(Circulation. 2000;102:2816.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Comparison of Novel Hemostatic Factors and Conventional Risk Factors for Prediction of Coronary Heart Disease
From the Medical Research Council (J.A.C., G.J.M., T.W.M., D.J.H., J.P.M.), Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, London, UK; the Department of Medicine (K.A.B., S.B., R.D.R.), Beth Israel Deaconess Medical Center, and the Boston VA Healthcare System (K.A.B.), Harvard Medical School, Boston, Mass; the Cardiovascular Biology Research Program (J.H.M.), Oklahoma Medical Research Foundation, Oklahoma City; and the Department of Biology (R.D.R.), Massachusetts Institute of Technology, Cambridge, Mass.
Correspondence to George J. Miller, MD, MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1 M 6BQ, UK. E-mail g.miller{at}mds.qmw.ac.uk
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Abstract |
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Background—This study sought to assess whether novel markers of hemostatic activity are predictive of coronary heart disease (CHD) and improve risk assessment.
Methods and Results—Conventional CHD risk factors, the activation peptides of factor IX and factor X, factor VII activity and antigen, activated factor XII, prothrombin fragment 1+2, fibrinopeptide A, and fibrinogen were measured in 1153 men aged 50 to 61 years who were free of myocardial infarction at recruitment. Activated factor VII (VIIa) was measured in 829 men. During 7.8 years of follow-up, 104 had a CHD event. Baseline status was related to outcome by logistic regression by using a modified nested case-control design. Screening performance was judged from receiver operating characteristic curves. A high activated factor XII was associated with increased CHD risk, but low levels were not protective. Plasma VIIa and factor X activation peptide were independently and inversely related to risk. Plasma factor IX activation peptide and fibrinogen were positively associated with risk, but the relations were no longer statistically significant after adjustment for other factors, including VIIa and apoA-I. Other hemostatic markers were not associated with CHD risk.
Conclusions—Hemostatic status did not add significant predictive power to that provided by conventional CHD risk factors yet was able to substitute effectively for these factors.
Key Words: coronary disease • coagulation • risk factors • epidemiology
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Introduction |
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Several methods have been devised for assessment of individual risk of coronary heart disease (CHD),1 2 but they have had insufficient sensitivity and specificity for general application. The distributions of values in those who develop an acute CHD event and those who remain event free so overlap that no cutoff value discriminates between these groups with sufficient accuracy for practical purposes. However, the events of concern are the thrombotic sequelae of coronary atherosclerosis,3 4 5 raising the possibility that risk assessment may be improved by measures of hemostatic status. Therefore, a prospective survey was undertaken to address the following questions: (1) Are novel markers of basal procoagulant activity associated with risk of a first CHD event? (2) Are such associations statistically independent of the conventional CHD risk factors? (3) Do these markers improve the estimation of CHD risk? (4) Are associations of markers of procoagulant activity with CHD consistent with a hypercoagulable state? (This topic is to be reported elsewhere.)
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Methods |
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Subjects and Procedures
The Second Northwick Park Heart Study (NPHS-II) has been described previously.6 Briefly, 4600 men aged 50 to 61 years registered with 9 general medical practices in Britain were screened for eligibility for study. Exclusion criteria were as follows: a history of unstable angina or acute myocardial infarction, a major Q wave on the ECG, regular antiplatelet or anticoagulant therapy, cerebrovascular disease, life-threatening malignancy, and conditions exposing the staff to risk or precluding informed consent. From April 1989, 3052 (76.1%) of 4009 eligible men entered the study.
Subjects did not fast for the study, but they had been instructed to avoid heavy meals to ensure that triglyceride concentration and clotting factors influenced by plasma lipids would be neither atypically low (fasting) nor high (heavy lipemia) at examination. They were requested to refrain from smoking and vigorous exercise from midnight beforehand. Each answered a questionnaire involving lifestyle and medical history and was classified as a current smoker or other and as a current drinker (at least 1 alcoholic drink in the previous week) or other. Blood pressure (BP) was recorded with a random-zero sphygmomanometer (average of 2 measurements). Body mass index (BMI) was calculated as weight/height2 (kg/m2).
