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Biomedical subjects

T W Meade

Publications and source records attributed to T W Meade.

At least 73 records · Page 4Linked to original sources
PubMed1994

Haemostatic function and arterial disease.

General recognition of the thrombotic component in ischaemic heart disease (IHD) is comparatively recent. Despite the obvious role of platelets, it has in many ways--and certainly epidemiologically--been work on the coagulation system that has been more rewarding in characterising those at high risk of IHD on account of haemostatic abnormalities. Raised plasma fibrinogen levels are clearly and independently associated with the onset of both clinically manifest IHD and stroke and probably with lower extremity arterial disease as well. High fibrinogen levels also increase recurrence rates and the progression of these conditions. High factor VII activity levels are associated with increased mortality from IHD but not with non-fatal episodes. Low fibrinolytic activity and raised factor VIII levels are also associated with increased IHD incidence. High fibrinogen levels predispose to thrombosis by effects on viscosity, platelet aggregability, fibrin deposition and the atherogenic process. There is increasing evidence that raised factor VII activity levels lead to increased thrombin production. Associations of several personal characteristics--notably smoking in the case of fibrinogen and dietary fat intake in the case of factor VII activity--influence the coagulation system in ways that are likely to predispose to thrombosis. Besides well known agents such as aspirin and anticoagulants, increasing attention ought now to be given to the antithrombotic potential of fibrinogen-lowering agents.

Blood Coagulation↗
PubMed1994

Changes in clot deformability--a possible explanation for the epidemiological association between plasma fibrinogen concentration and myocardial infarction.

This study examined the rheological properties of fibrin gels formed by adding thrombin to plasma samples from 99 subjects with fibrinogen concentrations ranging from 1.45 to 4.14 g/l. A highly significant (r = 0.757; P < 0.001) inverse correlation was observed between plasma fibrinogen concentration and the extent of clot deformability as estimated from the final value of the storage modulus (G') of the fibrin gel when obtained by rheological analysis. A similarly significant correlation (r = 0.844; P < 0.001) was obtained using samples from 47 subjects in which fibrin cross-linking was blocked by addition of 0.1 mM iodoacetamide to inactivate factor XIIIa. The characteristics of the relationship between G' and fibrinogen concentration in the plasma samples was comparable with that observed when the fibrin gel was formed by adding thrombin to purified fibrinogen. These results suggest that the increased risk of myocardial infarction associated with an elevated plasma fibrinogen concentration may, in part, be explained on the basis of a decreased deformability of the fibrin clot formed.

Aged↗
PubMed1994

Factor VIII, ABO blood group and the incidence of ischaemic heart disease.

Relations of factor VIII activity, FVIIIC, and von Willebrand factor antigen (vWFAg), with ischaemic heart disease (IHD) were examined in 1393 men aged between 40 and 64 years at entry to the Northwick Park Heart Study (NPHS) who experienced 178 first major episodes of IHD during an average follow-up period of 16.1 years. After allowing for the large factor VIII differences between the main ABO blood groups, FVIIIC was probably associated with IHD incidence, possibly more strongly with fatal than non-fatal episodes. Thus, an increase of 1 standard deviation in FVIIIC raised the risk of fatal IHD by about 28%. vWFAg was also significantly associated with fatal events. The observed relation of FVIIIC with IHD incidence probably underestimates the true strength of the association because of the considerable within-person and laboratory variability in factor VIII measurements. FVIIIC and vWFAg were strongly correlated (r = 0.57) and in statistical terms there may be little to choose between them in long-term studies of IHD. Taking account of evidence that haemophiliacs seem to experience less IHD than expected, high factor VIII levels may contribute to the incidence of IHD by increasing thrombogenic potential. The incidence of IHD was significantly higher in those of blood group AB than in those of groups O, A or B, particularly for fatal events. There was no evidence that the FVIIIC and vWFAg associations with IHD are determined by ABO group. The factor VIII and ABO blood group effects therefore appeared to be independent. Group AB may be a genetic marker of characteristics influencing other indices of IHD risk such as short stature, NPHS men (though not women) of group AB being about 2 cm shorter than those of other groups.

ABO Blood-Group System↗
PubMed1994

Factor-VII activity and ischaemic heart disease: fatal and non-fatal events.

The Northwick Park Heart Study suggested that factor VII activity might be more strongly related to fatal than non-fatal events of ischaemic heart disease. We used polychotomous logistic regression to model simultaneously the probabilities of fatal events, non-fatal myocardial infarction, dying of causes other than ischaemic heart disease and of events, non-fatal myocardial infarction, dying of causes other than ischaemic heart disease and of event-free survival. We followed 1459 white men aged 40-64 at recruitment for a mean period of 16.1 years. Of these, 92 died of ischaemic heart disease, 100 experienced non-fatal myocardial infarction, 173 died of other causes, and 1094 men were alive. Factor VII activity was strongly related to fatal events of ischaemic heart disease but not to non-fatal events (p = 0.008). A difference of 1 SD in factor VII activity was associated with a difference of nearly 50% in the probability of dying of ischaemic heart disease, but with no difference for non-fatal myocardial infarction. This contrast was not seen for smoking, cholesterol, blood pressure, fibrinogen or factor VIII activity. High levels of VII activity may influence outcome at the time of plaque rupture and tissue factor release by enhancing thrombin production and thus fibrin deposition and platelet aggregability. The apparently differential effect of factor VII activity on fatal and non-fatal ischaemic heart disease may have important screening and prophylactic implications.

