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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.

Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations.

As part of a study to determine the extent to which the haemostatic system is implicated in the onset of clinically manifest ischaemic heart disease, characteristics influencing fibrinolytic activity (FA) and plasma fibrinogen concentrations were examined in 1601 men aged 18-64 and 707 women aged 18-59 in several occupational groups in North-west London. In men FA noticeably decreased till the age of about 58, when there was a small rise. In women a small increase in FA between 18 and about 40 was followed by a slightly larger fall between 40 and 59. There was a pronounced negative association of FA with obesity. FA was significantly less in smokers than non-smokers, though the effect was not large. FA increased with alcohol consumption. FA in men appeared to be greatest in the lower social classes, and men on night shift had poorer FA than those on day work. FA was greater in women using oral contraceptives than in those not using these preparations. In both sexes FA increased with exercise, but there were no associations between any of the characteristics studied and the increase. Plasma fibrinogen concentrations increase with age and obesity, are higher in smokers than non-smokers, and fall with alcohol consumption. In women the concentrations are higher in those using oral contraceptives. The general epidemiology of FA and plasma fibrinogen concentrations suggests that they may well be implicated in the pathogenesis of ischaemic heart 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.

Factor VII in an Industrial Population

Factor‐VII levels were measured in members of an industrial population participating in a long‐term prospective study of arterial disease. A modified semi‐automated method with an artificially prepared factor‐VII deficient plasma, one batch of freeze‐dried thromboplastin and one freeze‐dried pooled reference plasma was used throughout. All calculations were carried out on a programmable desk calculator.

An epidemiological study of the haemostatic and other effects of oral contraceptives.

Summary. Factors V, VII and VIII (each determined by biological assay), fibrinogen, platelet count and adhesiveness, and fibrinolytic activity were measured in 234 white pre‐menopausal women, of whom 57 (24%) were on oral contraceptives and 177 (76%) were not. Cholesterol, triglyceride and blood pressure levels were also recorded. In 20 of the women on oral contraceptives, and in an age‐matched group of 20 who were not, prothrombin, factor X, antithrombin III and α2‐macroglobulin levels were determined, and factors VII and VIII were also measured immunologically. For the majority of the variables studied, the differences between those using and not using oral contraceptives were greater in younger than older women; in the case of factor VII (biological assay) and fibrinogen, the differences between the regression slopes on age were statistically significant, and mean values were substantially higher in those on oral contraceptives. There was also a significant difference between regression slopes on age for cholesterol. Mean levels of prothrombin, factors VII (immunological assay) and X, triglycerides and blood pressure were significantly higher, and mean levels of antithrombin III significantly lower, in those on oral contraceptives compared with those not. Overall, fibrinolytic activity was significantly higher in the women on oral contraceptives; this difference was, however, almost entirely due to the greatly increased fibrinolytic activity of the non‐smokers on oral contraceptives, activity in the smokers on oral contraceptives being similar to that of the women not on these preparations. There were no significant differences in mean platelet count or adhesiveness, or in haemoglobin, packed cell volume, uric acid and blood sugar levels. Among the women on oral contraceptives, there was a significant negative correlation between factor VIII and fibrinolytic activity; this was largely due to five women all of blood groups A and B, in whom, besides high factor‐VIII levels and poor fibrinolytic activity, other variables (e.g. fibrinogen) were raised in a direction that might be expected to favour thrombogenesis. It is possible that it is those women whose fibrinolytic activity does not increase in order to compensate for the effects of oral contraceptives on clotting factors, lipids and blood pressure, who are at special risk of thromboembolic episodes. The differential effects of oral contraceptives by age must be borne in mind in evaluating the effects of these preparations on the haemostatic and lipid systems.

Mean cell volume in a working population: the effects of age, smoking, alcohol and oral contraception.

Summary. The effects on mean cell volume (MCV) of age, smoking habit, alcohol consumption, menopausal status, and use of oral contraceptives have been studied as appropriate in 1596 white men and 892 white women in working populations in North‐West London. In men, increasing age, smoking and alcohol consumption each make an independent contribution to MCV. In women, the effect of smoking is similar to that in men; the effect of alcohol is less obvious, possibly because of the low stated alcohol intake in women. The effect of alcohol on MCV in the population studied is not as marked as in hospital patients who admit to excessive alcohol consumption; this may partly be due to differences in methods of eliciting intake. There is a small increase in MCV following the menopause. Women on oral contraceptives show a rise in MCV with increasing age; this is not seen in women not on oral contraceptives. There is a strong inverse association between MCV and red blood cell count, which may be part of a mechanism to ensure constant oxygen carrying capacity.

Haemostatic variables in vegetarians and non-vegetarians

Abstract Factors V, VII, VIII, fibrinogen, fibrinolytic activity and antithrombin III (immunological and biological), as well as blood lipids and blood pressure have been measured in 50 vegetarians, and compared with 282 participants in a prospective study of ischaemic heart disease. Mean levels of factor VII, cholesterol and diastolic blood pressure were lower in vegetarians of both sexes than in the comparison group. Factors II and X were measured in 25 of the male vegetarians and 25 age matched participants; the mean level of factor II was lower in the male vegetarians. These observations are consistent with the hypothesis that lower levels of certain coagulation factors are associated with a reduced incidence of IHD. However, fibrinolytic activity and antithrombin III (immunological) levels were also lower in male vegetarians. One explanation for these apparently paradoxical findings may be that those at low risk of IHD have a correspondingly low requirement for protective, antithrombotic mechanisms.

Factor V in an industrial population.

Summary. Factor‐V levels have been measured in a random sample of 626 men and 307 women working in a variety of occupations in North West London. The method is an automated one‐stage assay using the same batch of freeze‐dried thromboplastin, all results being expressed in terms of the same freeze‐dried standard plasma; it has been shown that only one dilution of test plasma is necessary. Factor‐V levels are significantly higher when venepuncture is difficult than when it is satisfactory, the mean levels being about 130% and 117% respectively. Factor‐V levels are approximately normally distributed; they are similar in men and women and in blacks and whites, and increase significantly with age at the rate of about 0.6% per annum. Factor‐V levels are not affected by oral contraceptives or the menopause, and there are no differences according to blood group or secretor status.