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PubMed1987

Fibrinogen Aarhus and factor XIII induced polymerization and gel formation.

Fibrinogen Aarhus is an abnormal fibrinogen for which the clotting time with thrombin is greatly prolonged both in plasma and in the isolated fibrinogen. The whole blood clotting time is only slightly prolonged. The patient with this fibrinogen has no bleeding tendency. In this report we have investigated fibrinogen Aarhus in two alternative, thrombin independent polymerization and gelation pathways. These pathways are the factor XIII dependent oligomerization and gelation of fibrinogen, and heteropolymer (fibrinogen-fibronectin) formation which also is catalysed by factor XIII. Both of these reactions are qualitatively the same in fibrinogen Aarhus as in normal fibrinogen, but the rate of oligomerization is somewhat slower in fibrinogen Aarhus. This may depend on impaired association between factor XIII and fibrinogen Aarhus.

Blood Coagulation Disorders↗

PubMed1984

Fibrinogen degradation by hementin, a fibrinogenolytic anticoagulant from the salivary glands of the leech Haementeria ghilianii.

The leech Haementeria ghilianii contains the anticoagulant hementin in its salivary glands, which renders ingested blood incoagulable. The loss of thrombin-coagulability of human fibrinogen, plasma, and blood was dependent on both dose and time, and it was attributable to direct proteolytic degradation of fibrinogen (Mr 340,000) by hementin. Using purified fibrinogen as the substrate, it was demonstrated that the enzyme cleaved with equal probability either through all three chains in the connector region between the D and E structural domains or in the COOH-terminal of the A alpha chain. The degradation pattern of fibrinogen in blood and purified counterpart was the same in respect to the types of degradation products formed and the rate of proteolysis. Three pairs of fibrinogen degradation products characterized by Mr were distinguished: 320,000 and 300,000, 225,000 and 200,000, 157,000 and 132,000. In each pair, the heavier product had the intact COOH-terminals of the A alpha, B beta, and gamma chains. Of special interest was the derivative of Mr 225,000 because it contained the intact A alpha, B beta, and gamma chains of the original fibrinogen. Hementin cleaved non-cross-linked and cross-linked fibrin clots; however, the rate of proteolysis was much slower than that of fibrinogen. Individual carboxymethylated chains of fibrinogen were not degraded by the enzyme. Hementin abolished coagulability of fibrinogen by a limited proteolysis that disassembled functionally bivalent polymerization sites. In addition, fibrin clot formation was inhibited by fibrinogen fragments generated by hementin. The enzyme appeared to have a unique and limited specificity for a few peptide bonds projected in the tertiary structure of the native fibrinogen molecule.

Animals↗

PubMed1992

Interactions of thermally denatured fibrinogen on polyethylene with plasma proteins and platelets.

During the investigation of fibrin deposition onto hydrophobic polymers in contact with human blood, a model was developed in which fibrinogen was denatured and irreversibly coated onto a polyethylene surface by heating to 70 degrees C for 10 min. The denatured fibrinogen-polyethylene surface is resistant to fluid wall shear rates of up to 550 s-1 and the fibrinogen does not desorb in the presence of plasma proteins. Compared to uncoated polyethylene, little albumin or fibrinogen adsorbs to heat-denatured fibrinogen. Thrombin binds to the denatured fibrinogen-coated polyethylene with low affinity and also acts on the surface-bound denatured fibrinogen and cleaves fibrinopeptide A (FPA) quantitatively. Washed, 51Cr-labeled platelets do not adhere to the thermally denatured fibrinogen at either low or high shear rates compared to surfaces coated with undenatured fibrinogen (p < 0.01). These observations support the role of the D domain of fibrinogen in platelet adhesion because this is the region that is denatured by heating. In contrast, the E domain of fibrinogen is not altered by heating to 70 degrees C and hence remains susceptible to thrombin and/or plasmin cleavage. The characteristics of this surface are such that it can be used to develop fibrin-coated surfaces for use in studies of thrombus formation on artificial surfaces.

Absorption↗

PubMed1994

Characterization of the antiphagocytic activity of equine fibrinogen for Streptococcus equi subsp. equi.

