R. Chakrabarti

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.

CHANGES IN HÆMOSTATIC SYSTEM AFTER APPLICATION OF A TOURNIQUET

In 35 patients undergoing routine orthopaedic operations in which occlusive tourniquets were used there was a pronounced rise in fibrinolytic activity in the systemic circulation which lasted for at least 15 minutes after the release of the tourniquet; this response was seen after operations on both arms and legs. In contrast there was no increase in fibrinolytic activity in the systemic circulation associated with venous occlusion. Neither the application of a tourniquet nor venous occlusion resulted in changes in factors V or VIII, fibrinogen, or platelet-count. The application of a completely occlusive tourniquet might be a simple form of prophylaxis against deep-vein thrombosis and would avoid the disadvantages of using heparin.

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.

Haemostatic changes following surgery.

Changes in factors V, VII and VIII and in fibrinogen were studied in 32 patients undergoing major abdominal surgery. Mean levels of factors V and VII were similar to population-based values preoperatively. Factor V fell following elective surgery and then rose above the mean pre-operative level before returning to it by the tenth post-operative day. Factor VII fell following both elective and emergency surgery and tended to remain depressed throughout the post-operative period. Pre-operative values of factor VIII and fibrinogen were higher than population-based values and higher in the emergency than in waiting-list patients. Both factor VIII and fibrinogen rose following elective surgery but no statistically significant change was seen following emergency surgery. The uncomplicated conditions leading to elective surgery, the acute complications leading to emergency surgery, and surgery itself may each have contributed to increases in factor VIII and fibrinogen levels, whereas the fall in factors V and VII was largely related to surgery itself. The findings may help in the interpretation of associations between clotting factors and thrombotic disease, particularly in the case of factor VII.