Review: Fibrinogen: Biochemistry, Epidemiology and Determinants

Q J Med 2003; 96:711–729
doi:10.1093/qjmed/hcg129
Review
Fibrinogen: biochemistry, epidemiology and determinants

S. KAMATH and G.Y.H. LIP
From the Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine,
City Hospital, Birmingham, UK
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
Downloaded from by guest on June 25, 2016

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: [email protected]
QJM vol. 96 no. 10 ! Association of Physicians 2003; all rights reserved.
712 S. Kamath and G.Y.H. Lip
Figure 1. Plasma fibrinogen, thrombogenesis and atherogenesis.

comprises of three pairs of non-identical polypep- Fibrinogen and inflammation
tide chains (alpha, beta and gamma chains)10 linked
to each other by disulphide bonds. Fibrinogen has a The process of inflammation is primarily mediated
biological half-life of about 100 h and is synthesized by its interaction with leucocytes through the
predominantly in the liver.11 As a clotting factor, surface receptors of the latter termed ‘integrins’.
fibrinogen is an essential component of the The 2 main receptors for fibrinogen on the surface of
blood coagulation system, being the precursor leukocytes include Mac-1 (CD11b/CD18, alpha M
of fibrin. However, at the ‘usual’ plasma levels beta 2) and alpha X beta 2 (CD11c/CD18, p150,
of 1.5 to 4.5 g/l, its concentration far exceeds 95). Leukocytes (both monocytes and myelocytes)
the minimum concentration of 0.5–1 g/l necessary can specifically induce MAC–1 receptor to bind
for haemostasis. fibrinogen.13,14 The ability of MAC–1 receptor to
Fibrinogen plays a vital role in a number of bind fibrinogen results from the maturational
physiopathological processes in the body, including changes occurring in the receptor during the process
inflammation, atherogenesis and thrombogenesis. of cell differentiation, and is not seen in a resting
Nevertheless, our understanding of the mechanisms leucocyte. The site on fibrinogen that interacts with
leading to the atherothrombogenic action of fibrino- MAC-1 is not shared by other integrins.15
gen is fragmentary. Proposed mechanisms include Fibrinogen is also a ligand for Intercellular
the infiltration of the vessel wall by fibrinogen, Adhesion Molecule-1 (ICAM-1), and enhances
haemorrheological effects due to increase in blood monocyte-endothelial cell interaction by bridging
viscosity, increased platelet aggregation and throm- the Mac-1 on monocytes to ICAM-1 on endothelial
bus formation. Furthermore, plasma fibrinogen is cells.16,17 Thus, ICAM-1 behaves as a cell surface
also a prominent acute-phase reactant. It augments ligand for alpha L beta 2 and alpha M beta 2
the degranulation of platelets in response to (MAC-1) integrins, and has a key role in leukocyte
adenosine diphosphate (ADP), when taken up by adhesion to the vascular endothelium. Furthermore,
the a granules. Thus, elevated concentrations of fibrinogen upregulates and increases the concentra-
fibrinogen, perhaps secondary to inflammation or tion of ICAM-1 proteins on the surface of endothe-
infection (Chlamydia pneumoniae or Helicobacter lial cells, resulting in increased adhesion of
pylori) implicated in cardiovascular risk may leukocytes on the surface of endothelial cells,18
operate, in part, by increasing the reactivity of even at high shear rates in flow conditions.19
platelets.12 Moreover, the fibrinogen binding to ICAM-1 on
Fibrinogen 713
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-
increased expression of neutrophil activation mar- lium. Tissue thromboplastin in turn triggers the
kers. These processes result in an increase in extrinsic pathway of coagulation by activating factor
phagocytosis, antibody-mediated leucocyte toxicity VII to VIIa. Contact of blood with the foreign surface
and delay in apoptosis.22 initiates the intrinsic pathway of coagulation, by
Fibrinogen is also involved in the facilitation of activating factor XII to XIIa, as well as platelets.
both cell–cell interaction and the interaction of Platelet aggregation, however, does not confer
cell and extracellular matrix such as collagen.13,23 adequate stability, and therefore activation of the
Thus, as explained above, fibrinogen is an important coagulation pathway is also necessary.
mediator of cell–cell interaction, adhesion and The final common pathway of the coagulation
inflammation. cascade involves the activation of factor X to Xa,
Finally, there is evidence that fibrinogen facilitates and the subsequent activation of prothrombin to
the biomaterial-provoked inflammatory response.24 thrombin. Thrombin, which is a protease enzyme,
Interaction with the biomaterial results in conforma- facilitates the cleavage of fibrinogen into fibrin

tional changes within the fibrinogen molecule monomers, which link to each other both sideways
and conversion into ‘proinflammatory’ fibrinogen, and end-to-end to form fibrin polymers. Activated
resulting in the exposure of the epitope that interacts factor XIII facilitates the cross linkage of fibrin
with the MAC-1 receptor for macrophages.24,25 polymers to form a stable fibrin clot.
Fibrinogen is also involved in the final common
Fibrinogen and atherogenesis pathway of platelet aggregation. Fibrinogen cross-
There seems to be little doubt that fibrin deposition links the platelets by binding the glycoprotein IIb-IIIa
can both initiate atherogenesis and contribute to the receptor on the platelet surface.30 This has become
growth of plaques.26,27 Fibrinogen and its metabo- more relevant with the advent of glycoprotein
lites appear to cause endothelial damage and IIb-IIIa receptor inhibitors, which block this final
dysfunction by a number of mechanisms.28 Many common pathway of platelet binding.
human atherosclerotic lesions, showing no evi-
dence of fissure or ulceration, can contain a large Determining plasma fibrinogen
amount of fibrin, which may either be in the form of
mural thrombus on the intact surface of the plaque, levels
in layers within the fibrous cap, in the lipid-rich The available methods of determining fibrinogen
core, or diffusely distributed throughout the plaque. can be classified into two groups, ‘functional’ and
This phenomenon may be compounded by the ‘direct’. The first category involves tests based on the
decrease in arterial intimal fibrinolytic activity and determination of the coagulation time, which in turn
plasminogen concentration observed in cardiovas- is proportional to the fibrinogen concentration. The
cular disease.26 most widely used method for the functional fibrino-
It has been proposed that once in the arterial gen assay in most clinical laboratories is the Clauss
intima, fibrin stimulates cell proliferation by provid- method, which records the time taken to reach the
ing a scaffold along which cells migrate, and by coagulation end point, (i.e. the formation of a clot).
binding fibronectin, which stimulates cell migration An adequate calibration procedure is indispensable
and adhesion.29 Fibrin degradation products, which for reliable fibrinogen measurements, whatever the
are present in the intima, may stimulate mitogenesis method used, as variation between the declared and
and collagen synthesis, attract leukocytes, and alter measured fibrinogen concentrations can exceed
endothelial permeability and vascular tone. In the 30%.31 The second group of tests quantifies fibrino-
advanced plaque, fibrin itself may be involved in gen molecules directly, either immunologically,
the tight binding of LDL and accumulation of lipid, gravimetrically or precipitation (by heat or salting
Figure 2. Interaction(s) between the coagulation system and fibrinolytic system. PL, phospholipid.
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
Table 1 Mean fibrinogen concentration in different epidemiological studies
Mean fibrinogen (g/l)
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
(Wilhelmsen et al. 1984)
Leigh Nephelometry 297 3.13 3.92 < 0.001
(Stone et al. 1985)
PROCAM Clauss 2187 2.62 2.86 < 0.01
(Heinrich et al. 1991)
Copenhagen Gravimetry 438 2.73
(Moller et al. 1991)
Caerphilly Nephelometry 134 3.60
(Yarnell et al. 1985)
Speedwell Nephelometry 226 2.97 2.87 NS
(Baker et al. 1982) Clauss 223 4.02 4.39 < 0.01
Adapted from Dippel K. Fibrinogen; a cardiovascular risk factor. Boehringer Mannheim GmbH 1992, 1st edition.

Table 2 Plasma fibrinogen levels according to endpoints in epidemiological studies
Fibrinogen level according to end point

Number of
Study (reference) Person-years events End point Fibrinogen level (g/l)
Northwick Park Heart Study 15 110 128 None 2.9