The antiphagocytic property of equine fibrinogen for Streptococcus equi subsp. equi strain CF32 was examined in vitro. The results of bactericidal assays demonstrated that the presence of fibrinogen enhanced the ability of overnight and early log-phase cultures of strain CF32 to resist killing by equine neutrophils by 12-fold and seven-fold, respectively (p > 0.01). In addition, fibrinogen-coated bacteria treated with fibrinogen specific F(ab')2 fragments were 32% more susceptible to killing by equine neutrophils after opsonization in serum (p > 0.05), indicating that specific epitopes on fibrinogen may be important for its antiphagocytic effect. Since complement deposition is inhibited on subsp. equi (Boschwitz JS, Timoney JF, Infect Immun 1994; 42, 3515-20, we examined the effect of fibrinogen on complement deposition by using colloidal gold labeling of surface-bound C3. No significant differences were detected in the quantity of C3 deposited on the cell surface after opsonization with serum, serum plus fibrinogen, or plasma. These results suggest that the antiphagocytic property of fibrinogen is not related to the inhibition of complement deposition on the bacterial surface. Pretreatment of CF32 with M protein specific antibody inhibited fibrinogen binding by 72%, and a strain of subsp. equi expressing low levels of M protein bound 64% less fibrinogen than CF32, suggesting that the some of the fibrinogen deposited on the surface of subsp. equi is bound to M protein.

Animals↗

PubMed1994

Inhibition of neutrophil activation by fibrinogen.

Physiological levels of human fibrinogen markedly inhibited the chemotactic activity of human neutrophils triggered by zymosan-activated serum (ZAS), C5a, or IL-8 in a Boyden chamber assay. Fibrinogen also slightly inhibited the N-formyl-methionyl leucyl-phenylalanine (FMLP)-induced migration of human neutrophils. Albumin was devoid of the inhibitory activities displayed by fibrinogen in this system. The inhibition of chemotaxis by fibrinogen was dose-dependent and saturable. Fibrinogen placed in the upper compartment of the Boyden chamber produced a larger inhibition than that obtained with fibrinogen placed in the lower compartment. Lysine as well as the lysine analog 6-aminohexanoic acid (AHA) decreased the inhibitory capacity of fibrinogen. In contrast, both arginine and glutamine failed to suppress the fibrinogen-mediated inhibition of neutrophil chemotaxis. AHA counteracts the inhibition of ZAS-induced chemotaxis by anti-CD18 monoclonal antibody, suggesting that lysine binding sites are required for integrin function in chemotaxis. Fibrinogen also inhibited, in a dose-dependent manner, the oxygen consumption of neutrophils activated by opsonized zymosan. Taken together, the present results indicate that fibrinogen modulates neutrophil functions and suggest that in addition to its role in blood coagulation, circulating fibrinogen may be involved in regulation of the inflammatory response.

Amino Acids↗

PubMed2004

Plasma fibrinogen and its association with cardiovascular risk factors in apparently healthy Japanese subjects.

Recent evidence has shown the association of increased plasma fibrinogen levels with subsequent coronary heart disease or stroke. Fibrinogen is an acute-phase inflammatory reactant as well as a clotting factor. The authors investigated an association between fibrinogen levels and cardiovascular risk factors in apparently healthy Japanese subjects, while considering C-reactive protein (CRP) levels, a marker of the inflammatory status. Plasma fibrinogen and serum CRP from 2 706 participants in an annual mass screening examination, held in Matsukawa, Nagano, Japan were measured. A total of 2 355 subjects (816 men and 1 539 women) were analyzed after excluding individuals with a history of diabetes mellitus, heart disease, or stroke. Plasma fibrinogen was strongly correlated with CRP levels. After adjusting the CRP levels, fibrinogen was positively associated with age, smoking status, total cholesterol, and hemoglobin A(1c) (HbA(1c)) in men, and with age, total cholesterol, and HbA(1c) in women. On the other hand, high-density lipoprotein (HDL) cholesterol was a strong negative correlate of fibrinogen in both genders. Fibrinogen levels also tended to be associated positively with body mass index in both genders and negatively with exercise habits in men. The present multiple regression analysis has shown that plasma fibrinogen levels are correlated with conventional cardiovascular risk factors even after adjusting for the CRP levels. Persons with cardiovascular risk factors tended to have higher fibrinogen levels, suggesting that all elevated plasma fibrinogen concentration in those with risk factors may further increase the risk of the development of atherothrombosis and subsequent cardiovascular disease through the blood coagulation system.

