FIBRINOGEN IS A CANDIDATE MEASURE OF ALLOSTATIC LOAD

The soluble protein fibrinogen circulates in the blood and provides the material from which the insoluble fibrin clot is formed during blood coagulation. High plasma fibrinogen concentration predicts future coronary heart disease in men and women. The adult fibrinogen level appears to be determined by environmental factors operating throughout the life course, and levels are inversely related to socioeconomic status. Fibrinogen, as an acute phase reactant, responds to infection and other short-term inflammatory stressors such as tobacco smoke. The Whitehall II study shows that low control at work is associated with a high fibrinogen level, thus providing evidence that chronic psychosocial stress is indexed by plasma fibrinogen. A single measure of plasma fibrinogen is a candidate allostatic load marker capturing information in particular on the adaptation of the haemostatic system to cumulative lifetime behavioural, biological and psychosocial exposures.

High plasma fibrinogen concentration in adulthood is associated with elevated risk of coronary heart disease and stroke. Prospective studies in healthy men (Meade et al 1993; Wilhelmsen et al 1984; Kannel et al 1987; Yamell et al 1991; Heinrich et al 1994) and women (Kannel et al 1987) have shown that a single fibrinogen measurement predicts fatal and non-fatal cardiovascular events as much as 16 years later (Meade et al 1993). Fibrinogen level predicts restenosis after angioplasty (Montalescot et al 1995). Fibrinogen may promote, together with other haemostatic factors, atherosclerotic changes and thrombosis through effects shown in vitro on platelet aggregability, blood viscosity and foam cell formation. Such processes are compatible with a causal role for fibrinogen. An alternative view is that the prospective fibrinogen-cardiovascular disease association may be a consequence, rather than a cause, of the disease process, perhaps due to an inflammatory response to progressive endothelial damage. This view identifies fibrinogen as a marker of long-term pathophysiological changes. Both perspectives, which are certainly not mutually exclusive, support the use of fibrinogen as a cardiovascular risk factor in epidemiological studies (Brunner et al 1996).

About one half of the population variance of fibrinogen appears to be genetically determined. Weight at one year, but not birth weight, has been shown to be related to fibrinogen level: heavier infants have lower fibrinogen levels in adulthood (Barker et al 1992). Measures of childhood environment, adult height, father's social class, and level of education, are inversely associated with adult plasma fibrinogen level in both sexes (Brunner et al 1996). Fibrinogen level is higher among smokers than non-smokers and lower among moderate consumers of alcohol compared with non-drinkers. The nature of the alcohol-fibrinogen relationship is congruent with the apparent protective influence of alcohol on risk of myocardial infarction. Fibrinogen level is directly associated with degree of obesity and inversely associated with reported leisure-time exercise (Brunner et al 1993).

A pilot study (Markowe et al 1985) in male civil servants suggested that low control, monotony and under-utilisation of skills at work are related to raised fibrinogen levels. These results have been replicated in the Whitehall II cohort (Brunner et al 1996). Control over work, as a measure of the psychosocial environment, predicts incident coronary disease (Bosma et al 1997) and was found to be inversely related to fibrinogen in both sexes when assessed by personnel managers. Men in the top tertile of both self-rated and externally-assessed control over work had lower fibrinogen levels than those in the bottom tertile of both measures (-0.16 (95% CI-0.07, -0.26) g/l, P<0.001). Though there was little difference according to self-rated control scores among women in Whitehall II, data from Stockholm (Theorell, personal communication) shows the expected inverse control-fibrinogen relationship in both sexes.

It may be that fibrinogen may account, in part, for the high rates of coronary disease experienced by people in unfavorable socio-economic circumstances, which cannot be explained by the classical determinants of coronary risk (Marmot et al 1978). In Whitehall II, lower socioeconomic status, indexed by Civil Service employment grade, was associated with higher fibrinogen level, with differences from top to bottom grade of 0.22 (0.13, 0.31) g/l in men and 0.37 (0.18, 0.56) g/l in women (P<0.0001, both sexes). Fibrinogen level was higher among those in rented rather than owned accommodation. The employment grade-fibrinogen association was not accounted for by our measures of childhood circumstances, and in men the associations of subject's height and father's social class with fibrinogen remained significant after adjustment for current employment grade. Fibrinogen may thus be a marker of the specific biological pathways which mediate the inverse socio-economic gradient in coronary disease.

Altered haemostatic function, signaled by a raised fibrinogen level, may not be an isolated phenomenon. Fibrinogen levels show direct associations with features of the metabolic or insulin resistance syndrome, including raised fasting insulin level in healthy men and patients with angina pectoris, high waist-hip ratio, raised serum triglycerides, and low levels of high density lipoprotein cholesterol in healthy adults. These associations are evident among Whitehall II subjects. Fibrinogen levels were directly associated with waist-hip ratio (men R=0.17, women R=0.20; both P<0.0001), with fasting insulin among normoglycaemics (men 0.12, women 0.21; both P<0.0001) and inversely associated with HDL cholesterol (men -0.18, women -0.22; both P<0.0001).

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Fibrinogen, viscosity and white blood cell count are major risk factors for ischemic heart disease.