(Meade et al. 1986) IHD deaths 3.1
IHD non-fatal 3.2
All IHD end points 3.2
Other deaths 3.0
Gothenburg Study 10 692 130 None 3.3
(Wilhelmsen et al. 1984) MI 3.6
Stroke 3.7
Other deaths 3.3
Leigh Study 2168 40 None 3.0
(Stone et al. 1985) MI 4.0
Framingham Study 15 780 404 16 events/1000/year < 2.7
(Kannel et al. 1987) 18 events /1000/year 2.7–3.1
26 events/1000/year > 3.1
Caerphilly and Speedwell Studies 20 325 251 None 3.7
(Yarnell et al. 1991) IHD 4.1
Munster Heart Study 4045 15 None 2.6
(Assmann et al. 1996) Any event 3.3
GRIPS 26 195 107 None 3.7
(Cremer et al. 1996) MI 4.0
GRIPS, Gottingen Risk, Incidence and Prevalence Study; IHD, Ischaemic Heart Disease; MI, myocardial infarction. Adapted
from reference 39.
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
the results being uniform despite the diversity of
In a random sample of 792 men aged 54 years, MI
study designs, sample compositions, follow-ups and
occurred in 92 men, stroke in 37, and death from
end-point criteria. In this meta-analysis of 92 147
causes other than MI or stroke in 60 during 13.5
person-years experience, all prospective studies
years of follow-up.2 Plasma fibrinogen was an
showed that plasma fibrinogen was associated
independent risk factor for MI and stroke on
with subsequent myocardial infarction (MI) or
univariate analysis. On multivariate analysis,
stroke. The odds ratio for the events in the
plasma fibrinogen was still statistically significant
upper vs. lower tertile varied between 1.8 (95% CI
for stroke risk.
1.2–2.5) in the Framingham study and 4.1 (95% CI
2.3–6.9) in the Gottingen risk incidence and
prevalence study, with a summary odds ratio of Leigh General Practice Study
2.3 (95% CI 1.9–2.8). Furthermore, there was uni- In the Leigh General Practice Study,41 505 men
form, continuous increase in risk from the lowest to aged 40–69 years and free from IHD, diabetes and
highest tertile. Plasma fibrinogen was associated hypertension were recruited from one general

with ‘true’ risk factors such as diabetes, hypertension practice in the UK. After a mean follow-up of 7.3
and hypercholesterolemia in the studies included years, 40 cases of MI occurred. On multivariate
in this meta-analysis. However, even when these analysis, plasma fibrinogen proved to be the
factors were included in the multivariate analysis, strongest predictor of adverse cardiovascular
the association between plasma fibrinogen and events, with an OR of 21:1 when those with high
cardiovascular disease remained statistically signifi- levels (> 3.5 g/l) were compared to those with
cant, suggesting that fibrinogen is an independent low levels (< 2.9 g/l) of fibrinogen.
cardiovascular risk factor.
In another meta-analysis,40 which included 22 Framingham Study
studies (13 prospective, 5 cross-sectional, and 4
In the Framingham Study,42,43 the risk of developing
case-control) trying to determine the role of fibrino-
cardiovascular disease was significantly related to
gen as a cardiovascular risk factor, the overall
plasma fibrinogen levels. In both sexes, cardiovas-
estimate of risk of cardiovascular events in subjects
cular and stroke risk increased progressively in
with plasma fibrinogen levels in the higher tertile,
relation to antecedent fibrinogen values over the
was twice as high as that of subjects in the lower
1.8–4.5 g/l range. As in NPHS, the influence of
tertile (OR 1.99; 95% CI 1.85–2.13). High plasma
plasma fibrinogen on cardiovascular risk was much
fibrinogen levels were associated with an increased
more pronounced in younger men. The impact of
risk of cardiovascular disease in healthy as much as
plasma fibrinogen levels on cardiovascular disease
in high-risk individuals.
was comparable with the major risk factors, such as
Thus, there is strong and unequivocal evidence
blood pressure, haematocrit, adiposity, cigarette
from epidemiological studies that plasma fibrinogen
smoking and diabetes; and was still an independent
levels are independently related to the presence
predictor of coronary artery disease on multivariate
of, and the subsequent development of, vascular
analysis.
disease. Principal findings from some of the pivotal
epidemiological studies are summarized below.
Munster Heart Study
In the Munster Heart Study (PROspective CArdio-
The Northwick Park Heart Study (NPHS) vascular Munster Study, PROCAM),44 plasma fibri-
In this study, out of 1511 White men aged between nogen, factor VIIc, blood pressure, and lipid
40 and 64 years, 109 subsequently experienced a parameters were measured in 2781 healthy men
first major IHD event.1 Elevated levels of plasma aged 40–65 years. After 8 years of follow-up, 130
Fibrinogen 717
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.
pared to men with both of these parameters in
the lower tertile.
Determinants of plasma
Caerphilly and Speedwell studies
fibrinogen levels
The Caerphilly and Speedwell collaborative heart
disease studies45 were based on a combined cohort Plasma fibrinogen level is dependent upon both
of 4860 middle-aged men from the general popula- genetic and environmental factors.
tion. After a follow-up of 5.1 years in the Caerphilly
study and 3.2 years in the Speedwell study, 251 Genetic influences
major IHD events occurred. The age-adjusted The evidence suggests that plasma fibrinogen levels
relative odds of IHD for men in the top 20% of the are probably under substantial genetic control, as
distribution compared with the bottom 20% were genetic polymorphisms account for some 20–51%
4.1 for fibrinogen, 4.5 for viscosity, and 3.2 for white of variations in plasma fibrinogen levels.49,50 The

blood cell count. Multivariate analysis showed that demonstration of such substantial genetic control
white blood cell count, fibrinogen and viscosity further supports the view that plasma fibrinogen is
were independent risk factors for IHD. a primary risk factor for atherothrombotic disorder
rather than just a reflection of such disorder
European Concerted Action on The fibrinogen locus comprises three genes
Thrombosis and disabilities study (ECAT) coding for fibrinogen gamma (FGG), fibrinogen
In the ECAT,46 plasma fibrinogen was a strong and alpha (FGA), and fibrinogen beta (FGB), clustered
independent risk factor for MI and sudden death, in a region of approximately 50 kb on the long arm
particularly in patients with pre-existing coronary of chromosome 4q23-q32, the direction of tran-
artery disease, along with plasma von Willebrand scription of the b gene being in the opposite
factor (vWF) antigen (a marker of endothelial direction to that of the other two.51 There is a
damage), and tissue plasminogen activator antigen single copy of each gene; the a gene in the middle
(a marker of thrombolytic activity). In patients with flanked by the b gene on one side and the g gene on
coronary artery disease, the relationship of plasma the other. Variation in the fibrinogen locus con-
fibrinogen levels to the incidence of acute coronary tributes to the individual differences in plasma
syndromes was stronger than that of low-density fibrinogen levels.52 However, the precise molecular
lipoprotein cholesterol. Fibrinogen (RR 1.31, 95% CI mechanism(s) underlying the genetic heritability of
1.07–1.61) had a stronger association with future plasma fibrinogen concentration remain unclear.
coronary events than either vWF antigen (RR 1.24, The genetic influence on the fibrinogen beta-
95% CI 1.00–1.53) or t-PA antigen (RR 1.29, 95% CI chain gene has been more extensively studied,
1.04–1.60). because b-chain synthesis is the limiting step in the
production of mature fibrinogen.53 In recent years,
several polymorphisms have been identified in the
Gottingen Risk Incidence and Prevalence fibrinogen chain genes that determine plasma levels
Study (GRIPS) of fibrinogen, mainly by restriction fragment length
As with any other conventional risk factor, very polymorphism (RFLP) and single-stranded confor-
occasionally studies have failed to provide the mation polymorphism (SSCP) analyses.49,52,54,55 For
expected results associating fibrinogen with coron- example, the BclI RFLP of the b fibrinogen gene is
ary artery disease. In the prospective GRIPS47,48 associated with between-person differences in
based on a sample of 6002 men aged 40–60 years, plasma fibrinogen levels.56 Similarly, van’t Hooft
initially free of cardiovascular disease, plasma et al.57 demonstrated that the 455G/A and
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
et al.59 found that plasma fibrinogen levels did not The observation of extrinsic influences on plasma
show any significant associations with the four fibrinogen levels suggests that elevated plasma
fibrinogen polymorphisms examined, at the a (TaqI), fibrinogen levels may be modifiable through appro-
b (BclI and HaeIII), and g (KpnI/SacI) fibrinogen priate lifestyle changes. Furthermore, there is
loci. Humphries et al.49 found that the individuals evidence that strategies that lower the cardiovascu-
with the genotype B1B1 had a mean fibrinogen of
2.74 g/l, while those with B2B2 had a mean plasma
Table 3 Factors influencing plasma fibrinogen levels
fibrinogen level of 3.69 g/l, a level previously
associated with a strongly increased risk of IHD.
Factors associated Factors associated
Those heterozygous for the two alleles, with the with raised fibrinogen with lower fibrinogen
genotype B1B2, had mean plasma fibrinogen levels
of 2.98 g/l. Advancing age Young age
Despite the recognition that plasma fibrinogen Female sex Male sex

levels are under a ‘significant’ degree of genetic Black race Caucasians
control, the precise genes/alleles/polymorphisms Smoking Cessation of smoking
that are responsible for the variation in levels Obesity Weight reduction
Physical inactivity Regular exercise
between different populations, and the clinical
Elevated cholesterol Moderate alcohol
significance, if any, still remains uncertain as consumption
much of the limited data are conflicting. Menopause Hormone replacement
therapy
Extrinsic influences Oral contraception
Low socio-economic
There is evidence that plasma fibrinogen level and
status
its associated cardiovascular risk may be dependent Stress
upon an interaction between environmental and
Table 4 Role of fibrinogen in hypertension
Reference n Age (years) Fibrinogen association
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
levels (0.33 0.1 g/l).
lar risk may also lower plasma fibrinogen levels.62 Surgical treatment of morbid obesity may have a
Nonetheless, whether these measures translate to long-term beneficial effect on mortality from cardio-
clinically relevant benefits remain uncertain, as the vascular and thromboembolic disease, as demon-
mediator(s) of the beneficial effects may be due to strated by the reduction of the decrease in
mechanisms (e.g. endothelial function, lipids, etc.), prothrombotic factors, including fibrinogen.74 In a
or combinations of mechanisms, other than the study by Primrose et al.74 haemostatic and fibrino-
reduction of plasma fibrinogen per se. Some of lytic factors were measured before and again 6 and
the more important extrinsic influences on plasma 12 months after surgery (vertical gastric stapling with
fibrinogen levels are discussed below. or without jejuno-ileal bypass) in 19 patients
suffering from morbid obesity. This resulted in a
Gender mean decrease in body weight of 64 kg at 12
The second World Health Organization MONItor- months, accompanied at 12 months by significant
reductions in median concentrations of serum