Adult↗

PubMed1984

The effect of high molecular weight kininogen on surface-adsorbed fibrinogen.

High molecular weight kininogen (HMWK) plays an important role in altering the association of plasma fibrinogen with surfaces. Plasma initially deposits fibrinogen onto most materials, but on hydrophilic surfaces within 10 min adsorbed plasma fibrinogen cannot be detected on the surface by anti-fibrinogen antisera. However, using HMWK-deficient plasma, fibrinogen remains immunologically identifiable. The interrelationship of adsorbed plasma fibrinogen with kininogen on hydrophilic surfaces is studied further using glass slides stained for protein with Coomassie Blue, and oxidized silicon crystal slices in an automated ellipsometer. On glass slides when plasma that is deficient in both low molecular weight kininogen (LMWK) and HMWK, is reconstituted with HMWK (0.04 Units/ml), fibrinogen is no longer detected on the surface. This finding is specific for HMWK, since, when the same plasma is reconstituted with LMWK (220 micrograms/ml), the amount of fibrinogen detected on the surface is unchanged. The alteration of surface-adsorbed fibrinogen by HMWK is not due to plasmin-induced fibrinolysis, since it occurs in plasminogen-free plasma. In the ellipsometer, surface adsorption of normal plasma is associated with a significantly less (p less than 0.0005) thick protein layer (1.99 +/- 0.08 degree change in azimuth) than plasmas deficient in HMWK (2.32 +/- 0.11). Using ellipsometry, HMWK in plasma is shown to shorten the time in which immunologically detectable surface-adsorbed fibrinogen was removed or altered. These studies in a whole plasma system present further evidence that HMWK specifically modifies the association of plasma fibrinogen with hydrophilic surfaces.

Adsorption↗

PubMed1988

Immunovisualization of fibrinogen A alpha-chain heterogeneity in normal plasma and plasma from patients with DIC or on streptokinase therapy.

Purified fibrinogen as well as normal plasma, or plasma from patients with DIC or undergoing streptokinase(SK)-therapy was subjected to 1D- and 2D SDS-electrophoresis under reducing conditions. The pattern was revealed either by Coomassie-staining or immunostaining after Western-blotting and then compared. The use of polyclonal antibodies to fibrinogen as well as two monoclonal anti-bodies reacting with FPA and C-terminal part of the A alpha-chain confirmed immunologically the previously reported molecular weight heterogeneity of the A alpha-chain of the fibrinogen molecule as being a constituent of normal plasma, and lead to the following conclusions: 1. The MW-heterogeneity is observed in the fibrinogen pool of normal plasma as well as in DIC-plasma, SK-plasma and in purified fibrinogen, being the least noticeable in normal plasma and most advanced in SK-plasma. Patterns obtained using immunostaining with monoclonal anti-FPA confirm that the MW-heterogeneity of fibrinogen is mainly due to C-terminal degradation of the A alpha-chain. 2. Numerous A alpha-chain remnants (at least 9), with intact N-terminal ends, are found to be present in normal plasma, with a MW range from 66,200 to 36,000 Da, demonstrating that each of the "classical" HMW, LMW, LMW' subgroups consist of fibrinogen molecules which are very heterogeneous. 3. Two populations of A alpha-chains in purified fibrinogen and in fibrinogen in plasma react with the C-terminal specific Mab G-8. This is in contrast to the findings in plasma from streptokinase-treated patients, where several bands of lower molecular weights than the gamma-chain can be seen, suggesting the presence of free, circulating A-alpha chains split in the N-terminal half of the chain beyond the last inter-chain disulphide bond. 4. 2D electrophoresis disclosed substantial deviations in the patterns obtained with DIC-plasma, SK-plasma and with fibrinogen purified by beta-alanine-precipitation from that observed with normal plasma. The present technique allows selective characterization of fibrinogen independently of the other proteins present in plasma and offers extreme sensitivity.

Blotting, Western↗

PubMed1990

Binding of hyaluronic acid to mammalian fibrinogens.

