Eur. J. Epidemiol. 0392-2990 Suppl. 1, 1992, p. 79-82
Vol. 8, Suppl. to No. 2
EUROPEAN
JOURNAL
Ov
EPIDEMIOLOGY
PLASMA FIBRINOGEN AND FACTOR VII AS RISK FACTORS FOR
CARDIOVASCULARDISEASE C.C. KELLEHER 1 MCR Epidemiology and Medical care Unit- Northwiek Park Hospital- Harrow Middlesex HA1 3UJ.
Key words: Fibrinogen - Factor VII - I H D Risk Factors
The importance of the thrombotic component of coronary heart disease is increasingly recognised, and in particular the role of the ccoagulation system in this process. The Northwick Park Heart study was the first major prospective study to identify both fibrinogen and factor VIIc as risk factors, as powerful as total cholesterol in predicting ischaemic events. Since then, a number of cpidemiological studies have confirmed the importance of fibrinogen, not just in C H D but in stroke as well. A variety of environmental factors are known to influence levels of factor VII and fibrinogen and therefore support their role in the development of coronary thrombosis. Both arc known to increase with age and body weight and are relativelyelevated in diabetes. Fibrinogen is strongly related to smoking habit and a substantial proportion of the I H D risk associated with smoking is mediated through this relationship. There is a dose response effect between number of cigarettessmoked and level of fibrinogen and an inverse relationshipwith time since cessation of the habit. Factor VII is known to correlatewith totalcholesterol level,and there is a relationshipbetween dietaryvariabilityof fatintake and factorVII, which islikelyto play an important role in the riskof CHD. The case for using either anticoagulation or anti platelet agents in secondary pevention of myocardial infarction is n o w clear, but there are stilluncertainties in primary prevention which relate to the ideal dose intensity of either aspirin or anti-coagulation and the type of patient most likely to benefit. The ongoing Thrombosis Prevention Trial identifies middle-aged males at high risk of a myocardial infarction. These are then randomised in a double blind placebo controlled factorial design to receive one of four treatments: 75 m g of aspirin and warfarin at a low intensitylevel of anticoagulation titratedto achieve an international normalised ratio of 1.5, either agent singly, or two types of placebo. The progress of this trial is discussed.
INTRODUCTION
GENERAL EPIDEMIOLOGY
The present paper will briefly review the epidemiology of the coagulation system in relation to risk o f Ischaemic Heart Disease. The important environmental determinants of Fibrinogen and Factor VII include smoking habit and diet, and some possible mechanisms of risk of thrombosis will be discussed.
The thrombotic c o m p o n e n t of coronary heart disease, and in particular the contribution to risk of the coagulation system, has been increasingly studied in recent years. The Northwick Park Heart study (NPSH) was the first prospective study to identify levels of these factors as predictors of an acute coronary event (7). This showed that fibrinogen and factor Vile measured at baseline were at least as powerful as total level of cholesterol in predicting risk.
1 Present address: Department of Health Promotion, University College Galway, Republic of Ireland. 79
Kelleher C.C.
Eur. J. Epidemiol.
Fibrinogen for instance shows an 84% increase in risk for every standard deviation increase in that variable and Factor VIIo a 62% increase. This effect was particularly marked within the first five years in the case of Factor VIIo. A number of studies have now reproduced these prospective findings for fibrinogen, not just for coronary risk, but also in the case of stroke. Among these were the work of Stone and Thorp (20) in England, The-Framingham study (5) and the Goteborg 1913 (21) cohort. The relevance of fibrinogen to risk of vascular disease from an epidemiological perspective is therefore very clear. A n important question is what environmental circumstances lead to variability of these factors and whether this is consistent with risk of cardiovascular disease. Levels of both fibrinogen and Factor VII increase with age and with body weight (8); in women both increase through use of oral contraceptives and unopposed hormone replacement therapy (10, 19) and around the time of the menopause (12). In addition diabetes mellitus is associated with raised levels (2). However, the two most important environmental influences are the relationship with smoking in the case of fibrinogen and with diet in the case of Factor VII.