ing Trends and Determinants in CArdiovascular
Disease (MONICA) Augsburg survey found the cholesterol (from 5.3 mmol/l to 3.6 mmol/l); factor
crude fibrinogen values to be consistently higher VII (from 113% of normal to 99%); fibrinogen
in women than in men of all ages, irrespective of (from 3.5 g/l to 2.8 g/l); and plasminogen activator
pregnancy or the use of oral contraceptives.63–67 inhibitor-1 activity (from 21 IU/ml to 6.3 IU/ml).
Plasma fibrinogen levels are higher in women than
in men, even after accounting for confounding Metabolic syndrome
factors, as observed in the Goteborg MONICA ‘Metabolic syndrome’ is characterized by the
survey.7 Furthermore, this pattern was observed presence of three or more of the following metab-
even among healthy adolescents in the Florence olic markers: high-density lipoprotein-cholesterol
Teenager Study.64 However, occasional studies < 1.13 mmol/l; triglycerides 1.80 mmol/l; glucose
have failed to demonstrate a significant gender 5.5 mmol/l; diastolic blood pressure 90 mm Hg.
difference in plasma fibrinogen levels between men Obesity, poor cardiorespiratory fitness and the
and women.65 It should also be noted that amongst metabolic syndrome are all closely linked to each
the prospective epidemiological studies, only the other. Furthermore, these may be related to the
Framingham study included women; thus the development of haemorrheological abnormalities
influence of plasma fibrinogen on cardiovascular (such as increased fibrinogen) associated with the
risk amongst women still needs to be more strongly metabolic syndrome. Plasma fibrinogen increases
established. with a number of components of the metabolic
syndrome, independent of major confounders.75
Age The age-adjusted OR for hyperfibrinogenaemia
Plasma concentrations of fibrinogen generally ( 3.47 g/l) was non-significantly higher at 1.69
increase with age.63,65,68,69 This age-related (95% CI 0.87–3.27; p ¼ 0.119) for subjects with the
increase in plasma fibrinogen may be due to a metabolic syndrome when compared with those
slower rate of disposal of fibrinogen, rather than an with no metabolic abnormalities.73
increased production rate.70
Physical exercise
Body mass index and body habitus
Acute exercise
Plasma fibrinogen concentration has been positively
correlated with body mass index, the waist circum- Changes in the plasma fibrinogen levels have been
ference, the hip circumference and waist-to-hip reported after acute exercise, especially when post-
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
fibrinogen levels in patients with some vascular
disorders.86–90 For example, the Rotterdam Study
disease states. For example, in patients with chronic
found a seasonal difference of 0.34 g/l (95% CI
AF exercised to exhaustion, plasma fibrinogen rose
0.29–0.39) and the difference was more pro-
significantly within 20 minutes with a simultaneous
nounced in subjects aged 75 years or older.90
alteration in fibrinolytic activity (i.e., reduced PAI).79
In the latter group, the difference between winter
In another study, in patients with stable chronic
and the summer months ranged as high as 23%.87
heart failure exercised to exhaustion, plasma fibri-
Seasonal variation in plasma fibrinogen levels
nogen level increased significantly within 20
with a rise in winter could be due partly to the
minutes.80 These observations may contribute to
observed seasonal variations in the known vascular
the thromboembolic risk associated with these
risk factors, and partly to the factors described
disease states.
below.
Vitamin C and infection

Regular exercise It has been suggested that a lower dietary intake of
Regular exercise over a span of few weeks or vitamin C and/or an increase in upper respiratory
months has shown a reduction in plasma fibrinogen infections (with its associated acute phase response)
levels both in healthy and diseased individuals. in the winter seasons might be the underlying cause
In healthy individuals, strenuous exercise over a for the raised levels of acute-phase reactants,
period of 4 weeks lowers plasma fibrinogen levels, especially fibrinogen. Furthermore, plasma fibrino-
equivalent to a difference of about 15% in the risk of gen levels correlate with various markers of
IHD.81 In one study, a 12-week exercise-training respiratory infection, such as neutrophil count,
programme in patients with mild hypertension C-reactive protein, self-reported cough and
resulted in a significant decrease in plasma fibrino- coryza.91 However, the studies have generally
gen and an improvement in overall coronary risk yielded inconsistent results.88–89,91–94
profile.77 Regular physical exercise may also be An increase in dietary vitamin C of 60 mg/day
beneficial in reducing overall coronary risk profile (contained in approximately one orange) was
by decreasing the blood pressure and plasma associated with a decrease in plasma fibrinogen
fibrinogen levels in otherwise healthy individuals; concentrations of 0.15 g/l, equivalent to a decline of
Nevertheless, plasma fibrinogen levels return to approximately 10% in risk of IHD.92 Nonetheless, it
baseline values after resumption of sedentary remains to be seen as to whether treatment of the
activity.82 infections results in decrease in plasma fibrinogen
Furthermore, in the Caerphilly Prospective Heart levels and whether decreasing the fibrinogen levels
Disease Study,83 plasma fibrinogen concentrations results in decreased cardiovascular morbidity and
were lowered by 0.24 g/l in the third of men who mortality.
were the most active in leisure activities. Overall, Organisms such as Chlamydia pneumoniae and
the average decrease achieved by regular endur- Helicobacter pylori are implicated in the pathogen-
ance exercise over several months was around esis of coronary artery disease.95,96 Fibrinogen may
0.4 g/l.84 Men with low level of social activities and be implicated in the complex interaction of these
activities at home had a higher plasma fibrinogen infectious agents and coronary artery disease.
concentration, when compared to those with high Antibodies to C. pneumoniae are significantly
levels of activity.85 increased in patients with stroke and severe
Therefore, the available evidence would suggest essential hypertension, but there was no apparent
that regular exercise over a period could exert its association between these titres and plasma fibrino-
beneficial influence on cardiovascular events gen levels.94 Fibrinogen is also thought to be an
Fibrinogen 721
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
Furthermore, in a recent meta-analysis of all in premenopausal women of the same age.106
published prospective studies, C. pneumoniae anti- However, lower plasma viscosity and plasma
body titres were not predictive of CHD in the fibrinogen levels are found in women on HRT
general population.99 Therefore, the question of (both with oestrogen-progesterone combinations
whether these infections increase the cardiovascular and oestrogen monotherapy).107 Theoretically
risk and if so, whether fibrinogen is an intermediary, therefore, the use of HRT may exert a protective
is still far from clear. effect by reducing plasma fibrinogen levels.105
However, evidence for the influence of meno-
pause and/or HRT on plasma fibrinogen has not
Psychosocial factors
been unequivocal. For example, Conard et al.
Adult plasma fibrinogen concentration is deter- (1997) reported a significant increase in plasma
mined by various factors operating throughout life. fibrinogen levels with oral oestrogen HRT.108 More-
The available data suggest that the inverse relation over, the only study on the effect of HRT on
between socio-economic status and coronary artery haemostatic factors following surgical menopause

disease may be partly explained by differences in (patients aged 43 6.5 years) did not find any
plasma fibrinogen levels. significant difference in the levels of plasma
In a cross-sectional study of civil servants in fibrinogen among patients, prior to the surgery and
London, aged 45–55 years, measures of childhood following oopherectomy while taking HRT.8
environment (adult height, father’s social class, and Interestingly, in the Postmenopausal Estrogen/
participant’s education) were inversely associated Progestin Interventions (PEPI) study, which was a
with adult plasma fibrinogen concentration in both three-year, double-blind, placebo-controlled trial of
sexes.100 Lower socio-economic status (as shown by HRT on risk factors in 875 postmenopausal women,
employment grade) was also associated with higher a lower baseline plasma fibrinogen level was
plasma fibrinogen concentrations, which were not significantly associated with venous thrombo-
accounted for by measures of childhood circum- embolic events among subjects who subsequently
stances. Control over work, assessed by personnel received HRT.109
managers and self, was also inversely related to Many questions relating to the interaction
plasma fibrinogen levels.100 between hormonal status, fibrinogen and cardiovas-
Furthermore, the results of the Stockholm Heart cular disorders remain unanswered. The available
Epidemiology Programme (SHEEP) study suggest data are inconsistent, and vary with regard to
that adverse job characteristics might also be related populations and type of hormone preparation
to plasma fibrinogen concentrations, particularly in studied.
female workers.101 Low self reported control over
the job, inferred high demand, and inferred job
Smoking
strain were significantly associated with increased
plasma fibrinogen concentration. Available evidence suggests that cigarette smoking
is strongly associated with increased plasma fibrino-
gen levels, and the adverse cardiovascular effects of
Hormonal status smoking may partly be mediated through an
Both cross sectional and longitudinal studies increase in plasma fibrinogen levels.110–112 Indeed,
demonstrate that oral contraceptive (OC) pill use each cigarette smoked per day increases mean
results in a significant rise in plasma fibrinogen plasma fibrinogen by 0.35 g/l.65
levels, an effect that seems to be strongest in OCs Similar data are available from epidemiological
with a high oestrogen concentration.69,102 Further- studies. In the Framingham study, plasma fibrinogen
more, there are positive and significant interactions values were significantly higher in smokers than in
non-smokers, with a dose-dependent increase with Alcohol