A blood sample was processed as described elsewhere.6 7 Siliconized tubes were used to collect 4.5 mL of blood into 0.5 mL of 0.106 mol/L trisodium citrate and 13.5 mL into 1.5 mL of an anticoagulant mixture of trasylol, EDTA, and a thrombin inhibitor (Byk-Sangtec). A 5-mL sample was taken for serum. Venipuncture performance was scored by predefined criteria.7
Assays
Factor VII antigen (VIIag) was measured by ELISA (a
gift from Novo Nordisk Biolabs, Bagsvaerd, Denmark). Factor VII
activity (VIIc)8 and
activated factor VII
(VIIa)9 were
determined as described previously. Fibrinogen concentration was
measured by a thrombin-clotting
method10 and
expressed in terms of a World Health Organization standard (code
label 89/644).
Prothrombin fragment 1+2 (F1+2)11 was measured by double-antibody radioimmunoassay, and fibrinopeptide A (FPA) was measured by commercial radioimmunoassay (Byk-Sangtec) as indices of turnover of prothrombin and fibrinogen, respectively. The activation peptides of factor IX (IXpep)12 and factor X (Xpep)13 were determined by double-antibody radioimmunoassay as indices of turnover of factor IX and factor X, respectively. Activated factor XII (XIIa) was measured by ELISA (a gift from Axis-Shield, Dundee, UK).14 Serum cholesterol and triglyceride levels were determined by automated procedures (Sigma and Wako Chemicals, respectively). Serum apoA-I was measured by immunoturbidimetry (Incstar).
For VIIa, the within-person coefficient of variation for measurements made during the study and within-run coefficient of variation of repeat measurements on split samples were 23% and 11.1%, respectively. The respective coefficients of variation for other indices were as follows: VIIc, 15.0% and 2.2%; VIIag, 11.1% and 3.5%; XIIa, 10.5% and 5.4%; IXpep, 14.7% and 8.6%; Xpep, 17.3% and 8.6%; F1+2, 25.0% and 7.6%; and FPA, 38.8% and 24.0%.
Follow-Up and End Points
CHD end points were as follows: (1) acute CHD events:
sudden coronary death, fatal acute myocardial infarction, and nonfatal
acute myocardial infarction (details of possible events were obtained
through medical practices, hospitals, and coroners’ offices; the
clinical history, ECGs, cardiac enzymes, and pathology were assessed by
independent review according to World Health Organization
criteria15 ; and
normal limits for cardiac enzymes were those for the reporting
laboratory); (2) a new major Q wave on the ECG after 5 years of
follow-up (Minnesota codes
11,12.1 to
12.7, and 12.8 plus
51 or
52)16 ;
and (3) surgery for angina pectoris with CHD angiographically
demonstrated.
Statistical Analysis
Variables were logarithmically transformed where
necessary and adjusted for age and medical practice by using regression
estimates of the effects. Logarithmically transformed data are
presented as geometric means with approximate SDs. Associations between
variables were assessed by Pearson correlation
coefficients.
Univariate and multivariate logistic regression were used to estimate the associations of risk factors with acute CHD events and all CHD end points. Results were expressed as the relative odds of an event associated with a 1-SD rise in the variable, estimated as follows: odds ratio (OR)=exp(logistic coefficientxSD). For transformed variables, the SD of the log was used. For categorical variables, odds were relative to a reference category. Some variables were measured at baseline and on up to 5 subsequent anniversaries in survivors. These results were averaged after exclusion of any taken after an end point. Models using the baseline measurements and averages were then compared. Because F1+2 and FPA are influenced by the quality of venipuncture,7 results were excluded when this was not fully satisfactory or when FPA exceeded 6 nmol/L.
Measurements of VIIc, VIIag, and XIIa were made in all subjects at baseline. Single measures of IXpep, Xpep, and VIIa were determined in a case-control study nested within the 3052 participants, with 3 controls matched by age and practice for each case. To this sample were added results from a random sample of those remaining who did not develop an end point during follow-up. Thus, the analysis included 1153 men with satisfactory venipunctures and results for IXpep and Xpep. To take account of the sampling strategy and nonrandom element in the design, in logistic regression the observations were weighted by the inverse of the probability of inclusion in the sample.
Multivariate risk scores were calculated for each
participant by use of selected permutations of characteristics weighted
by coefficients given by logistic regression. For each separate risk
factor and risk score, sensitivity (true positive rate) and
1-specificity (false-positive rate) were calculated for each value
across the range observed. Sensitivity was then plotted against
1-specificity to produce a receiver operating characteristic (ROC)
curve. The area under the ROC curve, computed by the trapezoid
rule,17 is the
predictive accuracy (probability of the score of a randomly chosen case
exceeding that of a randomly chosen control). A predictive accuracy of
0.5 is indicative of complete lack of discriminating power. Statistical
significance was accepted at P
0.05, with adjustment
for multiple comparisons when necessary (Bonferroni
technique).
