T.W. Meade

Haemostatic function and ischaemic heart disease: principal results of the Northwick Park heart study

The Northwick Park Heart Study (NPHS) has investigated the thrombotic component of ischaemic heart disease (IHD) by the inclusion of measures of haemostatic function. Among 1511 white men aged between 40 and 64 at the time of recruitment, 109 subsequently experienced first major events of IHD. High levels of factor VII coagulant activity and of plasma fibrinogen were associated with increased risk, especially for events occurring within 5 years of recruitment. These associations seemed to be stronger than for cholesterol, elevations of one standard deviation in factor VII activity, fibrinogen, and cholesterol being associated with increases in the risk of an episode of IHD within 5 years of 62%, 84%, and 43% respectively. Multiple regression analyses indicated independent associations between each of the clotting factor measures and IHD but not between the blood cholesterol level and IHD incidence. The risk of IHD in those with high fibrinogen levels was greater in younger than in older men. Much of the association between smoking and IHD may be mediated through the plasma fibrinogen level. The biochemical disturbance leading to IHD may lie at least as much in the coagulation system as in the metabolism of cholesterol.

HÆMOSTATIC FUNCTION AND CARDIOVASCULAR DEATH: EARLY RESULTS OF A PROSPECTIVE STUDY

Abstract Components of the haemostatic system which may be involved in the pathogenesis of ischaemic heart disease (IHD) were measured in the Northwick Park Heart Study. Of 1510 white men aged 40-64 at recruitment, 49 have since died. 27 died from cardiovascular disease (IHD in all but 3), 18 from cancer, and 4 from other causes. The mean recruitment levels of factor VIIc, factor VIIIc, and fibrinogen were significantly higher in those who died of cardiovascular disease than in those who survived. The independent associations of factor VIIc and fibrinogen with cardiovascular death were at least as strong as the association of blood cholesterol with cardiovascular death. A clustering of two or three high clotting-factor values (factor VIIc, factor VIIIc, and fibrinogen) was present at recruitment in 63% of those who died of cardiovascular disease, compared with 23% of those who survived. The clotting-factor results appeared to be specific for cardio- vascular disease: there was no evidence that high levels of factor VIIc, factor VIIIc, and fibrinogen were associated with death from cancer. The general epidemiology of fac- tor VIIc, factor VIIIc, and fibrinogen is consistent with their having a role in the pathogenesis of IHD.

EFFECTS OF CHANGES IN SMOKING AND OTHER CHARACTERISTICS ON CLOTTING FACTORS AND THE RISK OF ISCHAEMIC HEART DISEASE

The Northwick Park Heart Study (NPHS) has demonstrated associations of high levels of factor VII coagulant activity (VIIc) and of plasma fibrinogen concentration with the risk of subsequent ischaemic heart disease (IHD). In cross-sectional data from the 2023 white men in NPHS, lifetime duration of smoking was a determinant of initial plasma fibrinogen levels. Fibrinogen levels had apparently begun to fall soon after smoking was discontinued but it was over 5 years before they had returned to levels found in life-long non-smokers. In prospective data, smoking cessation and the adoption or resumption of smoking were associated with a decrease or an increase, respectively, of about 0.15 g/l in plasma fibrinogen. These changes would lower or raise the risk of IHD by about 20%. A switch from cigarettes to cigars was associated with a large increase in fibrinogen. A substantial part of the relation between smoking and IHD appears to be mediated through the fibrinogen concentration. Following changes in body mass, VIIc rose in those who had given up smoking and fell in those who resumed.

FÆCAL BILE-ACIDS AND CLOSTRIDIA IN PATIENTS WITH CANCER OF THE LARGE BOWEL

Of 44 patients with cancer of the large bowel, 36 ( 82%) had high faecal bile-acid concentrations compared with only 15 (17%) out of 90 patients with other diseases. 31 (70%) of the 44 patients with large-bowel cancer had high faecal bile-acid concentrations in the presence of faecal clostridia able to dehydrogenate the bile-acid nucleus, compared with only 8 (9%) out of 90 patients with other diseases. Thes findings support the hypothesis that cancer of the large bowel is caused by high concentrations of bile-acid derivatives produced by certain anaerobic bacteria.

ROLE OF GENETIC VARIATION AT THE FIBRINOGEN LOCUS IN DETERMINATION OF PLASMA FIBRINOGEN CONCENTRATIONS

Three restriction fragment length polymorphisms (RFLPs) of the fibrinogen genes were used in 91 individuals to investigate the role of genetic variation at this locus in the determination of plasma fibrinogen. The strongest association was with a polymorphism detected with the beta-fibrinogen probe and the enzyme BclI. The probe detects two alleles, designated B1 and B2. The individuals with the genotype B1B1 had a mean fibrinogen of 2.74 g/l; those with B2B2 had a mean fibrinogen of 3.69 g/l (a level previously associated with a strongly increased risk of ischaemic heart disease); and those heterozygous for the two alleles, with the genotype B1B2, had a mean of 2.98 g/l. Genetic variation at the fibrinogen gene locus accounted for 15% of the total phenotypic variance in fibrinogen.

