Articles |
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 |
|---|
|
|
|---|
Key Words: factor XII blood lipids blood pressure smoking clotting factors
| Introduction |
|---|
|
|
|---|
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 Xathrombin) 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 XIIa21 22 has now created the opportunity to examine the status of the contact system in participants in NPHS II.
| Methods |
|---|
|
|
|---|
|
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) |
![]() |
![]() |
![]() |
![]() |
![]() |
![]() |
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 |
|---|
|
|
|---|
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.
|
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.
|
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.
|
| Discussion |
|---|
|
|
|---|
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 |
|---|
|
| Acknowledgments |
|---|
Received January 10, 1996; accepted December 12, 1996.
| References |
|---|
|
|
|---|
2.
Kaplan AP, Silverberg M. The coagulation-kinin
pathway of human plasma. Blood. 1987;70:1-15.
3.
Hojima Y, Cochrane CG, Wiggins RC, Austen KF, Stevens
RL. In vitro activation of the contact (Hageman factor) system
of plasma by heparin and chondroitin sulfate. Blood. 1984;63:1453-1459.
4. Kellermeyer RW, Breckenridge RT. The inflammatory process in acute gouty arthritis, I: activation of Hageman factor by sodium urate crystals. J Lab Clin Med. 1965;65:307-315.[Medline] [Order article via Infotrieve]
5. Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med. 1974;140:797-811.[Abstract]
6. Shimada T, Kato H, Iwanaga S, Iwamori M, Nagai Y. Activation of factor XII and prekallikrein with cholesterol sulfate. Thromb Res. 1985;38:21-31.[Medline] [Order article via Infotrieve]
7. Connor WE. The acceleration of thrombus formation by certain fatty acids. J Clin Invest. 1962;41:1199-1205.
8. Mitropoulos KA, Esnouf MP. The autoactivation of factor XII in the presence of long-chain saturated fatty acids: a comparison with the potency of sulphatides and dextran sulphate. Thromb Haemost. 1991;66:446-452.[Medline] [Order article via Infotrieve]
9.
Bouma BN, Griffin JH. Human blood coagulation
factor XI: purification, properties, and mechanism of activation by
activated factor XII. J Biol Chem. 1977;252:6432-6437.
10.
Mandle R, Kaplan AP. Hageman factor substrates:
human plasma prekallikrein: mechanism of activation by
Hageman factor and participation in Hageman factor-dependent
fibrinolysis. J Biol Chem. 1977;252:6097-6104.
11.
Kerbiriou DM, Griffin JH. Human high
molecular weight kininogen: studies of structure-function relationships
and of proteolysis of the molecule occurring during contact activation
of plasma. J Biol Chem. 1979;254:12020-12027.
12. Miles LA, Greengard JS, Griffin JH. A comparison of the abilities of plasma kallikrein, ß-factor XIIa, factor XIa, and urokinase to activate plasminogen. Thromb Res. 1983;29:407-417.[Medline] [Order article via Infotrieve]
13. Osmond DH, Loh EK, Zingg EA, Hedlin AH. Kallikrein and plasmin as activators of inactive renin. Lancet. 1978;2:1375-1376.[Medline] [Order article via Infotrieve]
14. Derkx FHM, Bouma BN, Schalekamp MPA, Schalekamp MAD H. An intrinsic factor XIIprekallikreindependent pathway activates the human plasma renin-angiotensin system. Nature. 1979;280:315-316.[Medline] [Order article via Infotrieve]
15. Nagase H, Cawston JE, De Silva M, Barrett AJ. Identification of plasma kallikrein as an activator of latent collagenase in rheumatoid synovial fluid. Biochim Biophys Acta. 1982;702:133-142.[Medline] [Order article via Infotrieve]
16. Ghebrehiwet B, Randazzo BP, Duan JT, Silverberg M, Kaplan AP. Mechanism of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest. 1983;71:1450-1456.
17. Ratnoff OD, Davie EW. The activation of Christmas factor (factor IX) by activated plasma thromboplastin antecedent (activated factor XI). Biochemistry. 1962;1:677-685.
18. Seligsohn U, Osterud G, Brown SF, Griffin JH, Rapaport SI. Activation of human factor VII in plasma and in purified systems: roles of activated factor IX, kallikrein and activated factor XII. J Clin Invest. 1979;64:1056-1065.