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Results |
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Of the 1153 men included in the present analysis, follow-up was complete for 1097 (95.1%). One hundred four CHD end points (71 acute CHD events, 18 new major Q waves, and 15 cases of surgery for angina pectoris) were recorded during an average surveillance of 7.8 years.
Table 1
presents those variables for which, in men
free of terminating events, the distribution in the 1049 men with IXpep
and Xpep differed significantly from that in the 1899 men without these
measures. Differences were very small (although statistically
significant because of large samples) and most unlikely to have
introduced important bias.
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The OR for any CHD end point was 1.07 (95% CI 1.01
to 1.13) for each year of increase in age (P=0.03).
Table 2 is a correlation matrix of adjusted hemostatic
variables and serum triglycerides. The strongest associations were
between the indices of factor VII and between IXpep and Xpep. Weaker
but statistically significant positive associations were observed for
XIIa with VIIc, VIIag, and FPA, for IXpep with all factor VII indices
and F1+2, for Xpep with both VIIa and
F1+2, and for F1+2 with
VIIag. Plasma VIIc, VIIag, and XIIa were significantly related to
triglyceride level and also similarly to cholesterol concentration (not
shown).
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Table 3 gives age/practice-adjusted distributions of
measured variables by outcome. Cholesterol, triglycerides, systolic BP,
BMI, fibrinogen, VIIag, XIIa, and IXpep were higher, whereas apoA-I,
VIIa, and Xpep were lower in the event group than in the event-free
group. Plasma VIIc, F1+2, and FPA levels at
baseline were not related to outcome. The findings were very similar
when the analysis was restricted to acute CHD events.
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Univariate ORs for any CHD end point were 2.14 (95%
CI 1.41 to 3.23) for current smoking (P<0.0001), 7.59
(95% CI 3.27 to 17.65) for non–insulin-dependent diabetes mellitus
(NIDDM) (P<0.0001), and 0.56 (95% CI 0.35 to 0.88)
for recent alcohol consumption (P=0.01).
Table 4 presents univariate associations as ORs and
screening performance as predictive accuracy and sensitivity for 95%
specificity (detection rate for a 5% false-positive rate) for 14
characteristics with respect to any CHD end point. Statistically
significant positive associations were found for cholesterol level,
triglyceride level, systolic BP, BMI, fibrinogen, and IXpep. The
associations of apoA-I, Xpep, and VIIa were statistically significant
and inverse. The relation of XIIa with risk was nonlinear, with
concentrations in the lower third of the distribution not differing
significantly in associated risk from those in the middle third,
whereas risk was doubled for values in the upper third of the
distribution compared with the middle third (P=0.003).
Plasma VIIc, VIIag, F1+2, and FPA were not
related to risk. Similar ORs were found for acute CHD events, except
for BMI, which was no longer statistically significant.
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Predictive accuracy for any CHD event was 
0.6 for
cholesterol, apoA-I, fibrinogen, and VIIa and 0.55 to 0.59 for
triglycerides, systolic BP, BMI, IXpep, and Xpep. Highest values for
the detection rate for a 5% false-positive rate (>14%) were shown by
cholesterol and IXpep. Results were very similar for acute CHD events,
except for a relatively weak screening performance of BMI.
Averaged measurements of cholesterol, systolic BP, and
fibrinogen were better independent predictors of any CHD event than was
the baseline measurement, but averaged F1+2,
FPA, and triglyceride values were no more informative than were the
baseline values
(Table 5). The same pattern held for acute CHD events (not
shown).
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Table 6 presents ORs for any CHD end point adjusted for
other predictor variables, with and without the inclusion of VIIa and
apoA-I (adding the latter 2 variables substantially reduced the number
of subjects with complete data). In both analyses NIDDM, current
smoking, systolic BP, cholesterol, and Xpep were independently
associated with risk, although statistical significance was weakened in
the smaller data set. Fibrinogen and alcohol consumption were
independently related to risk only in the analysis excluding VIIa and
apoA-I. Plasma IXpep was not a statistically significant independent
predictor. Plasma XIIa was an independent risk predictor, but its
association was U-shaped when VIIa and apoA-I were considered in the
analysis. Both VIIa and apoA-I were independent predictors of risk.