smoking in both sexes; ex-smokers had values as
low as those of non-smokers. Over 10 years of Moderate drinking appears to lower plasma fibrino-
follow-up, the risk in both sexes increased pro- gen concentrations. The so-called ‘French paradox’
gressively in relation to antecedent plasma fibri- may be at least partly explained in relation to the
effects of alcohol on clotting factors. For example, in
nogen values over the 1.8–4.5 g/l range.113 In
the DESIR Study (Data from an Epidemiological
the second MONICA Augsburg survey, the
Study on the Insulin Resistance syndrome) of 4967
impact on the population plasma fibrinogen level
men and women aged 30–64 years, alcohol
was most pronounced for age in both sexes,
consumption was associated with plasma fibrinogen
followed closely by body mass index and cigarette
levels, with higher concentrations in those who
smoking.63 In the MUNSTER Heart Study, smoking-
were non-drinkers or who drank > 60 g of alcohol
related adverse changes in plasma fibrinogen were
per day.61 This U-shaped association was stronger
of greater magnitude in men than in women.114 A
amongst men than women. Consumption of wine
switch from cigarette to cigar smoking is also
and spirits was also associated with changes in
associated with a large increase in plasma fibri-
plasma fibrinogen levels, whereas consumption of
nogen levels,115 in keeping with the observation
beer or cider was not. In women, for example, 1 g of
that cigar smokers remain at an increased risk of
alcohol per day induces a 0.008 g/l decrease in
IHD.116
the mean plasma fibrinogen, while in men the
Passive smoking is not free of risk either, and may
decrease was 0.004 g/l within the down slope of
increase the risk of coronary heart disease partly by
the U-shaped curve.65
increasing plasma fibrinogen concentrations.117
These findings are further supported by other
On average, plasma fibrinogen concentrations studies. For example, a U-shaped relation between
were 0.86 g/l higher in women exposed to cigarette alcohol consumption and plasma fibrinogen levels
smoke outside the home and 1.12 g/l higher in was also found in the second MONICA Augsburg

women exposed both in and outside the home, survey (1989–1990), especially amongst men.63
when compared to women unexposed in either In the Scottish Heart Health Study, plasma
location. Thus, these effects of passive smoking fibrinogen was negatively associated with alcohol
were about 40–60% of that of current active consumption in both sexes.126 Nevertheless, as
smoking. Furthermore, smoking could have an with other factors, there have been occasional
acute effect on plasma fibrinogen levels. For reports of failure to correlate alcohol with plasma
example, post-MI patients who smoked within the fibrinogen, as in the Munster Arteriosclerosis Study
previous 24 h had significantly higher plasma (MAS).69
fibrinogen levels than patients who refrained from The precise mechanisms by which alcohol
smoking for 24 h.118 influences plasma fibrinogen levels remain uncer-
How does smoking alter plasma fibrinogen levels? tain. Animal experiments have suggested that
Smoking results in an inflammatory reaction, prob- alcohol exerts its effects through the action on the
ably of the pulmonary bronchi and alveoli and genetic expression of plasma fibrinogen in the liver
the blood vessels of the lung parenchyma, as cells.127 On the other hand, alcohol can also result
evidenced by an increase in the levels of C-reactive in high blood pressure and atrial fibrillation (AF),
protein.119,120 The resulting inflammation may which are conditions associated with high plasma
increase the production of the cytokines, such as fibrinogen levels.128,129
interleukin-6,121 which have major roles in the
regulation of synthesis in the liver of acute-phase
proteins, including fibrinogen.122,123 Thus increased
plasma fibrinogen levels in smokers may reflect a Fibrinogen: cause or effect?
chronic inflammatory state of the vascular wall, and As discussed above, epidemiological studies have
may act as an intermediary in the enhanced established that elevated plasma fibrinogen levels
coronary risk among smokers.124 are an independent and modifiable risk factor for
Smoking potentiates thrombosis at the dysfunc- coronary heart disease.130 Nonetheless, in patients
tional endothelium, at least partly by increasing the with established vascular disease, the strength of the
concentration of plasma fibrinogen and altering causal relationship needs to be addressed by
the activity of platelets. All these pro-atherogenic relating plasma fibrinogen levels to disease severity,
effects of smoking to injure the endothelium are prognosis and treatments for the condition, as well
also observed, albeit to lesser extent, in passive as considering whether the pathophysiological
smokers.125 mechanisms make this relationship plausible.
Fibrinogen 723
The clinical scenario modification of cardiovascular risk factors may

result in beneficial reduction of plasma fibrinogen
The concentration of plasma fibrinogen positively levels and better cardiovascular outcome.
correlated with the severity of the underlying
coronary heart disease in some studies.131–133 Fibrinogen as an acute-phase reactant
Plasma fibrinogen levels are higher in patients with
unstable angina than in patients with stable angina, Plasma fibrinogen is an acute-phase protein, and is
and higher in patients with severe vasospastic therefore likely to increase with inflammation or
angina than in those with mild vasospastic angina tissue necrosis. Interpretation of raised fibrinogen
and stable effort angina.133,134 Nevertheless, a more may be complicated by its behavior as an acute-
recent study by Hoffmeister et al. failed to demon- phase reactant. For example, plasma fibrinogen
strate a relationship between plasma fibrinogen concentrations are raised after acute stroke144 and
levels and the severity of IHD in any of the three acute MI,145 probably as an acute phase response.
systems used to score the severity.135 Nevertheless, measurement of plasma fibrinogen
Furthermore, raised plasma fibrinogen levels have levels could potentially be more useful than those of
prognostic implications, being a strong predictor of other acute phase reactants such as C-reactive
coronary heart disease, fatal or non-fatal, new or protein, as fibrinogen is probably more specific to
recurrent, and of death from an unspecified cause, vascular disease.
for both men and women,136–138 and therefore, a However, plasma fibrinogen strongly predicts
predictor of accelerated coronary atherosclerosis. cardiovascular events in patients with established
Furthermore, the beneficial effect of statins and atherosclerotic vascular disorders. Furthermore, it is
fibrates in reducing coronary artery diseases events raised even before the onset of acute stroke and
and mortality cannot entirely be explained by their acute MI in patients with transient ischaemic
beneficial effect on lipids. In addition to lipid attack146,147 and chronic stable angina pectoris,148
lowering, the modification of thrombus formation respectively. Therefore, though plasma fibrinogen is

and degradation, alteration in inflammatory raised in the context of acute cerebrovascular and
response, plaque stabilization and improved cardiovascular events, chronically raised plasma
endothelial function are thought to be responsible fibrinogen appears to be an independent risk factor
for additional reduction of morbidity and mortality for these events.
due to cardiovascular events.139 Nonetheless, as
explained below, although statins appear to Genetic variation in plasma
improve thrombogenicity and endothelial depen- fibrinogen—a causal relationship?
dent vasoresponsiveness, there is lack of convincing
evidence of a reduction in plasma fibrinogen levels Genetic variation in the fibrinogen gene may have
with statins, in contrast to the fibrates. For example, implications in prognosis of patients with vascular
in the Bezafibrate Coronary Atherosclerosis Inter- disorders.149 For example, the data from the
vention Trial (BECAIT), the beneficial effect of Edinburgh Artery Study provide evidence that a
bezafibrate on coronary events in young male polymorphism of the P fibrinogen gene is associated
survivors of MI, was attributed partly to the with a varying risk of peripheral atherosclerosis: the
reduction in plasma fibrinogen levels, in addition 455AA genotype was associated with over twice
to the beneficial effect on plasma lipid profile.140 the risk of PAD, compared with the 455GG
Fibrinogen is also associated with other well- genotype.150
known risk factors for cardiovascular disease, such Furthermore, in subjects with AF, Thr312Ala
as smoking, age, obesity, hypertension and dia- polymorphism gives rise to an increased suscept-
betes.141 Elevation of plasma fibrinogen levels may ibility for embolization of intra-atrial clot,149 and
therefore provide a mechanism for the risk factors to there was decreased survival in those possessing the
exert their effect. Certainly, the positive association A allele following stroke,149 Similarly, in some
between plasma fibrinogen levels and cardiovascu- patients with deep venous thrombosis, variations
lar events is as strong as that for elevated cholesterol in the fibrinogen genotype could predispose to the
levels.142 Higher levels of plasma fibrinogen mark- embolization of formed fibrin clot, resulting in
edly increase the predictive power of high serum pulmonary embolism.151
LDL cholesterol; conversely, low plasma fibrinogen It is important to appreciate that although several
levels are associated with low coronary risk, even studies demonstrate a strong association between
when LDL is raised.143 Interestingly, plasma fibrino- polymorphisms of the fibrinogen b-chain gene and
gen levels are also raised in people with family plasma fibrinogen concentration, only a few have
history of premature heart disease.126 Therefore, found a direct association between the former and
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 for screening programmes to identify people at high
Therefore, many questions remain unanswered. risk of vascular events, and attempts should be made
Does a particular genetic polymorphism predispose to strengthen the treatment of other risk factors in
to atherosclerotic disease? And if it does, is it these patient groups.
mediated through raised fibrinogen or some asso-
ciated mechanism? Some studies conducted on
twins suggest that the environment, rather than Acknowledgements
genetic influences could have a greater influence on
plasma fibrinogen levels.155 We acknowledge the support of the Peel Medical
Research Trust and the Sandwell & West Birming-
ham Hospitals NHS Trust Research and Develop-
ment programme for the Haemostasis Thrombosis
and Vascular Biology Unit. SK is supported by a
Conclusions non-promotional research fellowship from Sanofi-

