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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2103-2106.)
© 1997 American Heart Association, Inc.

Articles

Risk of Coronary Heart Disease and Activation of Factor XII in Middle-Aged Men

G.J. Miller; M.P. Esnouf; A.I. Burgess; J.A. Cooper; ; J.P. Mitchell

From the Medical Research Council Epidemiology and Medical Care Unit, St Bartholomew's and Royal London School of Medicine and Dentistry, London (G.J.M., J.A.C., J.P.M.), and the Nuffield Department of Clinical Biochemistry, Radcliffe Infirmary, Oxford (M.P.E., A.I.B.), UK.

Correspondence to Dr George J Miller, MRC Epidemiology and Medical Care Unit, St Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ. E-mail g.miller{at}mds.qmw.ac.uk

	Abstract

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Abstract Increased activity is known to be present in the extrinsic, intrinsic, and final common pathways of the hemostatic system in men at high risk of coronary heart disease (CHD), but the status of the contact system of coagulation in this condition is uncertain. Plasma levels of activated factor XII (XIIa), the initial product of contact activation, have therefore been measured by ELISA in 2464 men aged 51 to 62 years, clinically free of CHD, who were taking part in a prospective cardiovascular survey based in general medical practices. Statistically significant, independent, and positive associations of XIIa were found with serum cholesterol and triglyceride concentrations, blood pressure, body mass index, factor VII activity, plasma fibrinogen concentration, and tobacco smoking, all associated with CHD. Plasma XIIa also increased with recent alcohol intake. Men in the highest quintile of risk according to their conventional risk factors had a mean XIIa of 2.07 ng/mL (95% confidence interval 1.99-2.16), 31% higher than that of men in the lowest quintile (1.58; 95% confidence interval 1.51-1.65). Thus, the contact system of coagulation appears to be activated when CHD risk is increased. Furthermore, the independent associations of XIIa with the major conventional CHD risk factors and its broad range of values in the general population (0.1 to 12.5 ng/mL), combined with a relatively low day-to-day variability in individuals (the within-person component of its total variation being 14.7%), suggest its potential usefulness as a marker of atherosclerotic vascular damage.

Key Words: factor XII • blood lipids • blood pressure • smoking • clotting factors

	Introduction

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The contact system of coagulation and kinin formation consists of the four plasma proteins factor XII, prekallikrein, factor XI, and high-molecular-weight kininogen.^{1 2} Control of the system is provided by several circulating serine protease inhibitors, but especially C1 inhibitor. The essential step initiating activity is the conversion of factor XII to its derivative enzyme XIIa on contact with a variety of biological substances from which it is normally separated by healthy vascular endothelium. These substances, such as cerebroside sulfates (sulfatides), chondroitin sulfate, cholesterol sulfate, acidic phospholipids, collagen fibrils, basement membrane, and urate crystals,^{3 4 5 6} have in common a negatively charged activating surface. There is also evidence for factor XII activation after exposure to high concentrations of certain fatty acids, particularly on the surface of lipoprotein particles.^{7 8} XIIa converts factor XI to XIa⁹ and prekallikrein to kallikrein,¹⁰ thereby creating the potential for dissemination of activating reactions through a number of systems involved in tissue defense and repair. These include the generation of bradykinin from high-molecular-weight kininogen,¹¹ the conversion of plasminogen to the fibrinolytic enzyme plasmin¹² and prorenin to renin,^{13 14} the activation of collagenase¹⁵ and the classical pathway of complement,¹⁶ and the proteolytic cleavage of factor IX¹⁷ and factor VII¹⁸ in the intrinsic and extrinsic coagulation pathways, respectively. Some of these actions appear to be of low potency, however, and others have so far been described only in vitro. Our limited understanding of this complex system, the asymptomatic nature of factor XII deficiency,¹⁹ and the fact that the hemostatic, fibrinolytic, renin, and complement pathways are not dependent solely on the contact mechanism for activation have raised uncertainties about the significance of factor XII in health and disease.

The second Northwick Park prospective cardiovascular survey (Northwick Park Heart Study-II, NPHS-II) has revealed subthrombotic levels of activation at several steps throughout the intrinsic, extrinsic, and common (factor Xa–thrombin) pathways of the coagulation system in men at high risk of fatal CHD.²⁰ Increased activation of factor XII in such men might signify the presence of injured vascular surfaces and would help to explain their augmented activation of factor VII and factor IX,²⁰ thereby contributing to a hypercoagulable state. However, studies of factor XII have hitherto been limited by an inability to measure its rate of activation in vivo. The advent of assays for XIIa^{21 22} has now created the opportunity to examine the status of the contact system in participants in NPHS II.