We have postulated that the interaction of hyaluronic acid (HA), an extracellular matrix glycosaminoglycan, with fibrin is important during the early stages of wound healing and inflammation (J. Theor. Biol. 119:219; 1986), and have demonstrated the specific binding of 125I-labeled HA to human fibrinogen (J. Biol. Chem. 261:12 586; 1986). To determine whether HA binding is limited to human fibrinogen, we tested the ability of fibrinogens from various mammalian species to bind 125I-HA using a dot-blot assay. Increasing amounts of fibrinogen were adsorbed to nitrocellulose, and incubated with 125I-HA in the presence or absence of a 100-fold excess of nonradiolabeled HA to assess specific binding. In three independent experiments, the amount of 125I-HA bound/mg fibrinogen was determined from the slope derived by linear regression analysis of specifically bound 125I-HA versus protein concentration. A Student's t-test was performed to determine whether the slopes were statistically greater than zero. HA binding was considered statistically significant when P less than 0.05 was obtained by this analysis. Rabbit and dog fibrinogens significantly bound HA in all three trials. Baboon fibrinogen demonstrated significant HA binding in two of three trials. Pig, sheep and goat fibrinogens bound HA significantly in only one of three trials, whereas horse, rat and cow fibrinogens did not bind HA significantly at all. We conclude that fibrinogen from mammalian species other than human can specifically bind HA. The ability of fibrinogen to bind HA appears to correlate with an evolutionary divergence that separated human, baboon, dog, rabbit and rat from cow, pig, horse, goat and sheep.

Amino Acid Sequence↗

PubMed2006

Immunofixation reveals an apparent alpha heavy chain caused by precipitation of fibrinogen with IgA antiserum.

BACKGROUND: Fibrinogen present in serum specimens can interfere with the interpretation of serum protein electrophoresis. We report here the unexpected precipitation of fibrinogen by an IgA antiserum used in immunofixation electrophoresis. METHODS: Immunofixation electrophoresis of plasma combined with ethanol precipitation, serial dilution of plasma, and fibrinogen adsorption of the antiserum were used to investigate the apparent immunoreactivity of a commercial source of IgA antiserum to fibrinogen. RESULTS: Fibrinogen immunoreactivity by IgA antiserum was observed at fibrinogen concentrations > or =0.93 g/l. Ethanol precipitation of plasma removed fibrinogen and prevented the immunofixation of the protein by the IgA antiserum. Adsorption of the IgA antiserum with human fibrinogen removed its ability to precipitate fibrinogen, demonstrating cross-reactivity between the IgA antiserum and fibrinogen. CONCLUSIONS: Commercial sources of antiserum used for immunofixation electrophoresis may contain antibodies with specificity towards proteins typically absent from serum such as fibrinogen and can produce clinically misleading results.

Female↗

PubMed2006

Interaction of fibrinogen with n-alkylagaroses and its purification by critical hydrophobicity hydrophobic interaction chromatograpy.

A rational application of hydrophobic interaction chromatography (HIC) to the purification of proteins has remained an enigma in spite of over 30 years of research. The critical hydrophobicity parameter, which can be determined from a concentration series of n-alkyl Sepharose 4B (Seph-Cn) offers the possibility of adapting the HIC gel to the needs of purification. To this end a library of HIC gels (Seph-C4 to Seph-C6) of different immobilized alkyl residue concentrations was synthesized and tested with purified bovine fibrinogen. Binding of fibrinogen to such a concentration series resulted in sigmoidal binding curves. Analysis of the Seph-C5 data according to the lattices-site binding model yielded adsorption coefficients (nS) between 5 and 10 indicating that 5-10 lattice-sites (alkyl residues) interact multivalently with a fibrinogen molecule for adsorption at low ionic strength. The apparent lattice-site half-saturation constant of dissociation lies between 21 and 25 micromol/ml packed gel. For each alkyl chain length a critical hydrophobicity could be determined. For fibrinogen purification the critical hydrohobicity gel, Seph-C5 (13 micromol/ml packed gel), was selected. With the help of the cosolvents NaCl or glycine a fully reversible adsorption of fibrinogen could be facilitated on the critical hydrophobicity gel. Application of the method to human and bovine blood plasma resulted in a single step purification of fibrinogen in high yields. A comparison of the classical purification of fibrinogen with the critical hydrophobicity HIC (CHIC) method demonstrates a reduction in preparation time from several days to ca. 1 h. The subunit structure of HIC-purified human fibrinogen is identical to the classically purified protein. In the case of bovine fibrinogen however HIC-purified fibrinogen displayed a different subunit structure in that the Aalpha chain of fibrinogen had a ca. 5 kDa higher molecular mass. This may be due to the rapidity of the new one-step method and an avoidance of proteolysis.