A definite association exists between fibrinogen Winthrop. We thank Dr A.D. Blann for helpful
and atherothrombogenesis. However, the nature comments on the manuscript.
of the link is unclear. Although epidemiological
and clinical studies suggest that the link is causal,
no definite evidence exists. Furthermore, plasma References
fibrinogen concentration is positively correlated 1. Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti
with nearly all other cardiovascular risk factors, RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson
and may be a common mechanism by which SG. Haemostatic function and ischaemic heart disease:
principal results of the Northwick Park Heart Study. Lancet
these risk factors predispose to cardiovascular
1986; 2:533–7.
events. It appears that fibrinogen concentration
2. Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B,
and plasma viscosity are at least as predictive of
Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and
coronary events as are cholesterol concentration, MI. N Engl J Med 1984; 311:501–5.
diastolic blood pressure and body mass index.45 3. Folsom AR, Wu KK, Conlan MG, Finch A, Davis CE,
Encouragingly, plasma fibrinogen is partly a Marcucci G, Sorlie PD, Szklo M. Distributions of hemostatic
modifiable risk factor, and suitable lifestyle changes variables in blacks and whites: population reference values
usually result in favourable decreases in plasma from the Atherosclerosis Risk in Communities (ARIC) Study.
Ethn Dis 1992; 2:35–46.
fibrinogen levels, although drug therapy has not
been fully validated. 4. Gaines K, Burke G. Ethnic differences in stroke: black-white
differences in the United States population. SECORDS
The relationship between genetic polymorphism
Investigators. Southeastern Consortium on Racial Differences
in the fibrinogen gene and cardiovascular risk is in Stroke. Neuroepidemiology 1995; 14:209–39.
very complex. Although polymorphisms in the 5. Hajat C, Dundas R, Stewart JA, Lawrence E, Rudd AG,
fibrinogen gene could potentially augment the Howard R, Wolfe CD. Cerebrovascular risk factors and stroke
cardiovascular risk through increased fibrinogen subtypes: differences between ethnic groups. Stroke 2001;
levels, the effect appears to be antagonized by 32:37–42.
some unknown mechanism due to the same 6. Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD, Szklo
polymorphism. Therefore, polymorphisms of M. Population correlates of plasma fibrinogen and factor VII,
putative cardiovascular risk factors. Atherosclerosis 1991;
fibrinogen gene may modify the effect of external
91:191–205.
influences on the final phenotype (i.e. the vascular
7. Dotevall A, Johansson S, Wilhelmsen L. Association between
risk) rather than directly affecting the risk of fibrinogen and other risk factors for cardiovascular disease in
the disease through plasma fibrinogen levels. men and women. Results from the Goteborg MONICA survey
In future, gene-environment interactions should 1985. Ann Epidemiol 1994; 4:369–74.
Fibrinogen 725
8. Lip GY, Blann AD, Jones AF, Beevers DG. Effects of 24. Tang L. Mechanisms of fibrinogen domains: biomaterial
hormone-replacement therapy on hemostatic factors, lipid interactions. J Biomater Sci Polym Ed 1998; 9:1257–66.
factors, and endothelial function in women undergoing 25. Hu WJ, Eaton JW, Ugarova TP, Tang L. Molecular basis
surgical menopause: implications for prevention of athero- of biomaterial-mediated foreign body reactions. Blood 2001;
sclerosis. Am Heart J 1997; 134:764–71. 98:1231–8.
9. Doolittle RF, Spraggon G, Everse SJ. Three-dimensional 26. Smith EB. Fibrinogen, fibrin and fibrin degradation products in
structural studies on fragments of fibrinogen and fibrin. relation to atherosclerosis. Clin Haematol 1986; 15:355–70.
Curr Opin Struct Biol 1998; 8:792–8. 27. Levenson J, Giral P, Razavian M, Gariepy J, Simon A
10. Herrick S, Blanc-Brude O, Gray A, Laurent G. Fibrinogen. Fibrinogen and silent atherosclerosis in subjects with
Int J Biochem Cell Biol 1999; 31:741–6. cardiovascular risk factors. Arterioscler Thromb Vasc Biol
11. Haidaris PJ, Francis CW, Sporn LA, Arvan DS, Collichio FA, 1995; 15:1263–8.
Marder VJ. Megakaryocyte and hepatocyte origins of human 28. Cook NS, Ubben D. Fibrinogen as a major risk factor
fibrinogen biosynthesis exhibit hepatocyte-specific expres- in cardiovascular disease. Trends Pharmacol Sci 1990;
sion of gamma chain-variant polypeptides. Blood 1989; 11:444–51.
74:743–50. 29. Naito M, Funaki C, Hayashi T, Yamada K, Asai K, Yoshimine
12. Schneider DJ, Taatjes DJ, Howard DB, Sobel BE. Increased N, Kuzuya F. Substrate-bound fibrinogen, fibrin and
reactivity of platelets induced by fibrinogen independent of other cell attachment-promoting proteins as a scaffold for
its binding to the IIb-IIIa surface glycoprotein: a potential cultured vascular smooth muscle cells. Atherosclerosis 1992;
contributor to cardiovascular risk. J Am Coll Cardiol 1999; 96:227–34.
33:261–6. 30. Cahill M, Mistry R, Barnett DB. The human platelet
13. Altieri DC, Bader R, Mannucci PM, Edgington TS. Oligospe- fibrinogen receptor: clinical and therapeutic significance.
cificity of the cellular adhesion receptor Mac-1 encompasses Br J Clin Pharmacol 1992; 33:3–9.
an inducible recognition specificity for fibrinogen. J Cell Biol 31. Mackie J, Lawrie AS, Kitchen S, Gaffney PJ, Howarth D, Lowe
1988; 107:1893–900. GD, Martin J, Purdy G, Rigsby P, Rumley A. A performance
14. Colman RW. Interactions between the contact system, evaluation of commercial fibrinogen reference preparations
neutrophils and fibrinogen. Adv Exp Med Biol 1990; and assays for Clauss and PT-derived fibrinogen. Thromb
Haemost 2002; 87:997–1005.
281:105–20.