Adult↗
PubMed1994

Effects of low intensity antithrombotic regimes on the haemoglobin level.

The effects on the haemoglobin level of low dose aspirin and of low intensity oral anticoagulation with warfarin separately and in combination have been established in men aged between 45 and 69 at high risk of ischaemic heart disease. The findings confirm that combined treatment with warfarin and aspirin (WA) leads to a clear excess of minor bleeding episodes over warfarin alone (W) or aspirin alone (A). Each separate treatment on its own (either W or A) leads to an increase in these episodes compared with those on placebo (P) treatment. However, neither combined treatment (WA) nor the separate treatments (W or A) cause a fall in haemoglobin levels over a period of up to two years.

Aged↗
PubMed1994

Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bio-assay to activated factor VII: an international study.

Plasma from healthy individuals, pregnant women and patients on warfarin were distributed to 3 laboratories supporting major cardiovascular surveys (Northwick Park, Muenster and Houston) for assay of factor VII coagulant activity (VIIc) with their own bio-assays. The mean VIIc in 147 samples agreed to within 1% of standard in Northwick Park and Houston, but was 14% of standard lower in Muenster owing to its more potent standard. In samples with an increased VIIc the Northwick Park assay gave a higher result than the other assays owing to its increased responsiveness to activated factor VII (VIIa). Thus when VIIa concentrations were determined directly with a clotting assay which utilises a soluble recombinant tissue factor, the increase in VIIc with increase in VIIa was considerably greater with the Northwick Park assay than the Muenster assay. This feature of the Northwick Park assay was traced to the virtual absence of protein C in its substrate plasma. Factor Va appears rate-limiting for the coagulant expression of VIIa in test plasma. If the thrombotic response to release of tissue factor is determined by the circulating concentration of VIIa, then the Northwick Park factor VII bio-assay may be preferable to other bio-assays currently employed to estimate risk of acute coronary events.

Adult↗
PubMed1993

Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study.

Fibrinolytic activity (FA) was measured by dilute blood clot lysis time at entry to the Northwick Park Heart Study in 1382 white men aged 40-64, of whom 179 subsequently experienced episodes of ischaemic heart disease during a mean follow-up period of 16.1 years. There was a significant interaction between age and low FA (p = 0.02) with respect to ischaemic heart disease: a difference of one standard deviation in FA was associated with a difference of about 40% in ischaemic heart disease risk (p = 0.002) in those aged 40-54 at entry. The FA association remained after adjusting for plasma fibrinogen. High fibrinogen concentrations themselves were also associated with ischaemic heart disease, as was high factor VII activity with fatal events. Low FA in younger men may exert a long-term influence by impairing the removal of fibrin deposits that contribute to atherogenesis. Low FA appears to be a leading determinant of ischaemic heart disease in younger men and methods of enhancing fibrinolytic activity, whether by life-style changes or pharmacologically, should be considered.

Adult↗
PubMed1993

Plasma renin activity and ischemic heart disease.

BACKGROUND: An earlier prospective study reported an association between high levels of plasma renin activity (as measured by the renin-sodium profile) and the incidence of myocardial infarction in patients with hypertension. We have investigated the relation between plasma renin activity and ischemic heart disease in the Northwick Park Heart Study. METHODS: The study included 803 white men 40 to 64 years of age selected from industrial workers in London. Plasma renin activity and established risk factors for ischemic heart disease were measured at entry, which was between 1972 and 1978. Ascertainment of the primary clinical end points of fatal or nonfatal myocardial infarction and sudden death from coronary causes was carried out until the end of 1991. RESULTS: In an analysis of the 86 first coronary events, we found an independent relation between higher systolic blood pressure and coronary end points (relative risk per 1 SD increase in blood pressure, 1.47; 95 percent confidence interval, 1.16 to 1.85; P < 0.001), but no relation between plasma renin activity and coronary end points (relative risk per 1 SD increase in the level of plasma renin activity, 1.04; 95 percent confidence interval, 0.84 to 1.30). In the 242 men who had hypertension of a degree similar to that of the subjects in the earlier prospective study of the renin profile, and in whom 44 of the 86 coronary events occurred, the relative risk of those in the highest as compared with the lowest third for plasma renin activity was 1.26 (95 percent confidence interval, 0.63 to 2.56). CONCLUSIONS: Our results suggest that there is no association between plasma renin activity and myocardial infarction or sudden death from coronary causes, at least in normotensive men.