exposure to cold (17). The possible importance of this mechanism in the context of vascular disease is illustrated by the fact that Factor XII is in tum activated by negatively charged fatty acids in triglyceride rich lipoprotein particles (6, 17). A recent cross-sectional study at Northwick Park has confirmed that in post infarct patients, both fibrinogen and Factor ViIc relate to the degree of atheroma found at coronary angiography. However, significant differences in Factor VIIc also exist between infarct and non infarct patients with comparable degrees of atheroma, suggesting that coagulant activity is not simply a marker for degree of atheroma (1), but is part of a more complex relationship. Having established the predictive value of these factors on an epidemiological basis and having discussed some of the likely reasons for believing that elevated levels relate to the mechanism of thrombosis, a further question is whether their sucessful modification reduces risk of a coronary thrombosis. Most of the pharmacological agents such as stanazolol which can modify fibrinogen are not a feasible option for routine therapy. There is increasing interest in the potential of lipid lowering agents to modify fibrinogen as well and recent results of the WHO Clofibrate Study (3) indicated that this effect on fibrinogen might partially explain the more marked benefit of treatment seen in smokers. Such observations certainly merit further study, though dofibrate in itself is not a suitable therapy. However, a much more familiar treatment is available with potential for use in pervention; the anticoagulant warfarin. Factor VII, as one of the major Vitamin K dependent factors, is of course reduced by warfarin therapy in a dose dependent fashion. This established anticoagulant has been re-studied in secondary prevention of myocardial infarction (15, 18), (International Anticoagulant Review Group 1970 (4), Sixty Plus Reinfarction Study Research Group 1980). It is now clear that warfarin can substantially reduce both mortality and morbidity after an ischaemic event, and indeed in some of these studies probably at levels less that conventional anticoagulation. On an epidemiological basis, such levels of less intense coagulation relate to a level of Factor VIIc of about 70%, which approximates to the level seen in population at low risk of coronary heart disease (8). There is therefore a case for using such treatment as prophylaxis in men at risk of a first heart attack. In 1984 a pilot study was initiated in the MRC General Practice Research Framework to establish the feasibility of identifying men at high risk of a heart attack who might benefit from treatment with low levels of anticoagulation (11). A screening process is undertaken by a nurse is each practice of the clinical records of all men aged 45 to 69 years. Ineligible men are first excluded by means of a note search. This comprises principally those who have already had a heart attack and those for whom warfarin or aspirin therapy would be clinically
Smoking and Plasma Fibrinogen The NPHS data also demonstrated that current smokers had markedly higher levels of fibrinogen than never smokers (9). Ex smokers had intermediate levels in proportion to the time interval since cessation of smoking, averaging levels comparable with those of non smokers after 6 years. In addition to this there is a dose response relatioship, such that every 10 cigarettes smoked per day adds 0.1g/1 to the level of flbrinogen (22). It is likely therefore that a substantial proportion of the cardiovascular risk associated with smoking habit relates to the response of plasma fibrinogen (9).