Antithrombin III and procoagulant activity: sex differences and effects of the menopause

Among participants in the Northwick Park Heart Study, antithrombin III activity was lower in pre‐menopausal women than in men of the same age. In the women, however, the menopause was associated with a significant increase in antithrombin III, mean levels in these older women then exceeding levels in men of the same age. The occurrence of the menopause was also accompanied by large increases in factor VII coagulant activity, VIIc, and in plasma fibrinogen, these increases being greater in those experiencing a natural menopause than in those whose menopause was artificial. Sex differences in antithrombin III may form part of the explanation for the observed differences between men and women in their experience of ischaemic heart disease (IHD) and also for the contrasting effects of oral contraceptives and of hormone replacement therapy on the risk of thromboembolic disease.

HÆMOSTATIC, LIPID, AND BLOOD-PRESSURE PROFILES OF WOMEN ON ORAL CONTRACEPTIVES CONTAINING 50 µg OR 30 µg ŒSTROGEN

Abstract In 15 women on oral contraceptives containing 30 μg œstrogen, mean values for factors II, VII, and x, fibrinogen, fibrinolytic activity, antithrombin III, cholesterol, and fasting triglycerides were intermediate between values for 63 women on preparations containing 50 μg œstrogen and those for 243 premenopausal women not on oral contraceptives. Mean blood-pressure levels, however, were higher in women on 30 μg than in those on 50 μg preparations. In 28 women on 50 μg preparations containing 3 mg or 4 mg norethisterone, mean values of factor VII, fibrinogen, fibrinolytic activity, cholesterol, fasting triglycerides, and systolic blood-pressure were higher than in 15 women whose preparations contained only 1 mg of norethisterone. A less consistent picture was found in women on 30 μg œstrogen preparations containing either 250 μg (10 women) or 150 μg (5 women) d -norgestrel. It is concluded that 30 μg œstrogen preparations probably result in smaller haemostatic and lipid changes than 50 μg preparations but that they may have a blood-pressure-raising effect attributable to the particular progestagen, d -norgestrel, used in 30 μg preparations. The safety of these 30 μg œstrogen preparations may thus depend partly on the balance between these two sets of effects. It is also concluded that norethisterone may have effects similar to those attributed to œstrogens.

The effect of physiological levels of fibrinogen on platelet aggregation.

Results from the Northwick Park Heart Study (NPHS) suggest that physiological levels of plasma fibrinogen may influence platelet aggregability. This possibility has been further studied by the addition of purified fibrinogen to the blood of 17 study participants with low plasma fibrinogen levels. The results, which were highly consistent between different individuals, showed that fibrinogen increases aggregability as measured by the ADP ED50, the dose of adenosine diphosphate at which aggregation proceeds at half its maximum velocity. However, an increasing plasma fibrinogen level was associated with decreasing aggregability measured by another parameter, the ADP EMR (estimated maximum response). Although the balance of evidence is that the plasma fibrinogen level enhances aggregability, these conflicting results emphasize the limitation of any simple concept of platelet aggregability.

Antithrombin III and arterial disease.

Cross-sectional studies suggest that both low and high antithrombin III levels are associated with the risk of arterial disease, principally ischaemic heart disease (IHD). The prospective relation between antithrombin III and subsequent death from arterial disease has been investigated in 893 men in the Northwick Park Heart Study. Antithrombin III levels were directly correlated with high rather than low levels of factor VII activity and of plasma fibrinogen. There were more deaths from arterial disease in the low and high thirds of the antithrombin III distribution than in the middle third.

An association between the factor VII coagulant activity and thrombin activity induced by surface/cold exposure of normal human plasma

Summary. To test whether factor VII activation correlated with the generation of thrombin activity when plasma was exposed to a glass surface and reduced temperature, an association was sought between the changes in factor VII clotting activity (VIIc) and fibrinopeptide A concentration (an index of thrombin activity) in platelet‐poor citrated plasma from 42 healthy adults. The Spearman rank correlation (rs) between responses was 0.82 (P < 0.001). The VIIc assay response to surface/cold exposure was unaffected when thrombin was suppressed by hirudin. An assay for factor VII activity based upon its activation of tritiated factor X revealed an association between the increase in fibrinopeptide A concentration and reduction in functional factor VII concentration during activation of a subset of 22 plasma samples (rs= ‐0.62; (P < 0.003). This loss of functional factor VII was probably due to conversion of active factor VII to its non‐functional end‐product by factor Xa. The results suggest that VIIc is an index of flux within the coagulation system and support the hypothesis that a high VIIc is an indicator of a hypercoagulable state.