Serum triglyceride level was not an independent predictor of CHD, and
its inclusion had essentially no effect on the associations shown in
Table 6. Repeat analysis for acute CHD events gave similar
findings.
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Table 7 shows that the predictive accuracy of a risk score
based on NIDDM, systolic BP, current smoking, cholesterol, and recent
alcohol consumption was 0.71, increasing to 0.72 with the inclusion of
fibrinogen and to 0.77 with the further addition of VIIa, Xpep, XIIa,
and IXpep. A risk score based on the 4 novel hemostatic markers also
had a predictive accuracy of 0.71, increasing to 0.72 with the addition
of fibrinogen. Thus, the novel hemostatic markers performed very
similarly to conventional factors as predictors of CHD risk. This
conclusion held for acute CHD events.
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Discussion |
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In the present study, consideration of markers of hemostatic activity in addition to conventional risk factors for CHD failed to improve appreciably the identification of men at high risk for a first event. Rather, the hemostatic factors appeared to have predictive accuracy that was broadly similar to that given by a history of NIDDM, systolic BP, smoking habit, alcohol intake, and serum cholesterol. However, a potential weakness of the analysis was that estimates of associations with risk were based on only 104 events. A larger study would strengthen the comparisons of predictive accuracy.
An alternative approach to logistic regression would have been a survival model such as Cox proportional hazards, which takes advantage of the longitudinal nature of NPHS-II. However, ROC curves cannot be generated from the Cox model. Both methods of analysis were nevertheless used but gave very similar results. Hence, only the logistic regression is presented.
In an earlier cross-sectional analysis of NPHS-II, men at high CHD risk according to their levels of cholesterol, BP, and smoking habit had slightly but statistically significantly raised levels of XIIa,18 VIIc, VIIa, VIIag, IXpep, F1+2, and fibrinogen.19 These associations of hemostatic indices with predicted risk are probably the epidemiological counterpart to pathological evidence for the generation of thrombin and fibrin in response to injury in atherosclerosis.20 Importantly, the longitudinal associations of hemostatic factors with CHD differed in several respects from their cross-sectional associations with a CHD risk score based on conventional risk factors. Whereas XIIa increased linearly with the risk score,18 its association with outcome was nonlinear, there being no evidence for lower risk in men with XIIa in the bottom third of the distribution compared with those in the middle third. Plasma VIIa increased with risk score but was significantly reduced in men who developed a CHD event. Plasma IXpep increased with risk score,19 and high levels were also associated with CHD events. Plasma Xpep was unrelated to cross-sectional risk score (authors’ unpublished data, 2000) but was significantly reduced in men who later had a CHD event. Plasma F1+2 increased with the risk score19 but was not related to outcome. Plasma FPA was related neither to the risk score19 nor to CHD events. Although a potential weakness of the present study was the limited reproducibility of F1+2 and FPA, reduction of this source of error by using the mean of repeated measurements failed to improve the predictive power of these indices.
The association of VIIc with CHD events in the first Northwick Park Heart Study (NPHS-I) was not observed in NPHS-II, in agreement with other recent studies.21 22 23 Technical explanations for the apparent discrepancy between NPHS-I and NPHS-II appeared unlikely, inasmuch as both studies used the same laboratory and assay.8 The population mean±SD values for VIIc (percent standard) were 111.5±26.7% in NPHS-I and 109.1±28.9% in NPHS-II.
Between 1972 and 1989, the time between establishment of NPHS-I and NPHS-II, Britain experienced a significant decline in dietary fat intake.24 Plasma VIIc is positively associated with dietary fat intake,25 and VIIa increases transiently during postprandial lipemia.26 Thus, although not testable, the association of VIIc with CHD in NPHS-I may have been explained by dietary fat intake, an effect attenuated by subsequent changes in the national diet.