Adult↗
PubMed1993

Positive association between self-reported fatty food consumption and factor VII coagulant activity, a risk factor for coronary heart disease, in 4246 middle-aged men.

Raised levels of factor VII coagulant activity (VIIc) have been reported to increase the incidence of CHD. Preliminary evidence from observational and experimental studies suggests that dietary fat intake is positively associated with VIIc. We explored this further in 4,246 men aged 45-69, who were found to be free of major CHD when screened for a primary prevention trial of antithrombotic medication. All men were asked about their consumption of fatty foods and changes in consumption in the last month. In the 9% of men who reported avoidance of fatty foods in the month before interview, age adjusted VIIc was 7.8% of standard (95% CI 5.1-10.6%) lower than in the remainder. Serum cholesterol and body mass index (BMI) were also significantly lower. The extent to which fat consumed in the past month had deviated from usual intake was significantly and positively related with VIIc, serum cholesterol and BMI. Thus, the VIIc difference between those eating much less fatty food than usual and those eating much more than usual was 11% of standard, with those eating their usual amount having an intermediate level. This study adds to the evidence that dietary fat intake influences VIIc and coagulability. The effect is rapid, so that much of the benefit of dietary fat reduction on thrombogenic risk in CHD is likely to occur within a short time. Thus, the results reinforce the value of a low fat diet, even in individuals with advanced atheroma, in whom dietary intervention has sometimes been considered unlikely to be effective.

Antigens↗
PubMed1993

The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials.

The proven benefit of aspirin in the secondary prevention of cardiovascular disease and its possible value in primary prevention must be weighted against its potential hazards. This paper is an overview of the gastrointestinal toxicity of aspirin, its most serious complication after intracerebral haemorrhage. Information on toxicity has been drawn only from randomised trials, thus avoiding the potential biases of observational studies. All randomised placebo controlled trials listed in the Anti-platelet Trialists Collaboration where a direct aspirin-placebo comparison was possible were included. Twenty-one trials were included, all but one of secondary prevention. There were over 75,000 person years of aspirin exposure. The pooled odds ratios for categories of gastrointestinal bleeding (e.g. haematemesis, melaena) were between 1.5-2.0; fatal bleeds were very rare. The risk of peptic ulcers was 1.3 and of upper gastrointestinal symptoms 1.7. These risks were lower than those found in observational studies. Attributable disease rates are also presented. For haematemesis for example they varied from 0.2-1.0 per 1000 person years. Toxicity was dose related. Aspirin does have significant gastrointestinal toxicity, although this is rarely fatal. More recent work has demonstrated the efficacy of low doses of aspirin (75 mg daily) but there is limited information yet available on its toxicity.

Aged↗
PubMed1992

A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants.

A total of 333 patients with stable intermittent claudication at recruitment were followed up for 6 years to determine risk factors associated with subsequent mortality. Cardiovascular diseases were the underlying cause of death in 78% of the 114 patients who died. The strongest independent predictor of death during the follow-up period was the plasma fibrinogen level, an increase of 1 milligram being associated with a nearly two-fold increase in the probability of death within the next 6 years. Age, low ankle/brachial pressure index and a past history of myocardial infarction also increased the probability of death during the study period. The plasma fibrinogen level is a valuable index of those patients with stable intermittent claudication at high risk of early mortality. The results also provide further evidence for the involvement of fibrinogen in the pathogenesis of arterial disease.

Aged↗
PubMed1992

Extra-cranial bleeding and other symptoms due to low dose aspirin and low intensity oral anticoagulation.

Data from the early stages of the thrombosis prevention trial (TPT) have been used to establish and quantify the risk of extracranial bleeding due to low dose aspirin (75 mg) and low intensity oral anticoagulation with warfarin (international normalised ratio, INR, 1.5) singly or in combination, in men aged between 45 and 69 who are at high risk of ischaemic heart disease (IHD). The design of the trial is factorial, the four treatments being combined low dose aspirin and low intensity anticoagulation (WA), low intensity anticoagulation alone (W), low dose aspirin alone (A) and double placebo treatment (P). The trial is being carried out through the Medical Research Council's General Practice Research Framework, with participating practices throughout the United Kingdom. Results are based on the first 3,667 men entered. The risk of major gastrointestinal bleeding due to active treatment is probably about 1 in 500 man-years of treatment, there currently being no difference between the three active regimes (WA, W, A). Intermediate and minor bleeding episodes occur more frequently with WA than with W or A on their own, the excess being mainly due to minor nose bleeds and bruises. In turn, both W and A on their own cause more such minor episodes than placebo treatment, P. There is no evidence that any of the three active regimens increases the risk of peptic ulceration, nor do they increase reports of indigestion. Aspirin increases reports of constipation and reduces reports of blurred vision. Minor bleeding occurs less frequently in smokers than in non-smokers but is not influenced by age. The antithrombotic regimes used are feasible and acceptable.

Administration, Oral↗
PubMed1992

Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease.

The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis.

Biomarkers↗