	Methods

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The design of the study has been described previously.²⁰ Briefly, 4600 men, aged 50 to 61 years, belonging to nine general medical practices were screened for eligibility after giving informed consent. In all, 3179 (77%) of the 4141 men without a history of unstable angina, myocardial infarction, cerebrovascular disease, or malignancy were recruited. After exclusion of men who refused venipuncture, those with electrocardiograms suggestive of previous myocardial infarction, and a small number with missing results, 2951 men were available for follow-up. Two thousand eight hundred thirty-four men were reexamined after 1 year, at which time a blood sample for XIIa was obtained from 2464 (87%). Those without XIIa measurement were very similar to those with a result with respect to mean age, BMI, smoking habit, systolic blood pressure, VIIc, fibrinogen concentration, and triglyceride concentration but had a slightly increased mean serum cholesterol concentration and slightly lower diastolic blood pressure(Table 1).

View this table: [in this window] [in a new window]   Table 1. Coronary Risk Factors in Respondents With and Without Measurement of Factor XIIa

Subjects were seen nonfasting, having been requested not to smoke or take vigorous exercise from midnight beforehand. Each completed a questionnaire for smoking.²³ Alcohol consumption was recorded as the number of units consumed in the previous week.²⁴ Blood pressure was recorded twice with a random zero mercury sphygmomanometer (Hawksley) and the average value used in the statistical analysis. Height (meters) and weight (kilograms) were measured and BMI was calculated as weight/height². Venipuncture was performed by Vacutainer technique (Becton Dickinson). A 5-mL blood sample was collected into a glass tube without anticoagulant, and 4.5 mL was taken into a siliconed tube containing 0.5 mL of 0.106 mol/L trisodium citrate. Serum and plasma were stored at -45°C pending analysis.

XIIa was measured by an ELISA which employs a monoclonal antibody that does not recognize its zymogen factor XII²¹ (Shield Diagnostics). Serum cholesterol and triglyceride concentrations were measured by automated enzymic procedures with reagents from Sigma and Wako Chemicals (Alpha Laboratories), respectively. Plasma VIIc was measured by a one-stage clotting assay.²⁵ Plasma fibrinogen concentration was determined by a thrombin-clotting method.²⁶

Each man was given a risk score for CHD (nonfatal and fatal cases combined) within 5 years of follow-up, using weightings for serum cholesterol, systolic blood pressure, BMI, and current smoking given in a multiple linear regression analysis of data belonging to a previous prospective cardiovascular survey²⁷ :

(1)

A second risk score was then calculated with the addition of VIIc and fibrinogen concentration:

In a subsample of subjects (n=41), blood was drawn on a second occasion within 6 weeks to estimate the within-person and between-person components in the total variation of XIIa, cholesterol, and triglyceride concentration.

All variables with a skewed distribution were log transformed before statistical analysis. Simple correlations were calculated between XIIa and other variables before and after adjustment for differences between general practices and for within-subject variation. The significance of differences between current smokers and nonsmokers, by level of alcohol consumption, and by fifths of the distribution of the risk score for CHD was tested by ANOVA.

	Results

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The geometric mean XIIa concentration was 1.80 (approximate SD 0.92) ng/mL. The lower and upper deciles of the distribution were 0.93 and 3.40 ng/mL, respectively, and the range 0.10 to 12.50 ng/mL. The within-person and between-person components of the total variance in XIIa were 14.7% and 85.3%, respectively. No significant association was observed between XIIa and age in this group of middle-aged men (r=.03; P=.19).

Table 1 presents the distribution of the conventional and recognized hemostatic risk factors for CHD in the 2464 men with a result for XIIa. In univariate analysis, the conventional CHD risk factor associated most strongly with XIIa concentration was serum triglyceride concentration (r=.25; P<.0001, after adjustment for within-person variation). Recent alcohol consumption and smoking habit were also strongly associated with XIIa. After adjustment for between-practice and within-subject variation and allowance for triglyceride concentration and smoking habit, mean XIIa increased from 1.53 ng/mL in nondrinkers to 1.57 ng/mL in those taking 1 to 7 units, 1.68 ng/mL at 7 to 15 units, and 1.81 ng/mL at >15 units per week (P<.0001). Table 2 shows that nonsmokers had a significantly lower XIIa than ex-smokers and current smokers, even after allowance for alcohol intake.

View this table: [in this window] [in a new window]   Table 2. XIIa Concentration by Smoking Habit

Table 3 presents the associations of XIIa with other conventional risk factors for CHD, first on univariate analysis and then after allowance for all other risk factors measured. Although relatively weak, the associations of XIIa with cholesterol concentration, nonfasting triglyceride concentration, blood pressure, BMI, VIIc, and fibrinogen concentration were all statistically significant, positive, and independent of smoking habit, alcohol intake, and other conventional risk factors measured.

View this table: [in this window] [in a new window]   Table 3. Correlation Coefficients1 Between XIIa and Selected Risk Factors for CHD

Table 4 shows that mean XIIa increased progressively with the risk score for CHD based exclusively on nonhemostatic variables. The inclusion of VIIc and fibrinogen concentration in the risk score did not alter the results. Men above the highest quintile of risk had on average an XIIa that was 31% higher than that for those below the lowest quintile (P<.0001). Table 4 also presents mean fibrinogen and VIIc according to risk score for CHD for comparison, the respective increases in the highest-risk group being 12.5% and 16.4% above the lowest-risk group.

