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doi:10.1093/qjmed/hcg129
Review
Introduction
Plasma fibrinogen is an important component of the cholesterol lipoprotein(a) and leukocyte count. Con-
coagulation cascade, as well as a major determinant versely, it decreases with moderate alcohol intake,
of blood viscosity and blood flow. Increasing physical activity, increased high-density-lipoprotein
evidence from epidemiological studies suggests (HDL) cholesterol, and with hormone replacement
that elevated plasma fibrinogen levels are associated therapy (HRT).6–8
with an increased risk of cardiovascular disorders, We review the biochemistry, epidemiology, and
including ischaemic heart disease (IHD), stroke and genetic and extrinsic influences on plasma fibrino-
other thromboembolism.1,2 This increase in plasma gen levels, as well as the close association between
fibrinogen levels may promote a prothrombotic or plasma fibrinogen and various vascular disorders.
hypercoagulable state, and may in part explain the
risk of stroke and thromboembolism in conditions
such as atrial fibrillation (AF). Search strategy
Nevertheless, the relationship between hyperfibri-
We performed a search using electronic databases
nogenemia, atherosclerosis and thrombosis is com-
(MEDLINE, EMBASE, DARE), using the search terms
plicated. As the process of thrombogenesis is very
‘fibrinogen’ in combination with either ‘biochem-
closely related to atheroma formation (atherogen-
istry’, ‘epidemiology’, ‘pathophysiology’, ‘athero-
esis), it follows that specific thrombogenic factors
sclerosis’, ‘genetics’, ‘coronary artery disease’ or
such as fibrinogen (with important effects on blood
‘ischaemic heart disease’, ‘genetics’, ‘smoking’,
rheology) may play key roles in the process of
‘alcohol’, etc., to cover the range of subheadings
atherosclerotic lesion formation, with subsequent
addressed in the review. In addition, the reference
effects on cardiovascular diseases (Figure 1). How-
lists from papers were scrutinized, and abstracts
ever, knowledge about the precise determinants of
from national and international cardiovascular
plasma fibrinogen levels in health and disease is as
meetings were studied to identify further studies,
yet incomplete, and many paradoxes are still present. published or unpublished. The influence of growth
For example, it is known that plasma fibrinogen is in early life on fibrinogen concentrations in adult-
higher in Black than in White patients,3 but (in the UK hood, and interventions to reduce fibrinogen, were
at least) coronary artery disease is less common in not considered for this review.
Blacks than in White patients, while hypertension
and stroke are conversely more common.4,5 Plasma
fibrinogen is also influenced by many factors:
it increases with age, body mass index, smoking,
Pathophysiology
diabetes and post menopause and is related to Fibrinogen is a soluble glycoprotein found in the
fasting serum insulin, low-density-lipoprotein (LDL) plasma, with a molecular weight of 340 kDa.9 It
Address correspondence to Professor G.Y.H. Lip, Haemostasis Thrombosis and Vascular Biology Unit,
University Department of Medicine, City Hospital, Birmingham B18 7QH. e-mail: g.y.h.lip@bham.ac.uk
QJM vol. 96 no. 10 ! Association of Physicians 2003; all rights reserved.
712 S. Kamath and G.Y.H. Lip
the endothelial cells also mediates the adhesion resulting in the lipid core of atherosclerotic
of platelets. The interaction of fibrinogen and cells lesions.26 However, it cannot be overemphasized
expressing ICAM-1 is associated with cellular that many of these observations are only associa-
proliferation.20 tions, and a definite causal role for fibrinogen
Fibrinogen, on binding to its integrin receptor on cannot be fully demonstrated.
the surface of leukocytes also facilitates a chemo-
tactic response, thus playing a vital role in the Fibrinogen and thrombogenesis
process of inflammation.21 One of the proposed Thrombogenesis is regulated by a fine balance
mechanisms by which fibrinogen induces pro- between the coagulation and fibrinolytic pathways
inflammatory changes in leukocytes includes an (Figure 2). Subsequent to vessel wall trauma, tissue
increase in the free intracellular calcium and thromboplastin is released from the sub-endothe-
out). However, the latter tests do not provide Clauss method failed to correlate with the degree of
information about the coagulability (functional femoro-popliteal atherosclerosis (r ¼ 0.06), nephelo-
ability) of the fibrinogen. metric levels did correlate with extent of disease
The Expert Committee on Biological Standardiza- (r ¼ 0.2, p < 0.01).34 Another epidemiological study
tion of the World Health Organization, on proposal reported a correlation coefficient of 0.62 between
by Fibrinogen Sub-Committee of the Standardiza- the nephelometric and Clauss methods for fibrino-
tion and Scientific Committee of the International gen.35 While this is statistically significant
Society on Thrombosis and Haemostasis, has (p < 0.001), it could be argued that this is methodo-
recently established the 2nd International Standard logically of poor significance since, in an ideal
for Fibrinogen, Plasma (code 98/612) the potency of world, a correlation coefficient > 0.9 would be
which is 2.19 mg/ampoule by the automated Clauss expected if the assays do indeed measure the same
assay.32 Although a number of different fibrinogen molecule. Indeed, the association with ischaemic
assays are available, the total clottable protein heart disease was ten-fold more significant using the
assay, which was used to establish the 2nd Interna- nephelometric assay (p < 0.001) than with the
tional Standard for fibrinogen is the recommended Clauss assay (p < 0.01). The same group later
gold standard.32 reported nephelometric levels of fibrinogen to be
Indeed, one of the barriers to cross-study compar- 9.3% higher in those men who, after a ten year
isons are the differences due to the different interval, went on to suffer an incidence of ischaemic
methods for the determination of fibrinogen. The heart disease.36 This figure is remarkably close to
Clauss assays are generally reproducible between the difference of 9.5% in Clauss-defined levels
centres, analysers and reagents,31 but it is important between those suffering or free of a coronary event
to note that the normal reference interval must be in the PROCAM study.37 Thus, despite the close
determined for each laboratory for each assay, and agreement between these prospective studies,
is not a general value (Table 1), although the widely doubts as to the precise and comparative value
accepted normal reference value for fibrinogen is of each method remain.38
between 1.5 and 4.5 g/l.