Animals↗

PubMed2005

Plasma fibrinogen in ulcerative colitis: the effect of disease activity and nicotine therapy in a randomised controlled trial.

BACKGROUND: Smoking increases plasma fibrinogen and cardiovascular risk whereas transdermal nicotine may not. Fibrinogen is an acute phase protein and may reflect disease activity in ulcerative colitis. AIMS: To examine the effect of topical nicotine on plasma fibrinogen and any relationship between fibrinogen and ulcerative colitis disease activity. PATIENTS: Forty-eight non-smokers with moderately active ulcerative colitis. METHODS: Patients were randomised to 6 mg nicotine enema or placebo for 6 weeks, followed by open nicotine therapy for 4 weeks. Plasma fibrinogen was measured at baseline and after 6 and 10 weeks; at each assessment sigmoidoscopy with a rectal biopsy was performed. RESULTS.: At 6 weeks median plasma fibrinogen was 3.30 g/l on nicotine compared to 3.05 g/l on placebo, P = 0.90 when adjusted for baseline values. There was a correlation between fibrinogen and the UC disease activity index (UCDAI) at weeks 0 and 10, P = 0.036 and 0.033, respectively, and between fibrinogen and sigmoidoscopic grade at each assessment, P = 0.014, 0.021 and 0.034. Changes in fibrinogen did not correlate with changes in disease severity. CONCLUSIONS: There was no significant effect of nicotine enemas, in either direction, on plasma fibrinogen-this was raised in moderately active UC and correlated with the sigmoidoscopic grade of colitis and the UCDAI; however, fibrinogen was not sufficiently sensitive to be of practical clinical value.

Colitis, Ulcerative↗

PubMed2002

Association of fibrinogen and lipoprotein(a) as a coronary heart disease risk factor in men (The Quebec Cardiovascular Study).

Fibrinogen has been prospectively found to correlate with coronary heart disease (CHD) but a similar association has not been well established for lipoprotein (a) (Lp(a)). Plasma lipids, Lp(a), and fibrinogen levels were measured in 2,125 men (aged 47 to 76 years) who were free of clinical CHD. During a 5-year follow-up period, 116 first CHD events were documented. Men with CHD were older, smoked more, had a higher prevalence of diabetes, and higher levels of systolic blood pressure, cholesterol, low-density lipoprotein cholesterol, Lp(a), and fibrinogen, and lower plasma high-density lipoprotein cholesterol levels. Only fibrinogen levels in the upper tertile of the distribution compared with the lower tertiles were associated with a significant risk of CHD (adjusted risk ratio 2.5; 95% confidence interval [CI] 1.4 to 4.2; p = 0.0010). Such an association was not observed with Lp(a). To assess a possible relation between fibrinogen and Lp(a) to the risk of CHD events, men were assigned to 1 of 4 groups according to fibrinogen median levels and a Lp(a) cut-off level of 300 mg/L: group 1: fibrinogen < 4.05 g/L and Lp(a) < 300 mg/L; group 2: fibrinogen < 4.05 g/L and Lp(a) > or =300 mg/L; group 3: fibrinogen > or =4.05 g/L and Lp(a) < 300 mg/L; and group 4: fibrinogen > or =4.05 g/L and Lp(a) > or =300 mg/L. Using group 1 as a reference, a significant risk ratio was only documented in group 4 (2.5; 95% CI 1.2 to 5.1; p = 0.0132). In this population, high fibrinogen levels associated with high Lp(a) levels significantly increased the risk of CHD.

Adult↗

PubMed1998

Fibrinogen is an independent marker for thoracic aortic atherosclerosis.

The fibrinogen level is an independent risk factor for coronary events and stroke, but no detailed data are available concerning fibrinogen and atherosclerotic disease of the thoracic aorta. This prospective study using multiplane transesophageal echocardiography examined the relation between atherosclerotic thoracic aortic plaque and fibrinogen level. One-hundred forty-eight patients (65 +/- 11 years) with valvular heart disease underwent multiplane transesophageal echocardiography and coronary angiography. We measured plasma fibrinogen level for each patient and recorded the following cardiovascular risk factors: age, sex, systemic hypertension, history of smoking, hypercholesterolemia, diabetes mellitus, body mass index, and family history of coronary artery disease (CAD). Patients with thoracic aortic plaque had a higher level of plasma fibrinogen (p = 0.0001), were older (p = 0.0001), and had significantly more risk factors: history of smoking (p = 0.009), hypertension (p = 0.008), hypercholesterolemia (p = 0.0001), diabetes mellitus (p = 0.01), and family history of CAD (p = 0.003). Multivariate logistic regression analysis of fibrinogen level and risk factors revealed 4 independent predictors of thoracic aortic plaque: fibrinogen, age, hypercholesterolemia, and history of smoking. Fibrinogen was also an independent predictor of CAD. There was a relation between fibrinogen levels and the severity of aortic atherosclerosis (r = 0.46; p = 0.0001) and the severity of CAD (r = 0.30; p = 0.0001). This prospective study indicates that fibrinogen is an independent marker for thoracic aortic plaque related to the severity of thoracic aortic atherosclerosis and confirms that fibrinogen constitutes an independent marker for CAD related to the severity of angiographically evaluated coronary atherosclerosis.

Adult↗

PubMed2001

A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study.

PURPOSE: Plasma fibrinogen has emerged as an important predictor of cardiovascular disease, but few data are available on its association with stroke. We sought to determine if plasma fibrinogen is a marker of increased risk or a direct causative risk factor for stroke. SUBJECTS AND METHODS: Patients from the Bezafibrate Infarction Prevention Study, a placebo-controlled, randomized clinical trial of secondary prevention of coronary heart disease by lipid modification with bezafibrate retard (400 mg daily), were studied. Plasma fibrinogen levels were measured at baseline and yearly thereafter. Stroke, a prospectively monitored endpoint, was systematically assessed regarding stroke type, subtype, and functional outcome. RESULTS: Mean baseline fibrinogen levels were significantly higher in patients subsequently having a cerebrovascular event (140 strokes, 36 transient ischemic attacks; mean follow-up, 6.2 years) than in patients who did not (375 vs. 349 mg/dL, P <0.0001). Fibrinogen levels did not differ significantly by the type, subtype, or severity of the cerebrovascular event. Risk of ischemic stroke increased from 3.3% in the lowest tertile (baseline fibrinogen <314 mg/dL) to 7.% in the middle tertile (fibrinogen 314 to 373 mg/dL) to 10% in the upper tertile (fibrinogen >373 mg/dL, P <0.001). Adjusting for age, blood pressure, and other covariates, fibrinogen levels in the upper tertile were associated with more than a twofold increase in risk of ischemic stroke compared with in the lowest tertile (hazard ratio = 2.6; 95% confidence interval: 1.5 to 4.3). We did not find fibrinogen change from baseline to be related to subsequent ischemic stroke events. CONCLUSION: Plasma fibrinogen is a strong predictor of, rather than a direct causative factor for, subsequent stroke among patients at increased risk owing to manifest coronary heart disease.

Aged↗

PubMed1998

Cardiovascular disease, fibrinogen and the acute phase response: associations with lipids and blood pressure in patients with chronic renal disease.