The hemostatic changes in men at high CHD risk in the present study were not wholly compatible with a hypercoagulable state, insofar as for most steps examined in the coagulation pathway, no evidence was apparent for increased activity. This aspect of the present study will be presented elsewhere. We cannot exclude the possibility that to some extent the hemostatic changes observed reflect proteolytic activity of inflammatory origin on plasma proteins. Matrix metalloproteinases derived from macrophages weaken the atherosclerotic plaque,27 whereas neutrophil elastase attacks the surface of the lesion,28 thereby increasing the likelihood of disruption with occlusive thrombosis. Proteolytic enzymes also attack clotting factors.29 30 31 32 Neutrophil elastase is reported to inactivate factor IX with release of a peptide very similar to IXpep.30 Inactivation of factor IX could reduce the activation of factor VII and factor X, consistent with the relatively low levels of VIIa and Xpep in men at high CHD risk. Neutrophil elastase is also reported to inactivate factor VII.31
The inability of the hemostatic factors to add predictive power to that provided by conventional risk factors, and vice versa, was possibly due in part to technical factors, including sample size, laboratory errors of measurement, and the use of single measures to capture a long-standing disease process. Nevertheless, the overall modest predictive value undoubtedly points to aspects of CHD not measured by current techniques.
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Acknowledgments |
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This study was supported by the British Medical Research Council, National Institutes of Health (HL-33014 and HL-54502), and DuPont Pharma, Wilmington, Del. We thank the following medical practices for collaboration: Aston Clinton Surgery; Upper Gordon Road, Camberley; Carnoustie Health Center; Whittington Moor Surgery, Chesterfield; The Market Place Surgery, Halesworth; Harefield Health Center; Potterells Medical Center, North Mymms; Rosemary Medical Center, Parkstone; and The Health Center, St Andrews.
Received April 26, 2000; revision received July 14, 2000; accepted July 28, 2000.
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S. Rodriguez, T. R. Gaunt, S. D. O'Dell, X.-h. Chen, D. Gu, E. Hawe, G. J. Miller, S. E. Humphries, and I. N.M. Day Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits Hum. Mol. Genet., April 1, 2004; 13(7): 715 - 725. [Abstract] [Full Text] [PDF]
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S. E. Humphries, P. M. Ridker, and P. J. Talmud Genetic Testing for Cardiovascular Disease Susceptibility: A Useful Clinical Management Tool or Possible Misinformation? Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 628 - 636. [Abstract] [Full Text] [PDF]
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 D. Ardissino, P. A. Merlini, K. A. Bauer, M. Galvani, F. Ottani, F. Franchi, F. Bertocchi, R. D. Rosenberg, and P. M. Mannucci Coagulation activation and long-term outcome in acute coronary syndromes Blood, October 15, 2003; 102(8): 2731 - 2735. [Abstract] [Full Text] [PDF]
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 Y. E. Finnegan, D. Howarth, A. M. Minihane, S. Kew, G. J. Miller, P. C. Calder, and C. M. Williams Plant and Marine Derived (n-3) Polyunsaturated Fatty Acids Do Not Affect Blood Coagulation and Fibrinolytic Factors in Moderately Hyperlipidemic Humans J. Nutr., July 1, 2003; 133(7): 2210 - 2213. [Abstract] [Full Text] [PDF]
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 T. Tholstrup, G. J Miller, A. Bysted, and B. Sandstrom Effect of individual dietary fatty acids on postprandial activation of blood coagulation factor VII and fibrinolysis in healthy young men Am. J. Clinical Nutrition, May 1, 2003; 77(5): 1125 - 1132. [Abstract] [Full Text] [PDF]
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T. A. Sanders, S. E. Berry, and G. J Miller Influence of triacylglycerol structure on the postprandial response of factor VII to stearic acid-rich fats Am. J. Clinical Nutrition, April 1, 2003; 77(4): 777 - 782. [Abstract] [Full Text] [PDF]
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P. J. Talmud, E. Hawe, G. J. Miller, and S. E. Humphries Nonfasting Apolipoprotein B and Triglyceride Levels as a Useful Predictor of Coronary Heart Disease Risk in Middle-Aged UK Men Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1918 - 1923. [Abstract] [Full Text] [PDF]
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V. Salomaa, V. Rasi, S. Kulathinal, E. Vahtera, M. Jauhiainen, C. Ehnholm, and J. Pekkanen Hemostatic Factors as Predictors of Coronary Events and Total Mortality: The FINRISK '92 Hemostasis Study Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 353 - 358. [Abstract] [Full Text] [PDF]
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J. M. Edelberg, P. D. Christie, and R. D. Rosenberg Regulation of Vascular Bed-Specific Prothrombotic Potential Circ. Res., July 20, 2001; 89(2): 117 - 124. [Abstract] [Full Text] [PDF]
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