endothelial cell integrity and the Framingham cardiovascular disease risk-factor scores in apparently healthy individuals. Blood Coagul Fibrinolysis. 2002; 13: 513–518.[CrossRef][Medline] [Order article via Infotrieve]
   
10. Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor: basic and clinical aspects. Arterioscler Thromb Vasc Biol. 2002; 22: 539–548.[Abstract/Free Full Text]
    
11. Meade TW, Cooper JA, Stirling Y, et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol. 1994; 88: 601–607.[Medline] [Order article via Infotrieve]
    
12. Smith FB, Lee AJ, Fowkes FG, et al. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study. Arterioscler Thromb Vasc Biol. 1997; 17: 3321–3325.[Abstract/Free Full Text]
    
13. Folsom AR, Wu KK, Rosamond WD, et al. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 1997; 96: 1102–1108.[Abstract/Free Full Text]
    
14. Rumley A, Lowe GD, Sweetnam PM, et al. Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study. Br J Haematol. 1999; 105: 110–116.[CrossRef][Medline] [Order article via Infotrieve]
    
15. Thogersen AM, Jansson JH, Boman K, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation. 1998; 98: 2241–2247.[Abstract/Free Full Text]
    
16. Soejima H, Ogawa H, Yasue H, et al. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation. 1999; 99: 2908–2913.[Abstract/Free Full Text]
    
17. Dahm A, Van Hylckama Vlieg A, et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood. 2003; 30: 30.
    
18. Salomaa V, Matei C, Aleksic N, et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study. Lancet. 1999; 353: 1729–1734.[CrossRef][Medline] [Order article via Infotrieve]
    
19. Yarnell JW. The PRIME study: classical risk factors do not explain the severalfold differences in risk of coronary heart disease between France and Northern Ireland. Prospective Epidemiological Study of Myocardial Infarction. Q J Med. 1998; 91: 667–676.
    
20. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project: registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation. 1994; 90: 583–612.[Abstract/Free Full Text]
    
21. Ducimetiere P, Ruidavets JB, Montaye M, et al. Five-year incidence of angina pectoris and other forms of coronary heart disease in healthy men aged 50–59 in France and Northern Ireland: the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Int J Epidemiol. 2001; 30: 1057–1062.[Abstract/Free Full Text]
    
22. Luc G, Bard JM, Juhan-Vague I, et al. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: The PRIME Study. Arterioscler Thromb Vasc Biol. 2003; 23: 1255–1261.[Abstract/Free Full Text]
    
23. Thompson SG, Kienast J, Pyke SD, et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med. 1995; 332: 635–641.[Abstract/Free Full Text]
    
24. Whincup PH, Danesh J, Walker M, et al. von Willebrand factor and coronary heart disease: prospective study and meta-analysis. Eur Heart J. 2002; 23: 1764–1770.[Abstract/Free Full Text]
    
25. Jager A, van Hinsbergh VW, Kostense PJ, et al. von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler Thromb Vasc Biol. 1999; 19: 3071–3078.[Abstract/Free Full Text]
    
26. Caplice NM, Mueske CS, Kleppe LS, et al. Presence of tissue factor pathway inhibitor in human atherosclerotic plaques is associated with reduced tissue factor activity. Circulation. 1998; 98: 1051–1057.[Abstract/Free Full Text]
    
27. Crawley J, Lupu F, Westmuckett AD, et al. Expression, localization, and activity of tissue factor pathway inhibitor in normal and atherosclerotic human vessels. Arterioscler Thromb Vasc Biol. 2000; 20: 1362–1373.[Abstract/Free Full Text]
    
28. Zoldhelyi P, McNatt J, Shelat HS, et al. Thromboresistance of balloon-injured porcine carotid arteries after local gene transfer of human tissue factor pathway inhibitor. Circulation. 2000; 101: 289–295.[Abstract/Free Full Text]
    
29. Nishida T, Ueno H, Atsuchi N, et al. Adenovirus-mediated local expression of human tissue factor pathway inhibitor eliminates shear stress–induced recurrent thrombosis in the injured carotid artery of the rabbit. Circ Res. 1999; 84: 1446–1452.[Abstract/Free Full Text]
    