32. Whitton CM, Sands D, Hubbard AR, Gaffney PJ. A
15. Altieri DC, Agbanyo FR, Plescia J, Ginsberg MH, Edgington
collaborative study to establish the 2nd International
TS, Plow EF. A unique recognition site mediates the
Standard for Fibrinogen, Plasma. Thromb Haemost 2000;
interaction of fibrinogen with the leukocyte integrin Mac-1
84:258–62.
(CD11b/CD18). J Biol Chem 1990; 265:12119–22.
33. Smith FB, Lowe GDO, Fowkes FGR, Rumley A, Rumley AG,
16. van de Stolpe A, Jacobs N, Hage WJ, Tertoolen L, van Kooyk
Donnan PT, Housley E. Smoking, haemostatic factors and
Y, Novakova IR, de Witte T. Fibrinogen binding to ICAM-1
lipid peroxides in a population case control study of
on EA.hy 926 endothelial cells is dependent on an intact
peripheral artery disease. Atherosclerosis 1993; 102:155–62.
cytoskeleton. Thromb Haemost 1996; 75:182–9.
34. Smith FB, Lee AJ, Fowkes FGR, Rumley A, Lowe GDO.
17. Duperray A, Languino LR, Plescia J, McDowall A, Hogg N, Smoking, haemostatic factors and the severity of aorto-iliac
Craig AG, Berendt AR, Altieri DC. Molecular identification of and femoro-popliteal disease. Thromb Haemostas 1996;
a novel fibrinogen binding site on the first domain of ICAM-1 75:19–24.
regulating leukocyte-endothelium bridging. Biol Chem 1997;
35. Yarnell JWG, Sweetham PM, Elwood PC, Eastham R,
272:435–41.
Gilmour RA, O’Brien JR, Etherington MD. Haemostatic
18. Harley SL, Sturge J, Powell JT. Regulation by fibrinogen and factors and ischameic heart disease. The Caerphilly Study.
its products of intercellular adhesion molecule-1 expression Br Heart J 1985; 53:483–7.
in human saphenous vein endothelial cells. Arterioscler
36. Sweetnam PM, Thomas HF, Yarnell JWG, Beswick AD, Baker
Thromb Vasc Biol 2000; 20:652–8.
IA, Elwood PC. Fibrinogen, viscosity and the 10-year
19. Kuijper PH, Gallardo Tores HI, Lammers JW, Sixma JJ, indicence of isvhameic heart disease. Eur Heart J 1996;
Koenderman L, Zwaginga JJ. Platelet associated fibrinogen 17:1814–20.
and ICAM-2 induce firm adhesion of neutrophils under flow 37. Heinrich J, Ballseisen L, Schulte H, Assmann G, van de Loo J.
conditions. Thromb Haemost 1998; 80:443–8. Fibrinogen and factor VII in the prediction of coronary risk.
20. Gardiner EE, D’Souza SE. A mitogenic action for fibrinogen Results from the PROCAM study in healthy men. Arterioscler
mediated through intercellular adhesion molecule-1. J Biol Thromb 1994; 14:54–9.
Chem 1997; 272:15474–80. 38. Rosensen RS, Mosca L, Staffileno BA, Tangney CC. Varia-
21. Forsyth CB, Solovjov DA, Ugarova TP, Plow EF. Integrin bility in fibrinogen measurements: an obstacle to cardiovas-
alpha(M)beta(2)-mediated cell migration to fibrinogen and its cular risk stratification. Atherosclerosis 2001; 159:225–30.
recognition peptides. J Exp Med 2001; 193:1123–33. 39. Ernst E, Resch KL Fibrinogen as a cardiovascular risk factor: a
22. Rubel C, Fernandez GC, Dran G, Bompadre MB, Isturiz MA, meta-analysis and review of the literature. Ann Intern Med
Palermo MS. Fibrinogen promotes neutrophil activation and 1993; 118:956–63.
delays apoptosis. J Immunol 2001; 166:2002–10. 40. Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring
23. Walzog B, Schuppan D, Heimpel C, Hafezi-Moghadam A, plasma fibrinogen to predict stroke and MI: an update.
Gaehtgens P, Ley K. The leukocyte integrin Mac-1 (CD11b/ Arterioscler Thromb Vasc Biol 1999; 19:1368–77.
CD18) contributes to binding of human granulocytes to 41. Stone MC, Thorp JM. Plasm fibrinogen-a major coronary risk
collagen. Exp Cell Res 1995; 218:28–38. factor. J Roy Coll Gen Prac 1985; 35:565–9.
42. Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrino- 56. Green F, Humphries S. Control of plasma fibrinogen level.
gen and risk of cardiovascular disease. The Framingham Baillieres Clin Hematol 1989; 2:945–59.
Study. JAMA 1987; 258:1183–6. 57. van ‘t Hooft FM, von Bahr SJ, Silveira A, Iliadou A, Eriksson P,
43. Kannel WB, D’Agostino RB, Wilson PW, Belanger AJ, Hamsten A. Two common, functional polymorphisms in the
Gagnon DR. Diabetes, fibrinogen, and risk of cardiovascular promoter region of the beta-fibrinogen gene contribute to
disease: the Framingham experience. Am Heart J 1990; regulation of plasma fibrinogen concentration. Arterioscler
120:672–6. Thromb Vasc Biol 1999; 19:3063–70.
44. Assmann G, Cullen P, Heinrich J, Schulte H. Hemostatic 58. Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE,
variables in the prediction of coronary risk: results of the 8 Abildgaard S, Schnohr P, Nordestgaard BG. A common
year follow-up of healthy men in the Munster Heart Study mutation (G-455!A) in the beta-fibrinogen promoter is an
(PROCAM). Prospective Cardiovascular Munster Study. Isr J independent predictor of plasma fibrinogen, but not of
Med Sci 1996; 32:364–70. ischemic heart disease. A study of 9,127 individuals based
on the Copenhagen City Heart Study. J Clin Invest 1997;
45. Yarnell JW, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, 99:3034–9.
Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white
59. Connor JM, Fowkes FG, Wood J, Smith FB, Donnan PT,
blood cell count are major risk factors for ischemic heart
Lowe GD. Genetic variation at fibrinogen loci and plasma
disease. The Caerphilly and Speedwell collaborative heart
fibrinogen levels. J Med Genet 1992; 29:480–482.
disease studies. Circulation 1991; 83:836–44.
60. Kelleher CC. Plasma fibrinogen and factor VII as risk factors
46. Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo
for cardiovascular disease. Eur J Epidemiol 1992; 8
JC. Hemostatic factors and the risk of MI or sudden death in
(Suppl. 1):79–82.
patients with angina pectoris. European Concerted Action on
Thrombosis and Disabilities Angina Pectoris Study Group. 61. Mennen LI, Balkau B, Vol S, Caces E, Eschwege E.
N Engl J Med 1995; 332:635–41. Fibrinogen: a possible link between alcohol consumption
and cardiovascular disease? DESIR Study Group. Arterioscler
47. Cremer P, Nagel D, Seidel D, van de Loo JC, Kienast J. Thromb Vasc Biol 1999; 19:887–92.
Considerations about plasma fibrinogen concentration and
62. Ernst E. Plasma fibrinogen—an independent cardiovascular
the cardiovascular risk: combined evidence from the GRIPS
risk factor. J Intern Med 1990; 227:365–72.
and ECAT studies. Goettingen Risk Incidence and Prevalence
Study. European Concerted Action on Thrombosis and 63. Krobot K, Hense HW, Cremer P, Eberle E, Keil U.

Disabilities. Am J Cardiol 1996; 78:380–1. Determinants of plasma fibrinogen: relation to body weight,
waist-to-hip ratio, smoking, alcohol, age, and sex. Results
48. Cremer P, Nagel D, Labrot B, Mann H, Muche R, Elster H,
from the second MONICA Augsburg survey 1989–1990.
Seidel D. Lipoprotein Lp(a) as predictor of MI in comparison Arterioscler Thromb 1992; 12:780–8.
to fibrinogen, LDL cholesterol and other risk factors: results
64. Prisco D, Fedi S, Brunelli T, et al. Fibrinogen and factor VIIag
from the prospective Gottingen Risk Incidence and Preva-
in healthy adolescents: the Floren-teen (Florence teenager)
lence Study (GRIPS). Eur J Clin Invest 1994; 24:444–53.
Study. Thromb Haemost 1996; 75:778–81.
49. Humphries SE, Cook M, Dubowitz M, Stirling Y, Meade TW.
65. Tarallo P, Henny J, Gueguen R, Siest G. Reference limits of
Role of genetic variation at the fibrinogen locus in
plasma fibrinogen. Eur J Clin Chem Clin Biochem 1992;
determination of plasma fibrinogen concentrations. Lancet
30:745–51.
1987; 1:1452–5.
66. Laharrague PF, Cambus JP, Fillola G, Corberand JX Plasma
50. Hamsten A, Iselius L, de Faire U, Blomback M. Genetic and
fibrinogen and physiological aging. Aging (Milano) 1993;
cultural inheritance of plasma fibrinogen concentration. 5:445–9.
Lancet 1987; 2:988–91.
67. Giansante C, Fiotti N, Cattin L, Da Col PG, Calabrese S
51. Kant JA, Fornace AJ Jr, Saxe D, Simon MI, McBride OW, Fibrinogen, D-dimer and thrombin-antithrombin complexes
Crabtree GR. Evolution and organization of the fibrinogen in a random population sample: relationships with
locus on chromosome 4: gene duplication accompanied by other cardiovascular risk factors. Thromb Haemost 1994;
transposition and inversion. Proc Natl Acad Sci USA 1985; 71:581–6.
82:2344–8.
68. Ishikawa S, Kario K, Nago N, et al. Factor VII and fibrinogen
52. Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, levels examined by age, sex, and other atherosclerotic risk
Meade TW, Humphries SE. Variation in the promoter region factors in a Japanese population. The Jichi Medical School
of the beta fibrinogen gene is associated with plasma Cohort Study. Thromb Haemost 1997; 77:890–3.
fibrinogen levels in smokers and non-smokers. Thromb 69. Balleisen L, Bailey J, Epping PH, Schulte H, van de Loo J.
Haemost 1991; 65:487–90. Epidemiological study on factor VII, factor VIII and fibrinogen
53. Yu S, Sher B, Kudryk B, Redman CM. Fibrinogen precursors: in an industrial population: I. Baseline data on the relation to
order of assembly of fibrinogen chains. J Biol Chem 1984; age, gender, body-weight, smoking, alcohol, pill-using, and
259:10574–81. menopause. Thromb Haemost 1985; 54:475–9.
54. Fellowes AP, Brennan SO, George PM. Identification and 70. Fu A, Sreekumaran Nair K. Age effect on fibrinogen and
characterization of five new fibrinogen gene polymorphisms. albumin synthesis in humans. Am J Physiol 1998; 275
Ann N Y Acad Sci 2001; 936:536–41. (6 Pt 1):E1023–30.
55. Green F, Hamsten A, Blomback M, Humphries S. The role of 71. Ditschuneit HH, Flechtner-Mors M, Adler G. Fibrinogen in
beta-fibrinogen genotype in determining plasma fibrinogen obesity before and after weight reduction. Obes Res 1995;
levels in young survivors of myocardial infarction and 3:43–8.
healthy controls from Sweden. Thromb Haemost 1993; 72. Craveri A, Tornaghi G, Paganardi L, Ranieri R, Leonardi G,
70:915–20. Di Bella M. Hemorrheologic disorders in obese patients.
Fibrinogen 727
Study of the viscosity of the blood, erythrocytes, plasma, 89. Frohlich M, Sund M, Russ S, Hoffmeister A, Fischer HG,
fibrinogen and the erythrocyte filtration index. Minerva Med Hombach V, Koenig W. Seasonal variations of rheological
1987; 78:899–906. and hemostatic parameters and acute-phase reactants in
73. Carroll S, Cooke CB, Butterly RJ. Plasma viscosity, fibrinogen young, healthy subjects. Arterioscler Thromb Vasc Biol 1997;
and the metabolic syndrome: effect of obesity and cardio- 17:2692–7.
respiratory fitness. Blood Coagul Fibrinolysis 2000; 11:71–8. 90. van der Bom JG, de Maat MP, Bots ML, Haverkate F, de Jong
74. Primrose JN, Davies JA, Prentice CR, Hughes R, Johnston D. PT, Hofman A, Kluft C, Grobbee DE. Elevated plasma
Reduction in factor VII, fibrinogen and plasminogen activator fibrinogen: cause or consequence of cardiovascular disease?
inhibitor-1 activity after surgical treatment of morbid obesity. Arterioscler Thromb Vasc Biol 1998; 18:621–5.
Thromb Haemost 1992; 68:396–9. 91. Woodhouse PR, Khaw KT, Plummer M, Foley A, Meade
75. Bruno G, Cavallo-Perin P, Bargero G, Borra M, D’Errico N, TW. Seasonal variations of plasma fibrinogen and factor VII
Macchia G, Pagano G. Hyperfibrinogenemia and metabolic activity in the elderly: winter infections and death from
syndrome in type 2 diabetes: a population-based study. cardiovascular disease. Lancet 1994; 343:435–9.
Diabetes Metab Res Rev 2001; 17:124–30. 92. Khaw KT, Woodhouse P. Interrelation of vitamin C,
76. El-Sayed MS, Jones PG, Sale C. Exercise induces a change infection, haemostatic factors, and cardiovascular disease.
in plasma fibrinogen concentration: fact or fiction? Thromb Br Med J 1995; 310:1559–63.
Res 1999; 96:467–72. 93. Cook PJ, Honeybourne D, Lip GY, Beevers DG, Wise R,
77. Zanettini R, Bettega D, Agostoni O, Ballestra B, del Rosso G, Davies P. Chlamydia pneumoniae antibody titers are
di Michele R, Mannucci PM. Exercise training in mild significantly associated with acute stroke and transient
hypertension: effects on blood pressure, left ventricular mass cerebral ischemia: the West Birmingham Stroke Project.
and coagulation factor VII and fibrinogen. Cardiology 1997; Stroke 1998; 29:404–10.
88:468–73. 94. Cook PJ, Lip GY, Davies P, Beevers DG, Wise R,
78. Schuit AJ, Schouten EG, Kluft C, de Maat M, Menheere PP, Honeybourne D. Chlamydia pneumoniae antibodies
Kok FJ. Effect of strenuous exercise on fibrinogen and in severe essential hypertension. Hypertension 1998;
fibrinolysis in healthy elderly men and women. Thromb 31:589–94.
Haemost 1997; 78:845–51. 95. Wong YK, Dawkins KD, Ward ME. Circulating Chlamydia
79. Li-Saw-Hee FL, Blann AD, Edmunds E, Gibbs CR, Lip GYH. pneumoniae DNA as a predictor of coronary artery disease.