View this table: [in this window] [in a new window]   Table 4. Geometric Mean (95% Confidence Intervals) XIIa, Fibrinogen, and VIIc by Risk Score for CHD

	Discussion

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The most striking finding of this study was the wide spectrum of independent associations of XIIa with characteristics recognized as predisposing to CHD, including alterations in serum cholesterol and triglyceride concentrations, blood pressure, and BMI; tobacco smoking; and increased concentrations of the two hemostatic risk factors for CHD, VIIc and fibrinogen.²⁷ When these independent associations were aggregated as a risk score for CHD, men above the highest quintile of estimated risk had on average 31% higher XIIa than those at lowest risk. By comparison, the respective figures for fibrinogen concentration and VIIc were 12.5% and 16.4%. There have been very few previous studies of a related nature and no previous epidemiological surveys of XIIa to our knowledge. Gordon et al²⁸ reported significantly higher levels of XIIa and antigen in 16 male survivors of myocardial infarction than in 13 healthy control subjects. However, this finding was not confirmed by Kelleher et al,²⁹ who measured factor XII concentration indirectly by clotting assay and amidolytic assay in survivors of a myocardial infarction and healthy control subjects. Kelleher et al²⁹ also estimated XIIa concentration with an amidolytic assay in a subsample of their subjects and observed a significant positive association with plasma triglyceride concentration. Patrassi et al³⁰ reported an increase in XIIa in patients with essential hypertension. Increased levels of factor XII have also been found in pregnancy,³¹ during oral contraceptive therapy,³² and in patients undergoing thoracic surgery.³³ Finally, in a recent review, Catto and Grant³⁴ referred to preliminary data from their laboratory³⁵ showing a persistent elevation of XIIa in patients with acute stroke.

The pathophysiological significance of XIIa in men at high CHD risk cannot be ascertained from this study. A proportion of XIIa exists as a complex with C1 inhibitor²² and other inhibiting proteins, but the ELISA used in the present study is known to be insensitive to such complexes in plasma.³⁶ One possibility is that the XIIa recognized is bound to surfaces, for example on lipoprotein particles, which partially protect it from plasma inhibitors.³⁷ Thus, the plasma XIIa concentration given by the ELISA will be less than the combined concentration of unbound XIIa and that bound to plasma inhibitors. Irrespective of its nature, however, the increased level of circulating XIIa will have been generated by contact activation. Consequently, the independent associations of XIIa with a range of CHD risk factors most likely reflect contact between factor XII and surfaces that are not normally exposed to blood but have become accessible as a result of atherothrombotic injury to the vascular endothelium. Plasma XIIa concentration may therefore serve as a marker of the severity of the atherosclerotic process.

The precise concentration of XIIa differs in the same individual on different days (as do the values of all CHD risk factors). This is due partly to biological variation and partly to measurement error, which together comprise the within-subject variability. The remainder of the total variability in XIIa is due to differences between subjects. When within-subject variance accounts for an appreciable proportion of the total variance in any factor of interest, a single determination is unlikely to provide an adequate estimate of the individual's true mean value and thus will lack the power to discriminate reliably between individuals of differing rank, leading to appreciable misclassification. Within-person variance can also produce underestimates of the strength of association between two variables when the statistical analysis depends on single estimates. From this standpoint, XIIa affords considerable potential as a marker of risk, because the level within any individual varied little from one day to the next. In other words, the great majority of its total variance (85%) represented differences between individuals. In addition, XIIa has a broad range of concentration within the community, its coefficient of variation being about 50%. These properties compare favorably with serum cholesterol concentration, which possesses relatively more day-to-day variability than XIIa, only 79% of its total variance being explained by differences between subjects in this study. Furthermore, cholesterol concentration had a smaller coefficient of variation of only 18%. Future studies might therefore profitably examine the status of XIIa in other disorders associated with vascular injury, such as diabetes mellitus, homocysteinemia, renal failure, and cerebrovascular disease.

	Selected Abbreviations and Acronyms

 

BMI = body mass index CHD = coronary heart disease VIIc = factor VII coagulant activity XIIa = activated factor XII

	Acknowledgments

 
This study was supported by the British Medical Research Council, the US National Institutes of Health (grant No. NHLBI 33014), and Du Pont Pharma, Wilmington, Del. The ELISA kits for XIIa were a gift from Shield Diagnostics, Dundee, UK. We thank J.S. Heer, A. Foley, Y.M. Chin, N. Patel, and M.P. Amvrosiou for the assays of the blood samples. The following general practices collaborated in the study: The Surgery, Aston Clinton; Upper Gordon Road, Camberley; The Health Centre, Carnoustie; Whittington Moor Surgery, Chesterfield; The Market Place Surgery, Halesworth; The Health Centre, Harefield; Potterells Medical Centre, North Mymms; Rosemary Medical Centre, Parkstone, Poole; and The Health Centre, St Andrews, UK.

Received January 10, 1996; accepted December 12, 1996.

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