30. Ragni M, Golino P, Cirillo P, et al. Endogenous tissue factor pathway inhibitor modulates thrombus formation in an in vivo model of rabbit carotid artery stenosis and endothelial injury. Circulation. 2000; 102: 113–117.[Abstract/Free Full Text]
    
31. Westrick RJ, Bodary PF, Xu Z, et al. Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation. 2001; 103: 3044–3046.[Abstract/Free Full Text]
    

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				A. O. Spiel, J. C. Gilbert, and B. Jilma Von Willebrand Factor in Cardiovascular Disease: Focus on Acute Coronary Syndromes Circulation, March 18, 2008; 117(11): 1449 - 1459. [Abstract] [Full Text] [PDF]

				F. Addabbo, F. Mallamaci, D. Leonardis, R. Tripepi, G. Tripepi, M. S. Goligorsky, and C. Zoccali Searching for biomarker patterns characterizing carotid atherosclerotic burden in patients with reduced renal function Nephrol. Dial. Transplant., December 1, 2007; 22(12): 3521 - 3526. [Abstract] [Full Text] [PDF]

				S. J. Peterson, D. Husney, A. L. Kruger, R. Olszanecki, F. Ricci, L. F. Rodella, A. Stacchiotti, R. Rezzani, J. A. McClung, W. S. Aronow, et al. Long-Term Treatment with the Apolipoprotein A1 Mimetic Peptide Increases Antioxidants and Vascular Repair in Type I Diabetic Rats J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 514 - 520. [Abstract] [Full Text] [PDF]

				J.-M. Bugnicourt, B. Roussel, B. Tramier, C. Lamy, and O. Godefroy Cerebral venous thrombosis and plasma concentrations of factor VIII and von Willebrand factor: a case control study J. Neurol. Neurosurg. Psychiatry, July 1, 2007; 78(7): 699 - 701. [Abstract] [Full Text] [PDF]

				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]

				C. Vlachopoulos, K. Aznaouridis, N. Ioakeimidis, K. Rokkas, C. Vasiliadou, N. Alexopoulos, E. Stefanadi, A. Askitis, and C. Stefanadis Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease Eur. Heart J., November 2, 2006; 27(22): 2640 - 2648. [Abstract] [Full Text] [PDF]

				K. Auro, K. Komulainen, M. Alanne, K. Silander, L. Peltonen, M. Perola, and V. Salomaa Thrombomodulin Gene Polymorphisms and Haplotypes and the Risk of Cardiovascular Events: A Prospective Follow-Up Study Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 942 - 947. [Abstract] [Full Text] [PDF]

				D. Feinbloom and K. A. Bauer The role of other hemostatic factors in predicting arterial thrombotic events. Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): e29 - e29. [Full Text] [PDF]

				S. M. Kawut, E. M. Horn, K. K. Berekashvili, A. C. Widlitz, E. B. Rosenzweig, and R. J. Barst von Willebrand Factor Independently Predicts Long-term Survival in Patients With Pulmonary Arterial Hypertension Chest, October 1, 2005; 128(4): 2355 - 2362. [Abstract] [Full Text] [PDF]

				J. H. Zarifis Atherosclerosis, thrombosis, and inflammatory risk factors, from history and the laboratory to real life Eur. Heart J., February 2, 2005; 26(4): 317 - 318. [Full Text] [PDF]

				A. T. Hirsch and A. R. Folsom The Continuum of Risk: Vascular Pathophysiology, Function, and Structure Circulation, November 2, 2004; 110(18): 2774 - 2777. [Full Text] [PDF]

				H. S. Lim, G. Y. H. Lip, and A. D. Blann Plasma von Willebrand Factor and the Development of the Metabolic Syndrome in Patients with Hypertension J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5377 - 5381. [Abstract] [Full Text] [PDF]

				B. S. Wiggins and S. Spinler Antiplatelet and Antithrombin Therapy for Early Management of Acute Coronary Syndromes Journal of Pharmacy Practice, October 1, 2004; 17(5): 347 - 369. [Abstract] [PDF]

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