19. Lammle B, Wuillemin WA, Huber I, Krauskopf M, Zurcher C, Plugshaupt R, Furlan M. Thromboembolism and bleeding tendency in congenital factor XII deficiency: a study of 74 subjects from 14 Swiss families. Thromb Haemost. 1991;65:117-121.[Medline] [Order article via Infotrieve]
20. Miller GJ, Bauer KA, Barzegar S, Cooper JA, Rosenberg RD. Increased activation of the haemostatic system in men at high risk of fatal coronary heart disease. Thromb Haemost. 1996;75:767-771.[Medline] [Order article via Infotrieve]
21. Ford RP, Esnouf MP, Burgess AI, Sarphie AF. An enzyme linked immunosorbent assay (ELISA) for the measurement of activated factor XII (Hageman factor) in human plasma. J Immunoassay. 1996;17:119-131.[Medline] [Order article via Infotrieve]
22.
Kaplan AP, Gruber B, Harpel PC. Assessment of
Hageman factor activation in human plasma: quantification of
activated Hageman factorC1 inactivator complexes
by an enzyme-linked differential antibody immunosorbent assay.
Blood. 1985;66:636-641.
23. Medical Research Council's Committee on Research on Chronic Bronchitis. Questionnaire on Respiratory Symptoms. London, UK: Publications Group, Medical Research Council; 1976.
24. Patron A, ed. ABC of Alcohol. 2nd ed. London, UK: British Medical Journal; 1988.
25. Miller GJ, Stirling Y, Ensouf MP, Heinrich J, van de Loo J, Kienast J, Wu KK, Morrissey JH, Meade TW, Martin JC, Imeson JD, Cooper JA, Finch A. Factor VIIdeficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bioassay to activated factor VII: an international study. Thromb Haemost. 1994;71:38-48.[Medline] [Order article via Infotrieve]
26. von Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957;17:237-246.[Medline] [Order article via Infotrieve]
27. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533-537.[Medline] [Order article via Infotrieve]
28. Gordon EM, Hellerstein HK, Ratnoff OD, Arafah BM, Yamashita TS. Augmented Hageman factor and prolactin titers, enhanced cold activation of factor VII, and spontaneous shortening of prothrombin time in survivors of myocardial infarction. J Lab Clin Med. 1987;109:409-413.[Medline] [Order article via Infotrieve]
29. Kelleher CC, Mitropoulos KA, Imeson J, Meade TW, Martin JC, Reeves BEA, Hughes LO. Hageman factor and risk of myocardial infarction in middle-aged men. Atherosclerosis. 1992;97:67-73.[Medline] [Order article via Infotrieve]
30.
Patrassi GM, Fallo F, Martinelli S, Mantero F, Boeri G,
Girolami A. The contact phase of blood coagulation and renin
activation in essential hypertension before and after
captopril. Eur Heart J. 1984;5:561-567.
31. Mitropoulos KA, Martin JC, Burgess AI, Esnouf MP, Stirling Y, Howarth DJ, Reeves BEA. The increased rate of activation of factor XII in late pregnancy can contribute to the increased reactivity of factor VII. Thromb Haemost. 1990;63:349-355.[Medline] [Order article via Infotrieve]
32. Gordon EM, Ratnoff OD, Jones PK. The role of augmented Hageman factor (factor XII) titers in the cold-promoted activation of factor VII and spontaneous shortening of the prothrombin time in women using oral contraceptives. J Lab Clin Med. 1982;99:363-369.[Medline] [Order article via Infotrieve]
33.
Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh
S, Hunt B, Smith KJ. Mechanisms of thrombin generation during
surgery and cardiopulmonary bypass. Blood. 1993;82:3350-3357.
34. Catto AJ, Grant PJ. Risk factors for cerebrovascular disease and the role of coagulation and fibrinolysis. Blood Coagul Fibrinol. 1995;6:497-510.[Medline] [Order article via Infotrieve]
35. Carter AM, Catto AJ, Grant PJ. Activated factor XII concentrations in cerebrovascular disease. Blood Coagul Fibrinolysis. 1994;5:817. Abstract.
36. Esnouf MP, Bellhouse AF, Burgess AI. The characterization of a Mb raised against p XII a and its use in an ELISA. Br J Haematol. 1994;86(suppl):65. Abstract.
