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Background: Respiratory tract infections may acutely increase risk from coronary heart disease (CHD), though the mechanisms have not been defined. Patients with chronic obstructive pulmonary disease (COPD) are prone to repeated exacerbations that are often associated with respiratory infections. These patients also have increased cardiovascular morbidity and mortality. We hypothesized that transient acute increases in plasma fibrinogen, an independent risk factor for CHD, could occur at COPD exacerbation (mediated through a rise in IL6) and thereby provide a mechanism linking respiratory infection to risk of coronary heart disease., Methods: 93 COPD patients [mean (SD) age 66.8 (8.1) years] were followed regularly over one year, with daily diary card monitoring of respiratory symptoms and peak expiratory flow rate (PEFR); 67 patients [mean FEV1 1.06 (0.44) l, FVC 2.43 (0.79) l] were seen during 120 exacerbations. At each visit spirometry was measured and blood samples taken for plasma fibrinogen and Interleukin-6 (IL-6) levels., Result: At baseline, the mean (SD) plasma fibrinogen was elevated at 3.9 (0.67) g/l in the 67 patients with exacerbations during the study and the median (IQR) IL-6 at 4.3 (2.4 to 6.8) pg/ml. Plasma fibrinogen increased by 0.36 (0.74) g/l at exacerbation (p <0.001). with IL-6 levels rising by 1.10 (-2.73 to 6.95) pg/ml (p = 0.008). There was a relation between the changes in fibrinogen at exacerbation and IL-6 levels (r = 0.348, p <0.001). Multiple regression revealed significantly greater rises in fibrinogen when exacerbations were associated with purulent sputum (b = 0.34 g/l; p = 0.03), increased cough (b = 0.31 g/l, p = 0.019) and symptomatic colds (b = 0.228; p = 0.024)., Conclusions: Plasma fibrinogen levels were elevated in stable patients with COPD and may contribute to the increased cardiovascular morbidity and mortality in these patients. COPD exacerbations increased serum IL-6 levels, leading to a rise in plasma fibrinogen. Thus acute rather than chronic infection may have a role in predisposing to coronary heart disease or stroke.

The determinants of plasma levels of prothrombin fragment F1.2 (F1.2) and D-dimer in different populations are unclear and this may complicate their interpretation as predictors of thrombotic risk, particularly in the case of D-dimer. We therefore measured F1.2 and D-dimer levels together with a number of other haemostatic and lipid variables in a cross-sectional community-based study of 150 healthy adults (73 male, 77 female), age range 23-80 years, identified from the list of a general practice by stratified random sampling within sex and decade of age. Plasma F1.2 was significantly higher in females than males and was independently and positively associated with age, factor VII activity (FVIIc) and C1 inhibitor, and inversely associated with high density lipoprotein (HDL) cholesterol. Plasma D-dimer showed a quadratic association with age (p <0.0001). In those < or =55 years D-dimer was inversely associated with dilute clot lysis time (DCLT) and activated protein C (APC) ratio. In those >55 years it was significantly higher in females than males and associated positively with age, fibrinogen and, in males, activated factor XII (FXIIa). In a multiple-linear model which combined both age groups, F1.2 and D-dimer were independently associated with each other (r = 0.22, p = 0.03). Thus, thrombin generation and fibrin turnover/fibrinolysis are associated in healthy subjects. HDL cholesterol (inversely) and FVIIc are associated with basal thrombin generation (i.e. F1.2). Determinants of D-dimer differ according to age and interpretation of the biological significance of D-dimer levels in epidemiological studies may therefore not be straightforward.

Although studies in those who have already experienced clinical episodes of ischaemic heart disease (IHD) have suggested properties of platelets influencing recurrence, there is limited information on the value of platelet tests in predicting first episodes of IHD. One study has suggested that a raised platelet count and increased aggregability in response to adenosine diphosphate (ADP) may increase IHD incidence but the numbers of IHD events involved were small. The larger Northwick Park Heart Study (NPHS) included platelet count and both ADP and adrenaline-induced aggregation and this paper presents their associations with subsequent IHD. Platelet counts were performed in 1369 white NPHS men aged between 40 and 64 at recruitment, of whom 181 subsequently experienced a major episode of IHD over a follow-up period of 16.1 years. Platelet count was unrelated to the incidence of IHD. ADP-induced aggregation was performed in a random sample of 740 men in whom 66 IHD events occurred during the subsequent 10.1 years, aggregability being measured both as ED50, the ADP dose at which aggregation occurred at half its maximum velocity, and also as EMR, the maximum rate of aggregation achieved. Neither measurement showed any association with IHD incidence, nor did similar measurements in 460 men in whom adrenaline-induced aggregation was also carried out. There are at least three possible explanations for the lack of any association between the measures of aggregability used and IHD. First, the large within-person variability of platelet aggregation tests may make the demonstration of any associations difficult, though the study had reasonable power to show effects with ADP. Secondly, the tests used may not be a valid index of the contribution of platelet function to thrombosis and IHD. However, the clear effect of several personal and demographic influences associated with IHD on the tests used brings this explanation into question. Thirdly, the role of platelets in thrombogenesis may be determined mainly by plasma influences such as fibrinogen, rather than by intrinsic properties of platelets themselves. Platelet counts within the physiological range and the aggregation tests used in this and in some other studies are of no value as indices of the risk of first episodes of IHD.

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.

We investigated the association between fibrinogen levels and a HaeIII restriction fragment length polymorphism located at -453 bp from the start of transcription of the beta fibrinogen gene. 292 healthy men aged 45 to 69 years, recruited from general practices throughout Britain, were studied. None had a history of ischaemic heart disease. 41.1% (120) were smokers and fibrinogen levels were higher in this group. The frequency of the non-cutting allele (designated H2) was 0.19 and was the same in smokers and non-smokers. The H2 allele was associated with elevated levels of fibrinogen in both smokers and non-smokers and the effect of genotype was similar in both groups. After smoking, HaeIII genotype was the strongest predictor of fibrinogen levels and explained 3.1% of the variance in fibrinogen levels. These results confirm earlier studies that variation at the fibrinogen locus contributes to the between-individual differences in plasma fibrinogen level.