Dietary Variability and Factor VII Experimental studies in rabbits had already demonstrated the effects of variation of dietary fat intake on Factor VIIo (16). The Wembley Dietary Study (13) confirmed the correlation between cholesterol and Factor VII in human populations and also demonstrated the relationship between fat intake, as assessed by dietary inventory, and level of Factor VIIc. Factor VII combines with tissue factor and in turn goes on to activate factor X, ultimately resulting the production of thrombin (14). The sources of tissue factor in vivo include the acutely ruptured atheromatous plaque but also may result from cytokine activity on endothelial cells. In addition to this classical pathway, it is now established that VII may be directly activated by Factor XII, explaining the in vitro phenomenon of activitation of VII after 80
Coagulation o f IHD
Vol. 8, Suppl. to No. 2
coronary thrombosis - British Journal of Haematology 76 (suppl 1): 19 (Abstract)
inappropriate and amounts to about a third of the cohort. The remainder are then invited by letter to be screened. Seven variables are measured: blood pressure, body mass index, smoking history, family history of coronary disease, Factor VIIc, fibrinogen and total cholesterol. The relative contribution o f each of these is weighed using a risk score based on NPHS and the top 20% are selected to participate in the main trial. At the end of the feasibility stage it was decided to incorporate an aspirin treatment component as well, so that the final design is a double blind randomised controlled trial with factorial modification. There are 4 groups - warfarin treatmet titrated gradually to an INR (International Norrnalised Ratio) of about 1.5, in combination with aspirin 75 mg, either active agent in combination with placebo, or two types o f placebo. The aim is to follow 6000 cases for at least 5 years and the screening stage will be complete by early 1991. It is expected that those in each active cell will show a 30% reduction in ischaemic heart disease events at the end o f 5 years. This trial is likely to provide important information on the usefulness of anti-thrombotic therapy in primary prevention. In summary then, I have outlined for you the epidemiological case for the coagulation factors as predictors of risk o f ischaemic heart disease, I have summarised some of the mechanistic considerations now being studied and outlined a practical method of therapeutically modifying the coagulation system which may translate into a reduction of ischaemic heart disease events in treated men.
7. Meade T.IV., Brozovic M., Chakrabarti R.R., Haines A.P., Imeson J.D., Mellows S., Miller G.J., North W.R.S., Stirling Y and Thompson S.G. (1986): Haemostatic function and ischaemic Heart disease: Principal results of the Nortwick Park Heart Study Lancet. 2: 533-537. 8. Meade T.W. (1987): Epidemiology of Atheroma, thrombosis and ischaemic heart disease. Haemostasis and Thrombosis. Churcill Livingstone New York and London Chap. 40: 697-721. 9. Meade T. W., Imeson J. and Stirring Y(1987): Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease - The Lancet. 2: 986-988. 10. Meade T.W. (1988): Risks and mechanisms of cardiovascular events in users of oral contraceptives American Journal of Obstetrics and Gynaecology 158: 1646-1652. 11. Meade T.W., Wilkes H.C., Stirling Y., Brennan P.J., Kelleher C. and Browne W. (1988): Randomised controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study - European Heart Journal 9: 836-843. 12. Meade T.W., Dyer S., Howarth D.J., Imerson J.D. and Stifling Y. (1990): Antithrombin III and procoagulant activity: Sex differences and effects of the menopause - British Journal of Haematology 74: 7781.
REFERENCES
13. Miller G.J., Cruickshank J.K., Ellis L.J., Thompson
1. Broadhurst P., Kelleher C., Hughes L., Imerson J.D. and Raftery E.B. (1990): Fibrinogen, Factor VII clotting activity and coronary artery disease severity - Atherosclerosis 85: 169-173.
R.L., Wilkes It.C., Stirling Y., Mitropoulos K.A., Allison J.K, Fox T.E. and Walker A.O. (1989): Fat Consumption and factor VII coagulant activity in middle aged men - Atherosclerosis 78: 19-24.
2. Fuller J.H., Keen H., Jarrett R.J., Omer T., Meade T.W., Chakrabarti R., North W.R.S. and Stirling Y. (1979): Haemostatic variables associated with Diabetes and its complications - British Medical Journal 2: 964-966. 3.
14. Miller G.J., Seghatcian M.J., Walter S.J., Howarth D.J., Thompson S.G., Esnouf M.P. and Meade T.W. (1986): An association between the factor VII coagulant activity and thrombin activity induced by surface / cold exposure of normal human plasma - British Journal of Haematology 62: 379-384.
Green K.G., Heady A. and Oliver M.F. (1989): Blood pressure, cigarette smoking and heart attack in the WHO co-operative trial of clofibrate - International Journal of Epidemiology 18: 355-360.
15. Mitchell J.R.A. (1984): Anticoagulants in myocardial infarction: an appraisal of randomised clinical trials. In: Anticoagulants and myocardial infarction: A reappraisal (Meade T.W., ed) - New York: Wiley: Chap 5: 113-134.