37. Pixley RA, Schmaier A, Colman RW. Effect of negatively charged activating compounds on inactivation of factor XIIa by C1 inhibitor. Arch Biochem Biophys. 1987;256:490-498.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
![]() |
C. J. M. Doggen, F. R. Rosendaal, and J. C. M. Meijers Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII Blood, December 15, 2006; 108(13): 4045 - 4051. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. A. Sanders, F. Lewis, S. Slaughter, B. A Griffin, M. Griffin, I. Davies, D J. Millward, J. A Cooper, and G. J Miller Effect of varying the ratio of n-6 to n-3 fatty acids by increasing the dietary intake of {alpha}-linolenic acid, eicosapentaenoic and docosahexaenoic acid, or both on fibrinogen and clotting factors VII and XII in persons aged 45-70 y: the OPTILIP Study. Am. J. Clinical Nutrition, September 1, 2006; 84(3): 513 - 522. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. S. Ebbesen and J. Ingerslev Folate Deficiency-Induced Hyperhomocysteinemia Attenuates, and Folic Acid Supplementation Restores, the Functional Activities of Rat Coagulation Factors XII, X, and II J. Nutr., August 1, 2005; 135(8): 1836 - 1840. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Renne, M. Pozgajova, S. Gruner, K. Schuh, H.-U. Pauer, P. Burfeind, D. Gailani, and B. Nieswandt Defective thrombus formation in mice lacking coagulation factor XII J. Exp. Med., July 18, 2005; 202(2): 271 - 281. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Santamaria, J. Mateo, I. Tirado, A. Oliver, R. Belvis, J. Marti-Fabregas, R. Felices, J. M. Soria, J. C. Souto, and J. Fontcuberta Homozygosity of the T Allele of the 46 C->T Polymorphism in the F12 Gene Is a Risk Factor for Ischemic Stroke in the Spanish Population Stroke, August 1, 2004; 35(8): 1795 - 1799. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
J. D Mills and P. J Grant Insulin resistance, haemostatic factors and cardiovascular risk The British Journal of Diabetes & Vascular Disease, January 1, 2002; 2(1): 19 - 26. [Abstract] [PDF] |
||||
![]() |
S Donohoe, S Quenby, I Mackie, G Panal, R Farquharson, R Malia, J Kingdom, and S Machin Fluctuations in levels of antiphospholipid antibodies and increased coagulation activation markers in normal andheparin-treated antiphospholipid syndrome pregnancies Lupus, January 1, 2002; 11(1): 11 - 20. [Abstract] [PDF] |
||||
![]() |
S. Klein, M. Spannagl, and B. Engelmann Phosphatidylethanolamine Participates in the Stimulation of the Contact System of Coagulation by Very-Low-Density Lipoproteins Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1695 - 1700. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Orth, S. Westphal, J. Dierkes, C. Luley, and K. Schlatterer Rapid Factor XII (46C{->}T) Genotyping by Fluorescence Resonance Energy Transfer in Patients with Coronary Artery Disease or Thrombophilia Clin. Chem., June 1, 2001; 47(6): 1117 - 1119. [Full Text] [PDF] |
||||
![]() |
J. A. Cooper, G. J. Miller, K. A. Bauer, J. H. Morrissey, T. W. Meade, D. J. Howarth, S. Barzegar, J. P. Mitchell, and R. D. Rosenberg Comparison of Novel Hemostatic Factors and Conventional Risk Factors for Prediction of Coronary Heart Disease Circulation, December 5, 2000; 102(23): 2816 - 2822. [Abstract] [Full Text] [PDF] |
||||
![]() |
, , S. , M. , J. , S. , G. , and G. J. Miller Epidemiological and Genetic Associations of Activated Factor XII Concentration With Factor VII Activity, Fibrinopeptide A Concentration, and Risk of Coronary Heart Disease in Circulation, October 24, 2000; 102(17): 2058 - 2062. [Abstract] [Full Text] [PDF] |
||||
![]() |
K Woolf-May, W Jones, E M Kearney, R C R Davison, and S Bird Factor XIIa and triacylglycerol rich lipoproteins: responses to exercise intervention Br. J. Sports Med., August 1, 2000; 34(4): 289 - 292. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. C. Minnema, M. E. Wittekoek, N. Schoonenboom, J. J. P. Kastelein, C. E. Hack, and H. t. Cate Activation of the Contact System of Coagulation Does Not Contribute to the Hemostatic Imbalance in Hypertriglyceridemia Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2548 - 2553. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 1997 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |