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PubMed1993

Characterization of purified recombinant fibrinogen: partial phosphorylation of fibrinopeptide A.

Human fibrinogen has been expressed in Chinese hamster ovary (CHO) cells using a novel two-step procedure which permits efficient synthesis of engineered variant fibrinogens. CHO cells secreting recombinant fibrinogen were grown in roller bottles and maintained in serum-free media for several months. Recombinant protein was purified from media containing 2-4 micrograms/mL fibrinogen using protamine-Sepharose chromatography. Recombinant fibrinogen was identical to plasma fibrinogen when examined on Coomassie-stained SDS gels run under reducing conditions, and on SDS gels when run under nonreducing conditions after partial or complete plasmin degradation, indicating normal chain assembly, disulfide bond formation, and overall protein conformation. Thrombin digestion of purified fibrinogen led to clot formation with release of normal fibrinopeptides, as identified by HPLC. Fibrinopeptide A released from recombinant fibrinogen was partially phosphorylated (22%), similar to the degree of phosphorylation found for human plasma fibrinogen (20-25%), indicating that partial phosphorylation in inherent in fibrinogen synthesis.

Animals↗
PubMed1990

Estrogen regulation of Xenopus laevis gamma-fibrinogen gene expression.

Albumin gene expression in Xenopus is regulated by estrogen through changes in the stability of its mRNA. The goal of the present study was to determine whether a similar pathway regulates gamma-fibrinogen. Degenerate oligonucleotides directed to conserved regions of the carboxyl-terminal half (domain D) of human and lamprey gamma-fibrinogen were used to isolate a full-length cDNA clone for Xenopus gamma-fibrinogen. Analysis of codon utilization from the DNA sequence of this clone revealed that Xenopus gamma-fibrinogen mRNA shows the same bias against CG dinucleotides as present in human, but not lamprey, fibrinogen mRNA. Features of the protein shared with the human homologue include all of the cysteine residues, an N-linked glycosylation site at amino acid 50, and 75% sequence identity in domain D. Much of the same region is conserved in lamprey gamma-fibrinogen. There is only a single size mRNA encoding gamma-fibrinogen in Xenopus, unlike rats where two mRNAs of different length are generated by alternate splicing. Administration of estrogen to male Xenopus results in the disappearance of gamma-fibrinogen mRNA from the cytoplasm, with no effect on steady-state levels in the nucleus. This process can be blocked by prior treatment with anti-estrogen, indicating that, like the regulation of serum albumin mRNA, gamma-fibrinogen is regulated posttranscriptionally through an estrogen receptor dependent mechanism. It is postulated that a consensus sequence flanking the AAUAAA polyadenylation signal in gamma-fibrinogen and the 68- and 74-kDa albumin mRNAs, but not vitellogenin or beta-globin mRNA, may play a role in the hormonal regulation of mRNA stability.

Amino Acid Sequence↗
PubMed1998

Substitution of tyrosine for phenylalanine in fibrinopeptide A results in preferential thrombin cleavage of fibrinopeptide B from fibrinogen.

Phenylalanine at residue 8 in the Aalpha chain of fibrinogen is a highly conserved amino acid that is believed to be critical for binding and catalysis by the serine protease thrombin. We have examined the requirement for Phe at this position by constructing a variant recombinant fibrinogen with a conservative substitution of tyrosine for phenylalanine, Aalpha F8Y fibrinogen. We found that the variant fibrinopeptide A (F8Y 1-16) was cleaved by thrombin, in contrast to the lack of cleavage of an Aalpha 1-23 peptide and an Aalpha 1-50 fusion protein with the same substitution. This result indicates that fibrinogen residues other than Aalpha 1-50 participate in thrombin binding and fibrinogen proteolysis. We found, for the first time, that thrombin-catalyzed lysis of the fibrinogen Bbeta chain preceded lysis of the Aalpha chain, such that fibrinopeptide B (FpB) was released prior to F8Y 1-16. Kinetic analysis demonstrated that F8Y 1-16 was a very poor substrate for thrombin, with a specificity constant 280-fold lower than normal fibrinopeptide A. FpB was also a poor substrate, but the specificity constant for FpB was only 4-fold lower than normal. Consequently, FpB was preferentially released from Aalpha F8Y fibrinogen. This "role reversal" had a dramatic effect on polymerization, such that the rate of Aalpha F8Y fibrinogen polymerization was 13% of the rate of normal recombinant fibrinogen. These results confirm the importance of phenylalanine at Aalpha chain residue 8 for efficient thrombin-catalyzed proteolysis of fibrinogen, and further demonstrate that sequential fibrinopeptide release has an important role in normal polymerization.

Amino Acid Substitution↗
PubMed2001

Binding of oral streptococci to human fibrinogen.

The interaction of oral streptococci with human fibrinogen was investigated. Streptococcus gordonii was chosen as a representative species to study the binding to fibrinogen. S. gordonii DL1 adhered to immobilized fibrinogen and bovine serum albumin. Binding to immobilized fibrinogen was saturable, concentration and temperature dependent. The binding of S. gordonii DL1 to fibrinogen was inhibited by anti-fibrinogen antibody. Heating of the bacteria for 1 h at 95 degrees C resulted in 90% inhibition of the binding. Trypsin treatment of the bacteria resulted in decreased binding. Neither lipoteichoic acid nor culturing of the bacteria in a sucrose-supplemented medium had any effect on the binding. S. gordonii, Streptococcus sanguinis, Streptococcus mitis, and Streptococcus oralis bound to the immobilized fibrinogen, but mutans streptococci did not. None of the oral streptococci tested bound to the fibrinogen in fluid phase. These results suggest that the binding of S. gordonii DL1 to immobilized fibrinogen is mediated through a specific protein adhesin-receptor interaction, and fibrinogen acts as a cryptitope.

Adhesins, Bacterial↗
PubMed1993

Evidence for novel binding sites on the platelet glycoprotein IIb and IIIa subunits and immobilized fibrinogen.

The present study was designed to examine the interaction of the purified platelet glycoprotein IIb-IIIa complex (GP IIb-IIIa or integrin alpha IIb beta 3) and the individual subunits of the complex with immobilized fibrinogen. Although 125I-GP IIb-IIIa binding to fibrinogen immobilized on Sepharose was specific, this interaction exhibited properties distinct from those of reversible fibrinogen binding to platelets: 125I-GP IIb-IIIa binding appeared irreversible, but non-covalent, Ca(2+)-independent, and was inhibited only weakly, or not at all, by the anti-(GP IIb-IIIa) monoclonal antibodies 10E5 and 7E3 and synthetic peptides from known platelet-binding domains of fibrinogen. Reversibly dissociated GP IIb or GP IIIa subunits inhibited 125I-GP IIb-IIIa binding to immobilized fibrinogen and bound directly to the fibrinogen. However, these subunits did not bind to peptides derived from known platelet-binding domains within the fibrinogen alpha- and gamma-chains, although the GP IIb-IIIa complex did. These results show that the complexed form of full-length GP IIb and GP IIIa is required for binding to these synthetic peptides, but not necessarily for binding to immobilized fibrinogen. Thus GP IIb-IIIa can bind to immobilized fibrinogen by a distinct mechanism that appears to involve novel binding sites on each subunit of the GP IIb-IIIa complex and on fibrinogen.

Amino Acid Sequence↗
PubMed1996

Down-regulation of fibrinogen biosynthesis by IL-4, IL-10 and IL-13.

High levels of fibrinogen are recognized as an important vascular risk factor; however, it is not known if the increase of plasma fibrinogen is directly responsible for this risk, or is only a marker of vascular inflammation. To support this second hypothesis, Oncostatin M (OSM) is a potent stimulator of fibrinogen biosynthesis and induces smooth muscle cell proliferation. In the same way, we analysed whether interleukin-4 (IL-4), interleukin-10 (IL-10) or interleukin-13 (IL-13), which protect vessel walls from monocytes injuries leading to atherosclerosis, could influence fibrinogen biosynthesis. The two levels of regulation of fibrinogen biosynthesis were tested: firstly, the direct effect of these cytokines on fibrinogen production by the hepatoma cell line Hep G2, and secondly their effect on the secretion of hepatocyte stimulating factor (HSF) activity in the supernatant of lipopolysaccharide (LPS)-activated monocytes. IL-4 and IL-13 added to Hep G2 cells down-regulated both the increase of fibrinogen secretion induced by IL-6 and fibrinogen mRNA levels, this effect being more pronounced when Hep G2 were preincubated with the two cytokines before IL-6 addition. The effect of IL-10 was evidenced only on mRNA expression. IL-10 and IL-13 dose-dependently decrease HSF activity secreted by LPS-activated monocytes, whereas IL-4 had no effect. However, the three cytokines decreased HSF activity when monocytes were incubated with the cytokines before LPS activation. The effects of these cytokines on HSF activity are related to variations of IL-6 and OSM secretion. Our data strengthen the hypothesis that the fibrinogen level is a marker of vascular disease, since cytokines which have a protective vascular effect down-regulate fibrinogen production.

Animals↗
PubMed2003

Fibrinogen, mortality and incident cardiovascular complications in end-stage renal failure.

OBJECTIVE: Fibrinogen is an established predictor of cardiovascular events in the general population but the relationship between fibrinogen, mortality and incident cardiovascular complications has been very little investigated in patients with end-stage renal disease (ESRD). DESIGN AND SUBJECTS: We investigated the relationship between fibrinogen and all cause mortality and cardiovascular outcomes in a prospective cohort study in 192 patients on chronic haemodialysis treatment (follow-up: 34 +/- 16 months). RESULTS: Fibrinogen was significantly higher in patients who died during the follow-up than in those who survived. Similarly, fibrinogen was higher in patients who had fatal or nonfatal cardiovascular events than in event free patients. On multivariate Cox regression analysis fibrinogen was an independent predictor of survival [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.19, 95% confidence interval (CI): 1.05-1.35, P = 0.006] and a highly significant (P = 0.0008), independent predictor of fatal and nonfatal cardiovascular events [hazard ratio (1 g x L(-1) increase in plasma fibrinogen): 1.25, 95% CI: 1.10-1.43] in a model including traditional risk factors and serum C-reactive protein (CRP) and plasma homocysteine. CONCLUSIONS: Fibrinogen is as an independent risk factor for overall and cardiovascular mortality in patients with ESRD. Intervention studies are required to see whether reducing plasma fibrinogen may help to curb the exceedingly high cardiovascular risk of the uremic population.

Adult↗
PubMed2003

Increased albumin and fibrinogen synthesis rate in patients with chronic renal failure.

BACKGROUND: Hypoalbuminemia and hyperfibrinogenemia are frequently observed in patients with chronic renal failure (CRF) and are both associated with cardiovascular diseases. The mechanisms responsible for hypoalbuminemia and hyperfibrinogenemia in CRF are unknown. METHODS: In the present study, both albumin and fibrinogen kinetics were measured in vivo in predialysis patients (N = 6), patients on peritoneal dialysis (N = 7) and control subjects (N = 8) using l-[1-13C]-valine. RESULTS: Plasma albumin concentration was significantly lower in patients on peritoneal dialysis compared to control subjects (P < 0.05). Plasma fibrinogen was significantly increased in both predialysis patients (P < 0.01) as well as patients on peritoneal dialysis (P < 0.001) in comparison to control subjects. In contrast to albumin, fibrinogen is only lost in peritoneal dialysate and not in urine. The absolute synthesis rates (ASR) of albumin and fibrinogen were increased in patients on peritoneal dialysis (ASR albumin, 125 +/- 9 mg/kg/day versus 93 +/- 9 mg/kg/day, P < 0.05; ASR fibrinogen, 45 +/- 4 mg/kg/day versus 29 +/- 3 mg/kg/day, P < 0.01) compared to control subjects. Albumin synthesis is strongly correlated with fibrinogen synthesis (r2 = 0.665, P < 0.0001, N = 21). In this study, the observed hypoalbuminemia in patients on peritoneal dialysis is likely not explained by malnutrition, inadequate dialysis, inflammation, metabolic acidosis, or insulin resistance. We speculate that peritoneal albumin loss is of relevance. CONCLUSION: Synthesis rate of albumin and fibrinogen are coordinately up-regulated. Both albumin and fibrinogen are lost in peritoneal dialysis fluid. To compensate protein loss, albumin synthesis is up-regulated, but the response, in contrast to predialysis patients, does not fully correct plasma albumin concentrations in peritoneal dialysis patients. The increase in fibrinogen synthesis introduces an independent risk factor for atherosclerosis, since plasma fibrinogen pool is enlarged.

Adult↗
PubMed2002

Fibrinogen: associations with cardiovascular events in an outpatient clinic.

BACKGROUND: Fibrinogen, known to influence the coagulation process, is an independent risk factor for coronary artery disease (CAD). However, its association with myocardial infarction (MI) and its predictive potential for short-term mortality, in an ongoing clinical practice, has not been characterized. OBJECTIVES: In a high-risk outpatient practice we sought to demonstrate whether baseline fibrinogen levels related to MI rather than CAD alone, and whether baseline serum fibrinogen levels predicted mortality over a short-term follow-up. METHODS AND RESULTS: From a total of 2126 patients with baseline fibrinogen measurements (mean age, 56 +/- 12 years, 35% female), 1187 patients with CAD (n = 606 with MI) and 939 patients without CAD were evaluated in an active preventive cardiology unit of a large city hospital. Logistic regression models were used to determine the association of fibrinogen with differing CAD presentations. Fibrinogen quartile showed a significant correlation with CAD both univariately and after adjustment for Framingham risk score (odds ratio [OR] = 1.22, P <.001). Fibrinogen levels were significantly associated with the presence of CAD and history of MI (adjusted OR = 1.25, P =.001). Fibrinogen did not show a significant association to CAD when MI was not considered in the analysis (OR = 1.01, P =.82). In this same clinical cohort, after a mean follow-up of 24 +/- 13 months, 41 patients had died. Consistent with the observed association with MI, fibrinogen quartile showed a graded independent relation to mortality in a cohort of both men and women (hazard ratio = 1.81, P <.001). CONCLUSIONS: In the clinical setting of an outpatient clinic, fibrinogen was directly associated with the presence of MI and was revealed to be an independent short-term predictor of mortality.

Biomarkers↗
PubMed1982

Inhibition of fibrinogen binding to human platelets by the tetrapeptide glycyl-L-prolyl-L-arginyl-L-proline.

The role of fibrinogen as a cofactor in platelet aggregation is mediated by its binding to platelet receptors that are induced by stimuli such as ADP. In the present study, we demonstrate that the tetrapeptide glycyl-L-prolyl-L-arginyl-L-proline inhibits the interaction of fibrinogen with its platelet receptor. The primary effect of the peptide was on the extent rather than on the rate of fibrinogen binding. Significant inhibition occurred at a 1:1 molar ratio of peptide to fibrinogen and reached maximal levels at 100:1 ratio. The inhibition was dependent upon fibrinogen concentration and occurred in the presence of calcium or magnesium. The peptide inhibited the binding of fibrinogen to platelets with exposed receptors, suggesting that it interfered directly with the ligand-receptor interaction. Fibrinogen binding supported by epinephrine and thrombin as well as ADP was inhibited by the peptide. Fibrinogen-dependent aggregation of washed platelets by ADP was abolished by a 30-fold molar excess of the peptide. The tetrapeptide is an analog of the amino-terminal sequence of the alpha-chain of fibrin and has been shown to inhibit fibrin polymerization [Laudano, A. P. & Doolittle, R. F. (1978) Proc. Natl. Acad. Sci. USA 75, 3085-3089]. A peptide corresponding to the natural sequence, glycyl-L-prolyl-L-arginyl-L-valyl-L-valine, was also capable of inhibiting fibrinogen binding to the platelet. These results suggest that common structural features within fibrinogen may serve a dual function by permitting the molecule to participate in both platelet aggregation and fibrin formation.

Adenosine Diphosphate↗
PubMed2002

Allosteric effects potentiating the release of the second fibrinopeptide A from fibrinogen by thrombin.

Fibrin formation depends on the release of the two N-terminal fibrinopeptides A (FPA) from fibrinogen, and its formation is accompanied by an intermediate, alpha-profibrin, which lacks only one of the FPA. In this study, we confirm that the maximal levels of alpha-profibrin found over the course of thrombin reactions with human fibrinogen are only half of what would be expected if the first and second FPA were being released independently with equal rate constants. The rapidity of release of the fibrinopeptides by thrombin had been shown to depend on an allosteric transformation that is induced when Na(+) binds to a site defined by the 215-227 residues of thrombin, a transformation that results in the exposure of its fibrinogen-binding exosites transforming the thrombin from a slow to a fast acting form toward fibrinogen. When choline was substituted for sodium to transform thrombin to its slow form, the maximal levels of alpha-profibrin rose to those expected for independent release of the two FPA. Thus, it is only the fast thrombin that releases the second FPA fast, and that fast release only occurs when both FPA are present because of a partial coupling of its release with that of the first FPA. The release of the FPA from purified alpha-profibrin with the first FPA already missing is no faster than the release of any FPA. Surprisingly, we also found that slow thrombin became increasingly transformed to a fast form in the absence of sodium when the fibrinogen was elevated to high concentrations. This potentiation by concentrated fibrinogen also occurs with the recombinant mutant thrombin (Y225P), which is otherwise slow in both the presence and absence of Na(+). The potentiation of thrombin by fibrinogen must be short-lived so that the thrombin reverts to its slow acting form in the interim among encounters with other fibrinogen molecules in dilute fibrinogen solutions lacking Na(+), whereas at high fibrinogen concentrations the thrombin encounters other molecules before it reverts back to the slow form.

Allosteric Site↗
PubMed1987

The platelet fibrinogen receptor: an immunogold-surface replica study of agonist-induced ligand binding and receptor clustering.

Platelet aggregation requires the binding of fibrinogen to its receptor, a heterodimer consisting of the plasma-membrane glycoproteins (GP) IIb and IIIa. Although the GPIIb-IIIa complex is present on the surface of unstimulated platelets, it binds fibrinogen only after platelet activation. We have used an immunogold-surface replica technique to study the distribution of GPIIb-IIIa and bound fibrinogen over broad areas of surface membranes in unstimulated, as well as thrombin-activated and ADP-activated human platelets. We found that the immunogold-labeled GPIIb-IIIa was monodispersed over the surface of unstimulated platelets, although the cell surface lacked immunoreactive fibrinogen. On thrombin-stimulated platelets, approximately 65% of the GPIIb-IIIa molecules were in clusters within the plane of the membrane. Fibrinogen, which had been released from the alpha-granules of these cells, bound to GPIIb-IIIa on the cell surface and was similarly clustered. To determine whether the receptors clustered before ligand binding, or as a consequence thereof, we studied the surface distribution of GPIIb-IIIa after stimulation with ADP, which causes activation of the fibrinogen receptor function of GPIIb-IIIa without inducing the release of fibrinogen. In the absence of added fibrinogen, the unoccupied, yet binding-competent receptors on ADP-stimulated platelets were monodispersed. The addition of fibrinogen caused the GPIIb-IIIa molecules to cluster on the cell surface. Clustering was also induced by the addition of the GPIIb-IIIa-binding domains of fibrinogen, namely the tetrapeptide Arg-Gly-Asp-Ser on the alpha-chain or the gamma-chain decapeptide gamma 402-411. These results show that receptor occupancy causes clustering of GPIIb-IIIa in activated platelets.

Adenosine Diphosphate↗
PubMed2000

Inverse association of physical fitness with plasma fibrinogen level in children: the Columbia University BioMarkers Study.

Plasma fibrinogen has emerged as a risk factor for cardiovascular disease in adults, but relatively little is known about the correlates of plasma fibrinogen level in childhood. In the Columbia University BioMarkers Study (1994-1998), the authors evaluated the association between physical fitness and plasma fibrinogen level in 193 children 4-25 years old; 68% were Hispanic and 46% male. Fitness level assessed by treadmill testing was inversely associated with plasma fibrinogen (r = -0.24, p<0.001). Plasma fibrinogen levels showed a graded inverse relation with tertiles of fitness assessed by treadmill (p<0.001). In multivariate analyses, after adjustment for age, sex, race/ethnicity, body mass index, and presence of the A allele in the -455 position of the beta-fibrinogen promoter gene, the fitness level remained inversely associated with plasma fibrinogen level (beta = -1.3, 95% confidence interval (CI): -2.3, -0.34). Resting heart rate was also correlated with plasma fibrinogen level (r = 0.18, p<0.05). Fibrinogen levels (mg/dl) increased over tertiles of resting heart rate (p = 0.002) and were significantly associated with resting heart rate in multivariate analysis (beta = 0.82, 95% CI: 0.17, 1.5). These findings indicate that plasma fibrinogen is inversely associated with physical fitness in children independent of body mass index.

Adult↗
PubMed1995

Therapeutic interventions to lower plasma fibrinogen concentration.

A causal link between plasma fibrinogen levels and the risk of cardiovascular disease is now reasonably well established. Therefore the therapeutic lowering of fibrinogen has become a relevant area of research. Several options to achieve this aim have been reported in the literature. Changes in lifestyle can affect the fibrinogen level, of which smoking cessation is by far the most effective; weight or stress reduction or an increase in regular physical activity may have less pronounced effects; dietary changes appear to have even less effect, though a regular, moderate alcohol consumption may result in a small reduction. Many oral drugs have been shown to lower fibrinogen; however, the data should be viewed critically. In particular, the clinical situation in which a drug is administered must be considered and risk:benefit analyses should be performed before a drug is recommended for this indication. Among the oral fibrinogen-lowering drugs, fibrates rank first (e.g. bezafibrate has been reported to reduce increased fibrinogen by as much as 40%, and ticlopidine can induce a reduction of about 15% if fibrinogen was elevated at baseline). Whether concentration within the normal range can be altered by oral medication is less clear. Finally (and obviously), intravenous fibrinolytic agents or heparin-induced extracorporeal low-density lipoprotein precipitation will lower fibrinogen dramatically; yet these procedures are rarely indicated for this purpose alone. All options to lower fibrinogen also have prominent effects on other cardiovascular functions; thus, an intervention trial may not be the most appropriate method of testing the validity of the hypothesis of fibrinogen as a cardiovascular risk factor.

Cardiovascular Diseases↗
PubMed2000

High-density lipoproteins inhibit fibrinogen binding on adenosine diphosphate-activated monocytes.

High levels of fibrinogen and low levels of high-density lipoprotein (HDL) cholesterol were reported to be risk factors for coronary heart disease. CD11b/CD18, a fibrinogen-binding protein, is expressed on the surface of monocytes, which play a crucial role in the formation of atherosclerotic lesions. In the present study, we investigate the effects of antibodies against CD11b and CD18, as well as HDL3 and low-density lipoprotein (LDL) cholesterol on fibrinogen binding on monocytes. We find that binding of fibrinogen on monocytes activated with adenosine diphosphate (ADP) was reduced to 66.0+/-8.3% (mean +/- SD) in the presence of anti-CD11b antibodies (12.5 microg/ml; P < or = 0.02) and to 54.5+/-4.9% in the presence of anti-CD18 antibodies (20 microg/ml; P < or = 0.01), respectively. Fibrinogen binding on Cytochalasin-B-activated monocytes was reduced to 79.8+/-6.0% in the presence of anti-CD18 (20 microg/ml; P < or = 0.05). Incubation of ADP-activated monocytes with HDL3 (0.5 g/l) led to a lowering of fibrinogen binding to 65.0+/-6.6% (P < or = 0.05). No effect of HDL3 on fibrinogen binding was seen on Cytochalasin-B-activated monocytes. A slight, non-significant stimulatory effect of LDL on fibrinogen binding on ADP-activated but not on Cytochalasin-B-activated monocytes was additionally observed. Neither incubation with HDL3 or with LDL had a significant influence on ADP-activated cellular binding of anti-CD11b or anti-CD18 antibodies. The inhibition of fibrinogen binding on monocytes in the presence of HDL3 is a major new finding of this study. Since inhibition of fibrinogen binding in the presence of HDL might impair both monocyte recruitment to the arterial wall and foam cells formation, our findings suggests a novel mechanism by which HDL may prevent development of arteriosclerosis.

Adenosine Diphosphate↗
PubMed1998

Plasma fibrinogen and incident hypertension in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Several cross-sectional studies have reported a positive association between plasma fibrinogen levels and prevalent hypertension. Other studies have reported a positive association between hypertension and whole-blood or plasma viscosity, to which fibrinogen contributes. To our knowledge, there has been no prospective study of fibrinogen and incident hypertension. SUBJECTS AND METHODS: We measured plasma fibrinogen levels in a population-based cohort study of middle-aged adults and related it to the occurrence of incident hypertension (systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg or use of antihypertensive medication) over 6 years. RESULTS: There was a moderately strong positive association between fibrinogen levels and prevalent hypertension in both men and women, with the odds of hypertension elevated by 50% for the highest fibrinogen quartile versus the lowest. Among 7884 participants at risk, 1609 developed hypertension over 6 years. Adjusted for age, race, field center and baseline systolic blood pressure, the odds ratio of incident hypertension in relation to fibrinogen quartiles was 1.0, 1.07, 1.21 and 1.43 in men (P= 0.003 for trend) and 1.0, 0.92, 0.99 and 0.99 in women (P= 0.89 for trend). After adjustment for other risk factors, the odds ratios were 1.0, 1.03, 1.15 and 1.29 (P= 0.045 for trend) in men and remained nonsignificant in women. CONCLUSIONS: Despite a moderately strong positive association between fibrinogen levels and prevalent hypertension in both sexes, there was only a weak positive association between fibrinogen levels and incident hypertension in men and no association in women. Whether an elevated fibrinogen level is a risk factor for, or a consequence of, hypertension remains unclear.

Arteriosclerosis↗
PubMed2005

Fibrinogen and cigarette smoking in men and women in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population.

BACKGROUND: Plasma fibrinogen may be an independent risk factor for cardiovascular disease. Cigarette smoking is a well-recognized determinant of plasma fibrinogen however it remains unclear how fibrinogen levels relate to the degree and duration of smoking, or to time since smoking cessation. METHODS: In a population-based study of 11 059 men and women aged 45-74 years, we examined the cross-sectional relationship between plasma fibrinogen and cigarette smoking habit. RESULTS: Mean fibrinogen concentrations were higher in current smokers compared to non-current smokers (men: 3.13+/-0.77 versus 2.80+/-0.71 g/l, P<0.0001; women: 3.03+/-0.72 versus 2.95+/-0.71 g/l, P=0.01), independent of age, body mass index and hormone replacement therapy in women In men, fibrinogen concentrations declined with years since stopping smoking but remained higher than in life-long non-smokers for 15 years. No relationship between fibrinogen and duration of smoking cessation was observed in women. On multivariate analysis, age, body mass index, use of hormone-replacement therapy, smoking status and pack-years of smoking were independent predictors of plasma fibrinogen. CONCLUSIONS: Plasma fibrinogen is strongly associated with cigarette smoking with a dose-response relationship with total pack-years of smoking. In men who stop smoking plasma fibrinogen may remain elevated for several years after cessation.

Age Distribution↗
PubMed1990

Measurement of fibrinogen binding to platelets in whole blood by flow cytometry: a micromethod for the detection of platelet activation.

Platelet fibrinogen binding in whole blood has been measured in vitro by flow cytometry using a commercially available, fluorescein isothiocyanate (FITC)-conjugated polyclonal antifibrinogen antibody. Fibrinogen-antifibrinogen immune complexes were formed in experimental conditions approaching antigen-antibody equivalence, but optimal reaction conditions in which their formation was prevented or minimized could be achieved. Immune complex formation was associated with fibrinogen binding to unstimulated platelets but did not significantly affect ADP-induced fibrinogen binding. Half-maximal fibrinogen binding occurred at about 0.4 microM ADP, and ADP-induced fibrinogen binding continued progressively during 20 min incubation with 10 microM ADP. Fibrinogen binding correlated closely with platelet glycoprotein IIb-IIIa expression in members of a family with Glanzmann's thrombasthenia, and, in double labelling experiments, with the binding of PAC1, a monoclonal antibody that binds to GP IIb-IIIa only after the exposure of fibrinogen receptors. These studies show that platelet fibrinogen binding can be reliably measured in whole blood by means of a polyclonal antifibrinogen antibody which does not discriminate between plasma and platelet-bound fibrinogen, despite the presence of an approximately 100-fold excess of the former.

Adenosine Diphosphate↗