4. International Anticoagulant Review Group (1970): Collaborative analysis of long-term anticoagulant administration after acute myocardial infarction Lancet. 1: 203-209.
16. Mitropouos K.A., Esnouf M.P. and Meade T. W. (1987): Increased Factor VII coagulant activity in the rabbit following diet induced hypercholesterolaemia Atherosclerosis 63: 43-52.
5. Kannel W.B., D'Agostino R.B. and Belanger A.J. (1987): Fibrinogen, cigarette smoking and risk of cardiovascular disease. Insights from the Framingham Study - Am. Heart. J: 1006-1010.
17. Mitropoulos K.A,, Martin J.C., Reeves B.E.A. and Esnouf M.P. (1989): The activation of the contact phase of coagulation by physiologic surfaces in plasma: The effect o f large negatively charged liposomal vesicles - Blood. 73: 1525-1533.
6. Kelleher C.C., Mitropoulos K.A., Martin J.C., Imeson J., Hughes L.O. and Meade T.W. (1990): Hageman factor in middle aged men: Its relevance to risk of 81
Kelleher C.C.
Eur. J. Epidemiol.
18. Sixty-Plus Reinfarction Study Research group. (1980): A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction - The Lancet. 2: 989-994.
- a major coronary risk factor - J.R. Coll. Gen. Pract.
35: 565-569. 21. Wilhelmsen L., Svardsudd K., Korsan-Bengtsen K., Larsson B., Welin L. and Tibblin G. (1984): Fibrinogen as a risk factor for stroke and myocardial infarction - New England Journal of Medicine 331: 501-505.
19. Stanwell-Smith R. and Meade T.W. (1984): Hormone replacement therapy for menopausal women: a review of its effect on haemostatic function, lipids and blood pressure - Adv. Drug. React. AC. Pois. Rev. 4: 187-210.
22. Wilkes H.C., Kelleher C. and Meade T.W. (1988): Smoking and Plasma Fibrinogen - The Lancet. 2: 307-308.
20. Stone M.C. and Thorp J.M. (1985): Plasma Fibrinogen
82
Vol. 8, Suppl. to No. 2
EUROPEAN
JOURNAL
Ov
EPIDEMIOLOGY
PLASMA FIBRINOGEN AND FACTOR VII AS RISK FACTORS FOR
CARDIOVASCULARDISEASE C.C. KELLEHER 1 MCR Epidemiology and Medical care Unit- Northwiek Park Hospital- Harrow Middlesex HA1 3UJ.
Key words: Fibrinogen - Factor VII - I H D Risk Factors
The importance of the thrombotic component of coronary heart disease is increasingly recognised, and in particular the role of the ccoagulation system in this process. The Northwick Park Heart study was the first major prospective study to identify both fibrinogen and factor VIIc as risk factors, as powerful as total cholesterol in predicting ischaemic events. Since then, a number of cpidemiological studies have confirmed the importance of fibrinogen, not just in C H D but in stroke as well. A variety of environmental factors are known to influence levels of factor VII and fibrinogen and therefore support their role in the development of coronary thrombosis. Both arc known to increase with age and body weight and are relativelyelevated in diabetes. Fibrinogen is strongly related to smoking habit and a substantial proportion of the I H D risk associated with smoking is mediated through this relationship. There is a dose response effect between number of cigarettessmoked and level of fibrinogen and an inverse relationshipwith time since cessation of the habit. Factor VII is known to correlatewith totalcholesterol level,and there is a relationshipbetween dietaryvariabilityof fatintake and factorVII, which islikelyto play an important role in the riskof CHD. The case for using either anticoagulation or anti platelet agents in secondary pevention of myocardial infarction is n o w clear, but there are stilluncertainties in primary prevention which relate to the ideal dose intensity of either aspirin or anti-coagulation and the type of patient most likely to benefit. The ongoing Thrombosis Prevention Trial identifies middle-aged males at high risk of a myocardial infarction. These are then randomised in a double blind placebo controlled factorial design to receive one of four treatments: 75 m g of aspirin and warfarin at a low intensitylevel of anticoagulation titratedto achieve an international normalised ratio of 1.5, either agent singly, or two types of placebo. The progress of this trial is discussed.