Effect of acute exercise on the raised Plasma fibrinogen, J Am Coll Cardiol 1999; 34:1435–9.
soluble P-selectin and vWF levels in Chronic Atrial Fibrilla- 96. Zito F, Di Castelnuovo A, D’Orazio A, Negrini R, De Lucia
tion. Clin Cardiol 2001; 24:409–14. D, Donati MB, Iacoviello L. Helicobacter pylori infection
80. Gibbs CR, Blann AD, Edmunds E, Watson RDS, Lip GYH. and the risk of MI: role of fibrinogen and its genetic control.
Effects of acute exercise on hemorrheological, endothelial Thromb Haemost 1999; 82:14–18.
and platelet markers in patients with chronic heart failure in
97. Peach HG, Bath NE, Farish SJ. Helicobacter pylori infection
sinus rhythm. Clin Card 2001; 24:724–9.
is not a correlate of plasma fibrinogen in the Australian
81. Connelly JB, Cooper JA, Meade TW. Strenuous exercise, population. Clin Lab Haematol 1999; 21:41–3.
plasma fibrinogen, and factor VII activity. Br Heart J 1992;
98. Stone AF, Mendall MA, Kaski JC, Edger TM, Risley P,
67:351–4.
Poloniecki J, Camm AJ, Northfield TC. Effect of treatment for
82. Bettega D, Zanettini R, Ferretti M. Physical training exercise Chlamydia pneumoniae and Helicobacter pylori on mar-
reduces the plasma levels of fibrinogen in subjects with mild kers of inflammation and cardiac events in patients with
hypertension. Ann Ital Med Int 1995; 10:167–70. acute coronary syndromes: South Thames Trial of Anti-
83. Elwood PC, Yarnell JW, Pickering J, Fehily AM, O’Brien JR. biotics in Myocardial Infarction and Unstable Angina
Exercise, fibrinogen, and other risk factors for ischaemic heart (STAMINA). Circulation 2002; 106:1219–23.
disease. Caerphilly Prospective Heart Disease Study. Br Heart 99. Danesh J, Whincup P, Lewington S, Walker M, Lennon L,
J 1993; 69:183–7. Thomson A, Wong YK, Zhou X, Ward M. Chlamydia
84. Ernst E. Regular exercise reduces fibrinogen levels: a review pneumoniae IgA titres and coronary heart disease;
of longitudinal studies. Br J Sports Med 1993; 27:175–6. prospective study and meta-analysis. Eur Heart J 2002;
85. Rosengren A, Wilhelmsen L, Welin L, Tsipogianni A, Teger- 23:371–5.
Nilsson AC, Wedel H. Social influences and cardiovascular 100. Brunner E, Davey Smith G, Marmot M, Canner R, Beksinska
risk factors as determinants of plasma fibrinogen concentra- M, O’Brien J. Childhood social circumstances and psycho-
tion in a general population sample of middle aged men. social and behavioural factors as determinants of plasma
Br Med J 1990; 300:634–8. fibrinogen. Lancet 1996; 347:1008–13.
86. Murciano Revert J, Martinez-Lahuerta JJ, Porcar LA. The 101. Tsutsumi A, Theorell T, Hallqvist J, Reuterwall C, de Faire U.
seasonal variation in the plasma fibrinogen concentrations Association between job characteristics and plasma fibrino-
in patients with essential arterial hypertension. Aten Primaria gen in a normal working population: a cross sectional
1998; 22:298–301. analysis in referents of the SHEEP Study. Stockholm
87. Stout RW, Crawford V. Seasonal variations in fibrinogen Heart Epidemiology Program. J Epidemiol Community
concentrations among elderly people. Lancet 1991; Health 1999; 53:348–54.
338:9–13. 102. Task Force on Oral Contraceptives. A multicentre study of
88. Crawford VL, Sweeney O, Coyle PV, Halliday IM, Stout RW coagulation and haemostatic variables during oral contra-
The relationship between elevated fibrinogen and markers of ception: variations with four formulations. Task Force on
infection: a comparison of seasonal cycles. Q J Med 2000; Oral Contraceptives–WHO Special Programme of
93:745–50. Research, Development and Research Training in Human
Reproduction, World Health Organization, Geneva, Swit- 120. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC.
zerland. Br J Obstet Gynaecol 1991; 98:1117–28. C reactive protein and its relation to cardiovascular risk
103. Scarabin PY, Vissac AM, Kirzin JM, Bourgeat P, Amiral J, factors: a population based cross sectional study. Br Med J
Agher R, Guize L. Elevated plasma fibrinogen and increased 1996; 312:1061–5.
fibrin turnover among healthy women who both smoke 121. McCarty MF. Interleukin-6 as a central mediator of
and use low-dose oral contraceptives—a preliminary report. cardiovascular risk associated with chronic inflammation,
Thromb Haemost 1999; 82:1112–16. smoking, diabetes, and visceral obesity: down-regulation
104. Ernst E. Oral contraceptives, fibrinogen and cardiovascular with essential fatty acids, ethanol and pentoxifylline.
risk. Atherosclerosis 1992; 93:1–5. Med Hypotheses 1999; 52:465–77.
105. Lee AJ, Lowe GD, Smith WC, Tunstall-Pedoe H. Plasma 122. Castell JV, Gomez-Lechon MJ, David M, Andus T, Geiger T,
fibrinogen in women: relationships with oral contraception, Trullenque R, Fabra R, Heinrich PC. Interleukin-6 is the
the menopause and hormone replacement therapy. Br J major regulator of acute phase protein synthesis in adult
Haematol 1993; 83:616–21. human hepatocytes. FEBS Lett 1989; 242:237–9.
106. Meade TW, Haines AP, Imeson JD, Stirling Y, Thompson 123. Marinkovic S, Jahreis GP, Wong GG, Baumann H. IL-6
SG. Menopausal status and haemostatic variables. Lancet modulates the synthesis of a specific set of acute phase
1983; 1:22–4. plasma proteins in vivo. J Immunol 1989; 142:808–12.
107. Frohlich M, Schunkert H, Hense HW, Tropitzsch A, 124. de Maat MP, Pietersma A, Kofflard M, Sluiter W, Kluft C.
Hendricks P, Doring A, Riegger GA, Koenig W. Effects of Association of plasma fibrinogen levels with coronary artery
hormone replacement therapies on fibrinogen and plasma disease, smoking and inflammatory markers. Atherosclero-
viscosity in postmenopausal women. Br J Haematol 1998; sis 1996; 121:185–9.
100:577–81.
125. Powell JT. Vascular damage from smoking: disease
108. Conard J, Gompel A, Pelissier C, Mirabel C, Basdevant A. mechanisms at the arterial wall. Vasc Med 1998; 3:21–8.
Fibrinogen and plasminogen modifications during
126. Lee AJ, Lowe GD, Woodward M, Tunstall-Pedoe H.
oral estradiol replacement therapy. Fertil Steril 1997;
Fibrinogen in relation to personal history of prevalent
68:449–53.
hypertension, diabetes, stroke, intermittent claudication,
109. Whiteman MK, Cui Y, Flaws JA, Espeland M, Bush TL. coronary heart disease, and family history: the Scottish
Low fibrinogen level: A predisposing factor for venous Heart Health Study. Br Heart J 1993; 69:338–42.

