Methods and Results. The two studies have a common core protocol and are based on a combined cohort of 4,860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell; 251 major IHD events had occurred. Age-adjusted relative odds of IHD for men in the top 20% of the distribution compared with the bottom 20% were 4.1 (95% confidence interval, 2.6-6.5) for fibrinogen, 4.5 (95% confidence interval, 2.8-7.4) for viscosity, and 3.2 (95% confidence interval, 2.0-4.9) for white blood cell count. Associations with IHD were similar in men who had never smoked, exsmokers, and current smokers, and the results suggest that at least part of the effect of smoking on IHD is mediated through fibrinogen, viscosity, and white blood cell count.Multivariate analysis shows that white blood cell count is an independent risk factor for IHD as is either fibrinogen or viscosity, or possibly both. Jointly, these three variables significantly improve the fit of a logistic regression model containing all the main conventional risk factors. Further, a model including age, smoking habits, fibrinogen, viscosity, and white blood cell count predicts IHD as well as one in which the three hemostatic/rheological variables are replaced by total cholesterol, diastolic pressure, and body mass index.Conclusion. Jointly, fibrinogen, viscosity, and white blood cell count are important risk factors for IHD. (Circulation 1991;83:836-844) N mumerous epidemiological studies1'2 have found raised blood pressure, elevated total cholesterol, and smoking to be major factors associated with an increased risk of ischemic heart disease (IHD). Nevertheless, on an individual basis, the prediction of the risk of IHD from levels of blood pressure, lipids, and smoking is poor.3 There is evidence4,5 that occlusive thrombi are to be found in almost all cases of acute myocardial infarction and in

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The Caerphilly Collaborative Heart Disease Study is based on a large cohort of men (2,398) aged 49-66 years at the time of study. Platelet aggregation induced by collagen, thrombin, and ADP was measured in fasting blood samples and was related to prevalent angina, past myocardial infarction, and electrocardiographic evidence of ischemic heart disease. A number of subjects had taken aspirin, other nonsteroidal anti-inflammatory drugs, or other drugs affecting platelet aggregation 7 days before blood sample collection; after the exclusion of these subjects, data were available for 1,811 men. No relations were demonstrated with angina, but significant relations were shown between past myocardial infarctions and electrocardiographic evidence of ischemia and ADP-induced aggregation (both primary and secondary) and between electrocardiographic evidence of ischemia and thrombin-induced aggregation. The strongest relation indicated more than a twofold increase in the odds of a past myocardial infarction in subjects of the highest fifth of ADP-induced primary platelet aggregation compared with the lowest fifth. No significant relations were detected with collagen-induced aggregation. Accounting for a number of possible confounding factors had a relatively small impact on the relations between platelet aggregation and ischemic heart disease. Other evidence, including the well-established effect of aspirin on reducing the incidence of ischemic heart disease, indicates that the relations we describe are unlikely to be simply an effect of IHD on platelets.

SYNOPSIS Platelets in native blood adhere spontaneously to glass independently of temperature: if adenosine diphosphate is added to the blood the adhesiveness of the platelets is increased and this effect is largely independent of temperature. The mono-and triphosphates decrease adhesiveness at 20°C. and 37°C. but have no effect at 0°C.; cocaine inhibits adhesion at 37°C. and at 0°C.Aggregation and viscous metamorphosis of platelets in native plasma is induced at 37°C. by adenosine diphosphate or by thrombin; these reactions do not occur at 0°C. Cocaine and all the other anti-adhesive drugs inhibit thrombin or adenosine diphosphate-induced aggregation. The mono-and tri-phosphates appear to compete with adenosine diphosphate and inhibit aggregation; they also inhibit thrombin-induced aggregation. Aggregation induced by adenosine diphosphate or thrombin is not prevented by any of the usual enzyme inhibitors or uncoupling agents at the appropriate strength. At 37°C. aggregation and viscous metamorphosis induced by adenosine diphosphate or thrombin are reversible, and the addition of more adenosine diphosphate or of thrombin again produces aggregation and viscous metamorphosis.Platelets incubated with adenosine diphosphate but not agitated lose their power to aggregate but when more adenosine diphosphate is added with agitation, then aggregation is again produced. These observations are presumably explained by the finding that intact platelets, but not fragmented platelets, can inactivate adenosine diphosphate. From these results it is tentatively concluded that adhesion may involve intrinsic adenosine diphosphate in the platelet which may be activated by thrombin and inhibited by the added mono-or triphosphate. The anti-adhesive drugs act in a different manner. These phenomena have a remarkable similarity to those concerning mitochondrial swelling.It is not known why a platelet sticks, but Hellem (1960) reported that a factor R isolated from red cells caused platelets to stick to glass; 0llgaard (1961) also studied a non-protein extract from platelets and red cells that caused platelet aggregation. Gaarder, Jonsen, Laland, Hellem, and Owren (1961) showed that their factor is adenosine diphosphate, that it is highly specific, and that it induces platelet aggregation in citrated platelet-rich plasma. O'Brien (1961) showed that the adhesion of native platelets to glass and to damaged cells in vitro and in vivo was inhibited by many anti-malarial, anti-histaminic and local anaesthetic and some other drugs which will be called the 'anti-adhesive' drugs. These findings stimulated the present study of the Received for publication 5 February 1962. effects of adenosine diphosphate and thrombin on platelet adhesiveness to glass and on platelet aggregation and viscous metamorphosis. The effect of the anti-adhesive drugs and adenosine monophosphate and the triphosphate and enzyme inhibitors were also studied in an attempt to understand the processes involved in adhesion, aggregation, and viscous metamorphosis.