INTRODUCTION
GENERAL EPIDEMIOLOGY
The present paper will briefly review the epidemiology of the coagulation system in relation to risk o f Ischaemic Heart Disease. The important environmental determinants of Fibrinogen and Factor VII include smoking habit and diet, and some possible mechanisms of risk of thrombosis will be discussed.
The thrombotic c o m p o n e n t of coronary heart disease, and in particular the contribution to risk of the coagulation system, has been increasingly studied in recent years. The Northwick Park Heart study (NPSH) was the first prospective study to identify levels of these factors as predictors of an acute coronary event (7). This showed that fibrinogen and factor Vile measured at baseline were at least as powerful as total level of cholesterol in predicting risk.
1 Present address: Department of Health Promotion, University College Galway, Republic of Ireland. 79
Kelleher C.C.
Eur. J. Epidemiol.
Fibrinogen for instance shows an 84% increase in risk for every standard deviation increase in that variable and Factor VIIo a 62% increase. This effect was particularly marked within the first five years in the case of Factor VIIo. A number of studies have now reproduced these prospective findings for fibrinogen, not just for coronary risk, but also in the case of stroke. Among these were the work of Stone and Thorp (20) in England, The-Framingham study (5) and the Goteborg 1913 (21) cohort. The relevance of fibrinogen to risk of vascular disease from an epidemiological perspective is therefore very clear. A n important question is what environmental circumstances lead to variability of these factors and whether this is consistent with risk of cardiovascular disease. Levels of both fibrinogen and Factor VII increase with age and with body weight (8); in women both increase through use of oral contraceptives and unopposed hormone replacement therapy (10, 19) and around the time of the menopause (12). In addition diabetes mellitus is associated with raised levels (2). However, the two most important environmental influences are the relationship with smoking in the case of fibrinogen and with diet in the case of Factor VII.
exposure to cold (17). The possible importance of this mechanism in the context of vascular disease is illustrated by the fact that Factor XII is in tum activated by negatively charged fatty acids in triglyceride rich lipoprotein particles (6, 17). A recent cross-sectional study at Northwick Park has confirmed that in post infarct patients, both fibrinogen and Factor ViIc relate to the degree of atheroma found at coronary angiography. However, significant differences in Factor VIIc also exist between infarct and non infarct patients with comparable degrees of atheroma, suggesting that coagulant activity is not simply a marker for degree of atheroma (1), but is part of a more complex relationship. Having established the predictive value of these factors on an epidemiological basis and having discussed some of the likely reasons for believing that elevated levels relate to the mechanism of thrombosis, a further question is whether their sucessful modification reduces risk of a coronary thrombosis. Most of the pharmacological agents such as stanazolol which can modify fibrinogen are not a feasible option for routine therapy. There is increasing interest in the potential of lipid lowering agents to modify fibrinogen as well and recent results of the WHO Clofibrate Study (3) indicated that this effect on fibrinogen might partially explain the more marked benefit of treatment seen in smokers. Such observations certainly merit further study, though dofibrate in itself is not a suitable therapy. However, a much more familiar treatment is available with potential for use in pervention; the anticoagulant warfarin. Factor VII, as one of the major Vitamin K dependent factors, is of course reduced by warfarin therapy in a dose dependent fashion. This established anticoagulant has been re-studied in secondary prevention of myocardial infarction (15, 18), (International Anticoagulant Review Group 1970 (4), Sixty Plus Reinfarction Study Research Group 1980). It is now clear that warfarin can substantially reduce both mortality and morbidity after an ischaemic event, and indeed in some of these studies probably at levels less that conventional anticoagulation. On an epidemiological basis, such levels of less intense coagulation relate to a level of Factor VIIc of about 70%, which approximates to the level seen in population at low risk of coronary heart disease (8). There is therefore a case for using such treatment as prophylaxis in men at risk of a first heart attack. In 1984 a pilot study was initiated in the MRC General Practice Research Framework to establish the feasibility of identifying men at high risk of a heart attack who might benefit from treatment with low levels of anticoagulation (11). A screening process is undertaken by a nurse is each practice of the clinical records of all men aged 45 to 69 years. Ineligible men are first excluded by means of a note search. This comprises principally those who have already had a heart attack and those for whom warfarin or aspirin therapy would be clinically
Smoking and Plasma Fibrinogen The NPHS data also demonstrated that current smokers had markedly higher levels of fibrinogen than never smokers (9). Ex smokers had intermediate levels in proportion to the time interval since cessation of smoking, averaging levels comparable with those of non smokers after 6 years. In addition to this there is a dose response relatioship, such that every 10 cigarettes smoked per day adds 0.1g/1 to the level of flbrinogen (22). It is likely therefore that a substantial proportion of the cardiovascular risk associated with smoking habit relates to the response of plasma fibrinogen (9).
