No abstract

miological studies have reported positive associations between the risk of coronary heart disease (CHD) and plasma fibrinogen levels. Fibrinogen is the major coagulation protein in blood by mass, the precursor of fibrin, and an important determinant of blood viscosity and platelet aggregation. [38][39][40][41] Because fibrinogen levels can be reduced considerably by lifestyle interventions that also affect levels of established risk factors (such as regular exercise, smoking cessation, and moderate alcohol consumption), there is interest in the possibility that measurement (or modification) of fibrinogen may help in disease prediction or prevention. [38][39][40]42 A meta-analysis of published data from 18 such studies, involving about 4000 CHD cases, indicated a relative risk of 1.8 (95% confidence interval [CI], 1.6-2.0) per 1-g/L increase in plasma fibrinogen level. 43 However, such analyses are not able to provide detailed assessments of the nature of any independent association of fibrinogen level with CHD or with other vascular and nonvascular outcomes. [43][44][45] This meta-analysis differs from previous analyses in several ways that should increase its reliability and scientific value. First, it is large and comprehensive: the data comprise 6944 first nonfatal myocardial infarction (MI) or stroke events and 13 210 deaths (cause-*The Authors/Writing Committee, Authors/Members, and Other Members of the Fibrinogen Studies Collaboration are listed at the end of this article.

We have identified a genetic polymorphism of factor VII that is strongly associated with plasma factor VII coagulant activity (factor VIIc) in healthy individuals from the United Kingdom. This polymorphism was detected after Msp I digestion of polymerase chain reaction-amplified genomic DN A. In a sample of 284 men, the frequency of the M2 allele (loss of cutting site) is 0.1, and individuals with the M1M2 genotype have factor VIIc levels 22% below the sample mean (p<0.0001). F actor VII is a serine protease found in plasma and is one of the vitamin K-dependent coagulation factors, along with prothrombin (factor II), factors IX and X, and proteins C and S (for review, see Reference 1). Factor VII is synthesized principally in the liver and is secreted as a single-chain glycoprotein of apparent M, 48,000. 2Cleavage of human factor VII to factor Vila, a two-chain form held together by disulfide bonds, results in a 20-to 25-fold increase in enzyme activity.2 This cleavage can be effected by a number of activated coagulation factors, including factors Xlla, Xa, and IXa and thrombin.2 In the presence of tissue factor and calcium ions, factor Vila converts factor X to factor Xa in the initiating reaction of the extrinsic coagulation pathway.

Abstract'Objective-To determine whether reduced fetal and infant growth are associated with higher plasma fibrinogen and factor VII concentrations in adult life.Design-Follow up study of men born during 1920-30 whose weights at birth and at 1 year had been recorded by health visitors, and men born during 1935-43 whose size at birth had been measured in detail.Setting-Hertfordshire and Preston, England. Subjects-591 men born in east Hlertfordshire who still lived there and 148 men born in Preston who still lived-in or close to the city.Main outcome measures-Plasma fibrinogen and factor VII concentrations.Results-Among men in Hertfordshire mean plasma fibrinogen and factor VII concentrations fell with increasing weight at 1 year (from 3-21 g/l in men of -18 lb to 2-93 g/l in men of -27 lb and from 122% ofstandardto 103%;p<0 001, p<0 005 respectively).The trends were independent of cigarette smoking, alcohol consumption, body mass index, and social class. Neither plasma fibrinogen nor factor VII concentration was related to birth weight. In men in Preston, however, fibrinogen concentration fell progressively as the ratio of placental weight to birth weight decreased (p= 0.01).Conclusions-Reduced growth in fetal life and infancy is strongly related to high plasma concentrations of the haemostatic factors fibrinogen and -factor VII. This may be a persisting response to impaired liver development during a critical early period.

Summary and conclusionsAs 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.

No abstract

I'ree M. A microassav for active and total renin concentration in htomani plasma based tiO antibodv trapping. Chitn (/hinm lAt-t 1980;101:5-15 12 Dusterdieck G(, McEllwee Mortality from coronary heart disease in civil servants in the lowest grade of employment has been found to be about three times that of men in the highest grade of employment. As part of an investigation ofthis finding several haemostatic variables were measured in a sample of 29 men in lower grades of employment and 45 men in higher grades. There was a significant difference in plasma fibrinogen concentrations between men in lower grades of employment and those in higher grades (mean 3 39 g/l v 2-95 g/l, respectively; p

Factor VII (FVII) is the plasma serine protease zymogen which, on binding to its cellular receptor tissue factor (TF), initiates blood coagulation. A 47-year-old man with no clinical bleeding tendency was found to have undetectable plasma FVII activity when tested in a one- stage assay using rabbit brain TF, but 0.3 U/mL using recombinant human TF and 1.04 U/mL FVII antigen. Variant FVII purified from his plasma showed an identical migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis to wild-type zymogen. By enzyme kinetic analysis the Km of the variant using FX as a substrate was 12-fold higher than that of normal FVII. Also, the variant FVII was unable to compete with wild-type FVII for limited rabbit TF binding sites. A ligand blot procedure was used to directly demonstrate reduced binding of recombinant human TF to the variant FVII compared with normal FVII. Genetic analysis of leukocyte DNA showed a G to A mutation in the propositus' gene at codon 304 that results in the substitution of a glutamine for an arginine residue in the catalytic domain of the protease. We conclude that this region of the FVII molecule is important for its function.