Objective-To examine the associations between air temperature and risk factors for ischaemic heart disease. Method-Data on risk factors are available from up to 2036 men in the Caerphilly Prospective Heart Disease Study. Daily temperatures were obtained from the Meteorological Office. Relations between these were examined by regression. Results-The coldest month of the year has a mean temperature that is 16°C lower than that in the warmest month. A fall in temperature of this magnitude is associated with higher blood pressures (by 3-5 mm Hg) and a lower concentration of high density lipoprotein cholesterol (by 0-08 mmolRl). The most important effects however, seem to be on the haemostatic system. Fibrinogen is 0*34 gil higher in the coldest month than in the warmest (p < 0.001) and a, macroglobulin, a protein that inhibits fibrinolysis, is also raised. Platelet count is increased by 30%!. of a standard deviation and the sensitivity of platelets in whole blood to adenosine diphosphate is increased by cold. Conclusions-These effects on haemostasis, together with the effect on blood pressure, could explain a large part of the increase in ischaemic heart disease in the winter but are unlikely to explain much of the difference in mortality within different areas of England and Wales. (Br Heart3J 1993;70:520-523) Deaths from ischaemic heart disease and admissions to hospital for both myocardial infarction and pulmonary embolus are considerably higher in winter than the summer.l1 The meteorological factor of greatest importance seems to be temperature.25 West and Lowe have further suggested that the between town variation in the mortality of ischaemic heart disease in England and Wales may be a consequence of differences in environmental temperatures.6 The extent to which the seasonal rise in ischaemic heart disease and related mortality is truly cardiovascular is uncertain. Some have suggested that the effect of temperature is on respiratory disease and the apparent excess in cardiovascular deaths in winter is simply due to miscoding of the cause of death.7 Bainton et al showed that the proportionate increase in deaths was similar in both young and old patients, leading them to conclude that the effect of temperature on the cardiovascular system is direct.8 On the other hand, Mackenbach et al, who examined the seasonal pattern of deaths in The Netherlands over nine years, suggest that there is both an instantaneous effect of winter on the cardiovascular system, and a delayed effect mediated by respiratory infections.9In this report we examine the associations between ambient air temperature and a range of risk factors for ischaemic heart disease, including blood pressure, lipids, platelets, and other factors related to thrombosis. Patients and methodsThe Caerphilly study is fully described elsewhere.'10 1 It is based on a large cohort of men in South Wales. Each man was first seen at an afternoon or evening clinic at which blood pressure was recorded on a random zero muddler sphygmomanometer. Men were ...

SYNOPSIS The aggregating effects of adenosine diphosphate, thrombin, 5-hydroxytryptamine, tryptamine, adrenaline and noradrenaline, and tri-ethyl tin have been carefully compared. The first three compounds in some circumstances produce remarkably similar effects although there are important differences. The kinetics of aggregation induced by adrenaline (and noradrenaline) are quite different and the tri-ethyl tin effects are different again. Anti-serotonins specifically inhibit 5-hydroxytryptamine and the anti-adrenaline drug phentolamine specifically inhibits the effects of the catecholamines.Experiments presented suggest but do not prove that aggregation produced by all these compounds is accompanied by the liberation of diphosphate from the platelets and that platelet triphosphate may be converted to diphosphate. How these different compounds all produce this effect is discussed. Either the presence of diphosphate or the action of a triphosphatase might be the immediate cause of aggregation if there is a single final common cause. The anti-adrenaline phentolamine prolongs the bleeding time, so adrenaline or noradrenaline may be involved in platelet phenomena in haemostasis.