Dietary Variability and Factor VII Experimental studies in rabbits had already demonstrated the effects of variation of dietary fat intake on Factor VIIo (16). The Wembley Dietary Study (13) confirmed the correlation between cholesterol and Factor VII in human populations and also demonstrated the relationship between fat intake, as assessed by dietary inventory, and level of Factor VIIc. Factor VII combines with tissue factor and in turn goes on to activate factor X, ultimately resulting the production of thrombin (14). The sources of tissue factor in vivo include the acutely ruptured atheromatous plaque but also may result from cytokine activity on endothelial cells. In addition to this classical pathway, it is now established that VII may be directly activated by Factor XII, explaining the in vitro phenomenon of activitation of VII after 80
Coagulation o f IHD
Vol. 8, Suppl. to No. 2
coronary thrombosis - British Journal of Haematology 76 (suppl 1): 19 (Abstract)
inappropriate and amounts to about a third of the cohort. The remainder are then invited by letter to be screened. Seven variables are measured: blood pressure, body mass index, smoking history, family history of coronary disease, Factor VIIc, fibrinogen and total cholesterol. The relative contribution o f each of these is weighed using a risk score based on NPHS and the top 20% are selected to participate in the main trial. At the end of the feasibility stage it was decided to incorporate an aspirin treatment component as well, so that the final design is a double blind randomised controlled trial with factorial modification. There are 4 groups - warfarin treatmet titrated gradually to an INR (International Norrnalised Ratio) of about 1.5, in combination with aspirin 75 mg, either active agent in combination with placebo, or two types o f placebo. The aim is to follow 6000 cases for at least 5 years and the screening stage will be complete by early 1991. It is expected that those in each active cell will show a 30% reduction in ischaemic heart disease events at the end o f 5 years. This trial is likely to provide important information on the usefulness of anti-thrombotic therapy in primary prevention. In summary then, I have outlined for you the epidemiological case for the coagulation factors as predictors of risk o f ischaemic heart disease, I have summarised some of the mechanistic considerations now being studied and outlined a practical method of therapeutically modifying the coagulation system which may translate into a reduction of ischaemic heart disease events in treated men.
7. Meade T.IV., Brozovic M., Chakrabarti R.R., Haines A.P., Imeson J.D., Mellows S., Miller G.J., North W.R.S., Stirling Y and Thompson S.G. (1986): Haemostatic function and ischaemic Heart disease: Principal results of the Nortwick Park Heart Study Lancet. 2: 533-537. 8. Meade T.W. (1987): Epidemiology of Atheroma, thrombosis and ischaemic heart disease. Haemostasis and Thrombosis. Churcill Livingstone New York and London Chap. 40: 697-721. 9. Meade T. W., Imeson J. and Stirring Y(1987): Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease - The Lancet. 2: 986-988. 10. Meade T.W. (1988): Risks and mechanisms of cardiovascular events in users of oral contraceptives American Journal of Obstetrics and Gynaecology 158: 1646-1652. 11. Meade T.W., Wilkes H.C., Stirling Y., Brennan P.J., Kelleher C. and Browne W. (1988): Randomised controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study - European Heart Journal 9: 836-843. 12. Meade T.W., Dyer S., Howarth D.J., Imerson J.D. and Stifling Y. (1990): Antithrombin III and procoagulant activity: Sex differences and effects of the menopause - British Journal of Haematology 74: 7781.