These differences may be of relevance to clinical
research. For example, Smith et al.33 reported levels
of clottable fibrinogen to be 13.9% higher in
Epidemiological studies
patients with peripheral artery disease compared to Several epidemiological studies have provided
controls (p ¼ 0.001), but nephelometric levels to be prospective data on plasma fibrinogen levels in
14.9% higher (p < 0.001), a difference which may relation to cardiovascular disease (Tables 1 and 2).
be trivial. However, although levels defined by the According to these studies, the risk of developing a
Fibrinogen 715
Without With
Study (reference) Method n CHD CHD p
Northwick Park Heart Study Gravimetry 1511 2.90 3.15 < 0.001
(Meade et al. 1986)
Framingham Spectrophotometry 1315 2.91
(Kannel et al. 1987)
Goteborg Spectrophotometry 792 3.30 3.56 < 0.001
Adapted from Dippel K. Fibrinogen; a cardiovascular risk factor. Boehringer Mannheim GmbH 1992, 1st edition.
GRIPS, Gottingen Risk, Incidence and Prevalence Study; IHD, Ischaemic Heart Disease; MI, myocardial infarction. Adapted
from reference 39.
716 S. Kamath and G.Y.H. Lip
cardiovascular event such as IHD or stroke is 1.8 to factor VII coagulant activity and fibrinogen
4.1 times higher in subjects with fibrinogen levels in were associated with increased IHD risk. Indeed,
the top third than in those with levels in the lower elevations of one standard deviation in factor VII
third.39 Preliminary evidence also suggests that activity, fibrinogen, and cholesterol were associated
reducing fibrinogen levels in patients with high with increases in the risk of an episode of IHD
baseline levels and coronary disease may be within 5 years of 62%, 84%, and 43%, respectively,
beneficial.39 demonstrating that the association between haemo-
A meta-analysis of the six prospective epidemio- static markers and IHD to be stronger than that
logical studies39 with samples representative of the for cholesterol.
general population, concluded that plasma fibrino-
gen was an independent cardiovascular risk factor, Gothenburg study
coronary events were observed, and the mean fibrinogen was an independent risk factor for the
plasma fibrinogen level of the ‘event group’ incidence of acute coronary events during the initial
exceeded that of the non-event group by 0.32 g/l. 5 years of follow-up, although this relationship was
The incidence of coronary events among men lost during the subsequent 5 years of follow-up.
within the upper tertile of plasma fibrinogen Similarly when adjusted for LDL, there was no
concentration was threefold higher than among significant association between plasma fibrinogen
men within the lower tertile. When fibrinogen and and the development of chronic coronary artery
LDL concentration were considered together, there disease without acute MI. This could partly be
was a graded and dramatic eightfold increase in attributed to the lack of reliable recommendations
8-year risk among men with both fibrinogen and for the elevated plasma fibrinogen levels, and
LDL cholesterol in the higher tertiles, when com- choosing different cut-off points.