BACKGROUND: Fibrinogen, an acute phase reactant and coagulation factor is a major independent risk factor for cardiovascular disease (CVD) in the general population and may interact with lipids to promote CVD risk. METHODS: Plasma fibrinogen, lipids and interleukin-6 were measured in 126 patients with chronic renal disease (low proteinuria (LP) and high proteinuria (HP) groups) or on maintenance dialysis (haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD)) and 31 healthy controls (N). RESULTS: Fibrinogen was increased in all patients, and by each treatment category, when compared with the control group (421+/-143 all, 361+/-72 HD, 429+/-91 CAPD, 395+/-102 LP, 490+/-220 HP vs. 268+/-54 (N) mg/dl; P=0.0001) and correlated with urinary protein concentration, diastolic blood pressure and inversely with albumin. Interleukin-6, the mediator of the acute phase response, was increased in the combined patient group (3.2 vs. 1.5, median, pg/ml, P=.0002) and correlated with fibrinogen (r=0.32, P=0.01) and inversely with HDL-cholesterol (r=0.39, P < 0.01), consistent with a persistent inflammatory response. Patients with CVD complications (CVD +, n=46) were older, had an increased total:HDL-cholesterol ratio (7.7+/-4.3 CVD + vs. 5.9+/-1.8 CVD -, P < 0.005), but fibrinogen did not significantly differ (450+/-172 CVD + vs. 404+/-121 CVD -, P=0.09). Multiple logistic regression analysis identified categorisation of patients by values of fibrinogen and the total:HDL-cholesterol ratio greater than 95%, of the values for the controls as the only significant independent predictor of CVD complications. (Odds ratio for CVD complications of 13.5 (95%, CI 3.5-52) fibrinogen > 374 and total:HDL-cholesterol > 6.9 versus fibrinogen < 374 and total:HDL-cholesterol < 6.9). CONCLUSIONS: The significant increase in fibrinogen in all renal disease states was associated with evidence of an acute phase response, protein losing states and hypertension. Persistence of an acute phase response was also correlated with an adverse lipid profile. Fibrinogen alone was a weak discriminator of prevalent CVD disease but in conjunction with an increased total:HDL-cholesterol ratio, was associated with the prevalence of CVD complications. Hypertension and a persistent acute phase response in patients with renal disease could contribute to CVD risk by effects upon fibrinogen and lipids, but requires confirmation by prospective evaluation.

Acute-Phase Reaction↗

PubMed1987

Quantitative character of fibrinogen uptake by M+ and M- variants of Streptococcus pyogenes.

Fibrinogen was labelled with 125Iodine by mild chemical oxidation and its binding to Streptococcus pyogenes was subjected to quantitative analysis, inhibition and desorption studies. Fibrinogen was bound both by virulent and avirulent (M protein-positive and M protein-negative) matched strains of several serotypes. In all pairs of strains fibrinogen uptake was much higher by the M-positive variants. The ratio of bound fibrinogen to total fibrinogen was highly dependent both on the concentration of fibrinogen and the concentration of cocci. Equilibrium binding studies showed that the binding was a multifactorial process. Probably not only receptor fibrinogen interactions but also interactions between bound and unbound fibrinogen molecules took place. The uptake of fibrinogen was highly depressed in avirulent strains and practically uninfluenced in virulent strains by the presence of albumin or immunoglobulin. The bond between fibrinogen and streptococci is therefore different in virulent and avirulent variants. The fibrinogen receptors on the cell surface are specific.

Fibrinogen↗

PubMed2002

Reduced platelet adhesion in flowing blood to fibrinogen by alterations in segment gamma316-322, part of the fibrin-specific region.

The interaction of platelets with fibrinogen is a key event in the maintenance of a haemostatic response. It has been shown that the 12-carboxy-terminal residues of the gamma-chain of fibrinogen mediate platelet adhesion to immobilized fibrinogen. These studies, however, did not exclude the possibility that other domains of fibrinogen are involved in interactions with platelets. To obtain more insight into the involvement of other domains of fibrinogen in platelet adhesion, we studied platelet adhesion in flowing blood to patient dysfibrinogen Vlissingen/Frankfurt IV (V/FIV), to several variant recombinant fibrinogens with abnormalities in the gamma-chain segments gamma318-320 and gamma408-411. Perfusion studies at physiological shear rates showed that platelet adhesion was absent to gammaDelta408-411, slightly reduced to the heterozygous patient dysfibrinogen V/FIV and strongly reduced to the homozygous recombinant fibrinogens: gammaDelta319-320, gamma318Asp-->Ala and gamma320Asp-->Ala. Furthermore, antibodies raised against the sequences gamma308-322 and gamma316-333 inhibited platelet adhesion under shear conditions. These experiments indicated that the overlapping segment gamma316-322 contains amino acids that could be involved in platelet adhesion to immobilized fibrinogen under flow conditions. In soluble fibrinogen, this sequence is buried inside the fibrinogen molecule and becomes exposed after polymerization. In addition, we have shown that this fibrin-specific sequence also becomes exposed when fibrinogen is immobilized on a surface.

Antibodies, Monoclonal↗