REFERENCES
13. Miller G.J., Cruickshank J.K., Ellis L.J., Thompson
1. Broadhurst P., Kelleher C., Hughes L., Imerson J.D. and Raftery E.B. (1990): Fibrinogen, Factor VII clotting activity and coronary artery disease severity - Atherosclerosis 85: 169-173.
R.L., Wilkes It.C., Stirling Y., Mitropoulos K.A., Allison J.K, Fox T.E. and Walker A.O. (1989): Fat Consumption and factor VII coagulant activity in middle aged men - Atherosclerosis 78: 19-24.
2. Fuller J.H., Keen H., Jarrett R.J., Omer T., Meade T.W., Chakrabarti R., North W.R.S. and Stirling Y. (1979): Haemostatic variables associated with Diabetes and its complications - British Medical Journal 2: 964-966. 3.
14. Miller G.J., Seghatcian M.J., Walter S.J., Howarth D.J., Thompson S.G., Esnouf M.P. and Meade T.W. (1986): An association between the factor VII coagulant activity and thrombin activity induced by surface / cold exposure of normal human plasma - British Journal of Haematology 62: 379-384.
Green K.G., Heady A. and Oliver M.F. (1989): Blood pressure, cigarette smoking and heart attack in the WHO co-operative trial of clofibrate - International Journal of Epidemiology 18: 355-360.
15. Mitchell J.R.A. (1984): Anticoagulants in myocardial infarction: an appraisal of randomised clinical trials. In: Anticoagulants and myocardial infarction: A reappraisal (Meade T.W., ed) - New York: Wiley: Chap 5: 113-134.
4. International Anticoagulant Review Group (1970): Collaborative analysis of long-term anticoagulant administration after acute myocardial infarction Lancet. 1: 203-209.
16. Mitropouos K.A., Esnouf M.P. and Meade T. W. (1987): Increased Factor VII coagulant activity in the rabbit following diet induced hypercholesterolaemia Atherosclerosis 63: 43-52.
5. Kannel W.B., D'Agostino R.B. and Belanger A.J. (1987): Fibrinogen, cigarette smoking and risk of cardiovascular disease. Insights from the Framingham Study - Am. Heart. J: 1006-1010.
17. Mitropoulos K.A,, Martin J.C., Reeves B.E.A. and Esnouf M.P. (1989): The activation of the contact phase of coagulation by physiologic surfaces in plasma: The effect o f large negatively charged liposomal vesicles - Blood. 73: 1525-1533.
6. Kelleher C.C., Mitropoulos K.A., Martin J.C., Imeson J., Hughes L.O. and Meade T.W. (1990): Hageman factor in middle aged men: Its relevance to risk of 81
Kelleher C.C.
Eur. J. Epidemiol.
18. Sixty-Plus Reinfarction Study Research group. (1980): A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction - The Lancet. 2: 989-994.
- a major coronary risk factor - J.R. Coll. Gen. Pract.
35: 565-569. 21. Wilhelmsen L., Svardsudd K., Korsan-Bengtsen K., Larsson B., Welin L. and Tibblin G. (1984): Fibrinogen as a risk factor for stroke and myocardial infarction - New England Journal of Medicine 331: 501-505.
19. Stanwell-Smith R. and Meade T.W. (1984): Hormone replacement therapy for menopausal women: a review of its effect on haemostatic function, lipids and blood pressure - Adv. Drug. React. AC. Pois. Rev. 4: 187-210.
22. Wilkes H.C., Kelleher C. and Meade T.W. (1988): Smoking and Plasma Fibrinogen - The Lancet. 2: 307-308.
20. Stone M.C. and Thorp J.M. (1985): Plasma Fibrinogen
82