854G/A polymorphisms of the b fibrinogen gene intrinsic (genetic) factors (Table 3) rather than just
have a significant impact on the plasma fibrinogen the latter. For example, there is a dose-response
concentration. The 455G/A mutation in the effect between the number of cigarettes smoked and
promoter region of the b fibrinogen gene is one of plasma fibrinogen level, as well as an inverse
the strongest genetic variations, associated with an relationship with time since cessation of smoking.60
increase in plasma fibrinogen in both genders in the Moderate drinking may lower plasma fibrinogen
general population.55,58 concentration, and if fibrinogen is a causal risk
However, the results have been conflicting, and factor for cardiovascular disease, it may be one of
some studies have failed to demonstrate such the variables that explain the protective effect of
relationships between these genetic polymorphisms moderate alcohol consumption on cardiovascular
and plasma fibrinogen levels. For example, Connor disease.61
Lee et al. 1990 4515 M, 4309 F 40–59 SBP: r ¼ 0.13 (M); r ¼ 0.01 (F)
Moller et al. 1991 439 M 51 SBP: NS in regression analysis
Lowe et al. 1992 477 M, 438 F 25–64 DBP: r ¼ 0.12 (M); r ¼ 0.14 (F)
SBP: r ¼ 0.2 (M); r ¼ 0.2 (F)
Smith et al. l992 1264 M and F 25–64 DBP: r ¼ 0.03 (M); r ¼ 0.07 (F)
SBP: r ¼ 0.02 (M); r ¼ 0.12 (F)
Folsom et al. 1993 1933 M, 2260 F 18–30
Fowkes et al. 1993 809 M, 783 F 55–74 DBP: r ¼ 0.23 (M); r ¼ 0.17 (F)
SBP: r ¼ 0.22 (M); r ¼ 0.09 (F)
Eliasson et al. 1994 776 M, 807 F 25–64 DBP: r ¼ 0.14 (M); r ¼ 0.23 (F)
SBP: r ¼ 0.17 (M); r ¼ 0.32 (F)
de Boever et al. 1995 745 M 35–59 DBP: r ¼ 0.09
SBP: r ¼ 0.12
Adapted from: Lee AJ. The role of rheological and haemostatic factors in hypertension. J Hum
Hypertens 1997; 11:767–76. r ¼ correlation coefficient.
Fibrinogen 719
Table 5 Interventions to decrease plasma fibrinogen ratio in both sexes.63,69,71 Indeed, plasma fibrinogen
levels level is significantly higher amongst patients with a
body mass index of > 30 kg/m2, compared to those
Beneficial Cessation of smoking with body mass index < 25 kg/m2,72 and rises with
Medication: fibrates, doxazosin higher quartiles of skin fold thickness.73
Plasmapheresis
Moreover, weight reduction can reduce plasma
Moderate alcohol consumption
fibrinogen. For example, Ditschuneit et al.71
May be beneficial Weight loss
Lowering blood pressure reported that in patients who were extremely
Hormone replacement therapy overweight and had high plasma fibrinogen levels,
Not beneficial Statins a reduction in weight (mean SEM 20 3 kg)
correlated with a decrease in plasma fibrinogen
exercise raw data were corrected for the contraction through a beneficial effect on plasma fibrinogen
of plasma volume.76 However, the results reported levels.
from various studies have been conflicting, due to
differences in the populations studied, exercise Seasonal differences
protocols, testing procedures, and the analytical
Cardiovascular disorders, cerebrovascular disorders,
methods used for the assessment of plasma fibrino-
associated risk factors and mortality all show a
gen.77,78 Moreover, whether exercise-induced
seasonal variation, with a peak during winter
blood hypercoagulability in vitro corresponds to
season, especially among the elderly. Correspond-
in vivo thrombin generation and fibrin formation is
ingly, plasma fibrinogen levels show a seasonal
unknown.
variation, with the peak in winter, both in normal
Acute exercise may cause a rise in plasma
healthy adults and in patients with cardiovascular
intermediary in the apparent link between H. pylori between OC use and smoking in their effects on
infection and coronary artery disease but once haemostatic variables, including fibrinogen.103 Con-
again, studies have yielded inconsistent results.96,97 versely, plasma fibrinogen level returns to normal on
The recent STAMINA (South Thames Trial of discontinuation of the OC pill, usually within about
Antibiotics in Myocardial Infarction and Unstable 3 months.104
Angina) study showed that although antibiotic Both the menopausal status and HRT have
treatment failed to reduce plasma fibrinogen independent effects on plasma fibrinogen levels.105
levels significantly, it significantly reduced adverse The increases in factor VIIC, fibrinogen, and
cardiac events in patients with acute coronary cholesterol levels with the menopause would
syndromes; however, the effect was independent increase the risk of fatal IHD in postmenopausal
of H. pylori or C. pneumoniae seropositivity.98 women by about 40%, compared with the risk
in premenopausal women of the same age.106
the risk of ischaemic heart disease. A substantial be considered in evaluating the relevance of
number of studies failed to find an association genetic variations on the risk of cardiovascular
between polymorphisms in the fibrinogen gene and disease.
cardiovascular risk.90,152–154 For example, van der Future directions require determination of the
Bom et al. found that the 455G/A polymorphism ‘critically elevated’ fibrinogen threshold value,
was associated with increased plasma fibrinogen development of drugs that would specifically and
levels, but not with an increased risk for MI. These safely decrease plasma fibrinogen levels and
findings indicate that an increased plasma fibrino- conduction of interventional trials to study the
gen level due to this genetic factor may not increase influence of lowering fibrinogen levels on overall
the risk for MI. Similarly, Doggen et al. found that cardiovascular risk profile. Meanwhile, plasma
the TaqI, HaeIII and BclI polymorphisms in the fibrinogen levels could potentially be considered
fibrinogen gene were not associated with MI.152
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