thromboembolic events with hormone replacement ther-
127. Wang Z, Barker TH, Fuller GM. Alcohol at moderate levels
apy. Am J Hematol 1999; 61:271–3.
decreases fibrinogen expression in vivo and in vitro.
110. Eliasson M, Asplund K, Evrin PE, Lundblad D. Relationship Alcohol Clin Exp Res 1999; 23:1927–3.
of cigarette smoking and snuff dipping to plasma fibrinogen,
fibrinolytic variables and serum insulin. The Northern 128. Saunders JB, Beevers DG, Paton A Alcohol-induced
Sweden MONICA Study. Atherosclerosis 1995; 113:41–53. hypertension. Lancet 1981; 2:653–6.
111. Cigolini M, Targher G, de Sandre G, Muggeo M, Seidell JC. 129. Lip GY, Lowe GD, Rumley A, Dunn FG.Increased markers
Plasma fibrinogen in relation to serum insulin, smoking of thrombogenesis in chronic atrial fibrillation: effects of
habits and adipose tissue fatty acids in healthy men. warfarin treatment. Br Heart J 1995; 73:527–33.
Eur J Clin Invest 1994; 24:126–30. 130. Danesh J, Collins R, Appleby P, Peto R. Association of
112. Dotevall A, Kutti J, Teger-Nilsson AC, Wadenvik H, fibrinogen, C-reactive protein, albumin, or leukocyte count
Wilhelmsen L. Platelet reactivity, fibrinogen and smoking. with coronary heart disease: meta-analyses of prospective
Eur J Haematol 1987; 38:55–9. studies. JAMA 1998; 279:1477–82.
113. Kannel WB, D’Agostino RB, Belanger AJ. Fibrinogen, 131. Lowe GD, Drummond MM, Lorimer AR, Hutton I, Forbes
cigarette smoking, and risk of cardiovascular disease: CD, Prentice CR, Barbenel JC. Relation between extent of
insights from the Framingham Study. Am Heart J 1987; coronary artery disease and blood viscosity. Br Med J 1980;
113:1006–10. 280:673–4.
114. Cullen P, Schulte H, Assmann G. Smoking, lipoproteins 132. Handa K, Kono S, Saku K, Sasaki J, Kawano T, Sasaki Y,
and coronary heart disease risk. Data from the Munster Hiroki T, Arakawa K. Plasma fibrinogen levels as an
Heart Study (PROCAM). Eur Heart J 1998; 19:1632–41. independent indicator of severity of coronary atherosclero-
115. Meade TW, Imeson J, Stirling Y. Effects of changes in sis. Atherosclerosis 1989; 77:209–1.
smoking and other characteristics on clotting factors and 133. Umemoto S, Suzuki N, Fujii K, Fujii A, Fujii T, Iwami T,
the risk of ischaemic heart disease. Lancet 1987; 2:986–8. Ogawa H, Matsuzaki M. Eosinophil counts and plasma
116. Kaufman DW, Palmer JR, Rosenberg L, Shapiro S. Cigar and fibrinogen in patients with vasospastic angina pectoris. Am J
pipe smoking and MI in young men. Br Med J (Clin Res Ed) Cardiol 2000; 85:715–19.
1987; 294:1315–16. 134. Leschke M, Blanke H, Stellwaag M, Motz W, Strauer BE.
117. Iso H, Shimamoto T, Sato S, Koike K, Iida M, Komachi Y. Hyperfibrinogenemia and pathological plasma viscosity.
Passive smoking and plasma fibrinogen concentrations. Pathogenetic factors in unstable angina pectoris? Dtsch Med
Am J Epidemiol 1996; 144:1151–4. Wochenschr 1988; 113:1175–81.
118. Fisher SD, Zareba W, Moss AJ, Marder VJ, Sparks CE, 135. Hoffmeister A, Rothenbacher D, Bazner U, Frohlich M,
Hochman J, Liang C, Krone RJ. Effect of smoking on Brenner H, Hombach V, Koenig W. Role of novel markers
lipid and thrombogenic factors two months after acute MI. of inflammation in patients with stable coronary heart
Am J Cardiol 2000; 86:813–18. disease. Am J Cardiol 2001; 87:262–6.
119. Das I. Raised C-reactive protein levels in serum from 136. Woodward M, Lowe GD, Rumley A,Tunstall-Pedoe H.
smokers. Clin Chim Acta 1985; 153:9–13. Fibrinogen as a risk factor for coronary heart disease and
Fibrinogen 729
mortality in middle-aged men and women. the Scottish attacks and minor ischaemic strokes. Br Med J 1991;
heart health study. Eur Heart J 1998; 19:55–62. 303:605–9.
137. Ma J, Hennekens CH, Ridker PM, Stampfer MJ. A 147. Coull BM, Beamer N, de Garmo P, Sexton G, Nordt F, Knox
prospective study of fibrinogen and risk of MI in the R, Seaman GV. Chronic blood hyperviscosity in subjects
Physicians’ Health Study. J Am Coll Cardiol 1999; 330 with acute stroke, transient ischemic attack, and risk factors
:1347–52. for stroke. Stroke 1991; 22:162–8.
138. Kannel WB. Influence of fibrinogen on cardiovascular 148. Rainer C, Kawanishi DT, Chandraratna PA, Bauersachs RM,
disease. Drugs 1997; 54 (Suppl. 3):32–40. Reid CL, Rahimtoola SH, Meiselman HJ. Changes in blood
rheology in patients with stable angina pectoris as a result of
139. Joukhadar C, Klein N, Prinz M, Schrolnberger C, Vukovich
coronary artery disease. Circulation 1987; 76:15–20.
T, Wolzt M, Schmetterer L, Dorner GT. Similar effects of
atorvastatin, simvastatin and pravastatin on thrombogenic 149. Carter AM, Catto AJ, Grant PJ. Association of the alpha-
and inflammatory parameters in patients with hypercholes- fibrinogen Thr312Ala polymorphism with poststroke mor-
terolemia. Thromb Haemost 2001; 85:47–51. tality in subjects with atrial fibrillation. Circulation 1999;
99:2423–6.
140. de Faire U, Ericsson CG, Grip L, Nilsson J, Svane B,
Hamsten A. Retardation of coronary atherosclerosis: the 150. Lee AJ, Fowkes FG, Lowe GD, Connor JM, Rumley A.
Bezafibrate Coronary Atherosclerosis Intervention Trial Fibrinogen, factor VII and PAI-1 genotypes and the risk of
(BECAIT) and other angiographic trials. Cardiovasc Drugs coronary and peripheral atherosclerosis: Edinburgh Artery
Ther 1997; 11 (Suppl. 1):257–63. Study. Thromb Haemost 1999; 81:553–60.
141. Kannel WB, D’Agostino RB, Belanger AJ. Update on 151. Carter AM, Catto AJ, Kohler HP, Ariens RA, Stickland MH,
Grant PJ. Alpha-fibrinogen Thr312Ala polymorphism
fibrinogen as a cardiovascular risk factor. Ann Epidemiol
and venous thromboembolism. Blood 2000; 96:1177–9.
1992; 2:457–66.
152. Doggen CJ, Bertina RM, Cats VM, Rosendaal FR. Fibrinogen
142. Montalescot G, Collet JP, Choussat R, Thomas D. Fibrino-
polymorphisms are not associated with the risk of myocar-
gen as a risk factor for coronary heart disease. Eur Heart J
dial infarction. Br J Haematol 2000; 110:935–8.
1998; 19 (Suppl. H):H11–17.
153. Blake GJ, Schmitz C, Lindpaintner K, Ridker PM. Mutation
143. Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J.
in the promoter region of beta-fibrinogen gene and the risk
Fibrinogen and factor VII in the prediction of coronary
of future myocardial infarction, stroke and venous throm-
risk. Results from the PROCAM study in healthy men.

bosis. Eur Heart J 2001; 22:2262–6.
Arterioscler Thromb 1994; 14:54–9.
154. Leander K, Wiman B, Hallqvist J, Falk G, De Faire U. The
144. Eisenberg S. Blood viscosity and fibrinogen concentration
G-455A polymorphism of the fibrinogen BBeta-gene relates
following cerebral infarction. Circulation 1966; 33(5 to plasma fibrinogen in male cases, but does not interact
Suppl):II10–14. with environmental factors in causing myocardial infarction
145. Dormandy J, Ernst E, Matrai A, Flute PT. Hemorrheologic in either men or women. J Intern Med 2002; 252:332–41.
changes following acute MI. Am Heart J 1982; 104:1364–7. 155. Reed T; Tracy RP; Fabsitz RR. Minimal genetic influences
146. Qizilbash N, Jones L, Warlow C, Mann J. Fibrinogen and on plasma fibrinogen level in adult males in the NHLBI twin
lipid concentrations as risk factors for transient ischaemic study. Clin Genet 1994; 45:71–7.

Review: Fibrinogen: Biochemistry, Epidemiology and Determinants

Uploaded by

Copyright:

Available Formats

Review: Fibrinogen: Biochemistry, Epidemiology and Determinants

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Review: Fibrinogen: Biochemistry, Epidemiology and Determinants

Uploaded by

Copyright:

Available Formats

Q J Med 2003; 96:711–729

Fibrinogen: biochemistry, epidemiology and determinants

Downloaded from by guest on June 25, 2016

Figure 1. Plasma fibrinogen, thrombogenesis and atherogenesis.

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Table 1 Mean fibrinogen concentration in different epidemiological studies

Mean fibrinogen (g/l)

Downloaded from by guest on June 25, 2016

Fibrinogen level according to end point

Northwick Park Heart Study 15 110 128 None 2.9

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Table 4 Role of fibrinogen in hypertension

Reference n Age (years) Fibrinogen association

Downloaded from by guest on June 25, 2016

Vitamin C and infection

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

non-smokers, with a dose-dependent increase with Alcohol

Downloaded from by guest on June 25, 2016

The clinical scenario modification of cardiovascular risk factors may

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

Downloaded from by guest on June 25, 2016

You might also like