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PubMed1981

Photosensitized labeling of solvent-exposed parts of proteins. Studies on fibrinogen and the fibrinogen-fibrin conversion.

A new technique for surface labeling of biological structures based on dye-sensitized photochemical coupling of labeled low molecular weight substances has been applied to studies on fibrinogen. When a solution of fibrinogen containing fluorescein and 3H-labeled tryptophan was illuminated with visible light, radioactive labeling of fibrinogen occurred in proportion to the illumination time. Determination of the relative labeling of the various peptide chains after reduction and separation by polyacrylamide gel electrophoresis showed the following labeling pattern; alpha : beta : gamma = 2.7 : 1.0 : 1.0, suggesting that the alpha chain is relatively more exposed to solvent than the other chains. When the illumination was performed in the presence of urea the labeling pattern was changed to 1.0 : 1.9 : 1.5, showing that the labeling is sensitive to conformation. When fibrinogen was transformed to fibrin and then labeled the labeling ratio was 3.0 : 1.3 : 1.0.

Fibrin↗
PubMed1985

Evidence that rat platelet fibrinogen molecules lack the gamma' chain variant found in plasma fibrinogen molecules.

Heterogeneity of rat plasma fibrinogen gamma chains (gamma A, gamma') is due to differential splicing of the primary mRNA transcript. Human gamma' chains, which amount to 7% of the total gamma chain population of plasma (hepatic) fibrinogen, are not detectable in fibrinogen isolated from platelets. In this investigation, we extended our studies to rats and found that gamma' chains, representing 30% of the rat plasma gamma chain population, are not detectable in their platelet fibrinogen.

Animals↗
PubMed1989

High-resolution NMR studies of fibrinogen-like peptides in solution: structural basis for the bleeding disorder caused by a single mutation of Gly(12) to Val(12) in the A alpha chain of human fibrinogen Rouen.

In human fibrinogen Rouen, which is the origin of a bleedin disorder, a single amino acid is mutated from Gly(12) to Val(12) in the A alpha chain. In the previous paper of this series, this mutation was predicted to disrupt the structure of fibrinogen-like peptides bound to bovine thrombin. The structural basis of this bleeding disorder has been further assessed by studying the interaction of the following Val(12)-substituted human fibrinogen-like peptides with bovine thrombin in aqueous solution by use of two-dimensional NMR spectroscopy (including TRNOE): Ala-Asp-Ser-Gly-Glu-Gly-Asp(7)-Phe-Leu-Ala- Glu-Val(12)-Gly-Gly-Val-Arg(16)-Gly(17)-Pro-Arg-Val-NH2 (F16), Ala-Asp-Ser-Gly-Glu-Gly-Asp(7)-Phe-Leu-Ala-Glu-Val(12)-Gly-Gly-Val- Arg(16) (tF16), Ala-Asp-Ser-Gly-Glu-Cys(Acm)-Asp(7)-Phe-Leu-Ala-Glu-Val(12)-Gly-Gly-Val- Arg(16)-Gly(17)-Pro-Arg-Val-Cys(Acm)-NH2 (F17), and Ala-Asp-Ser-Gly-Glu-Cys(Acm)-Asp(7)-Phe-Leu-Ala-Glu-Val(12)-Gly-Gly- Val-Arg(16) (tF17). Binding of thrombin to peptides F16 and F17, and hence to tF16 and tF17 as a result of the cleavage of the Arg(16)-Gly(17) peptide bond, broadens the proton resonances of residues Asp(7) to Arg(16), suggesting that thrombin interacts specifically with this sequence of residues. Medium- and long-range TRNOE's were observed between the NH proton of Asp(7) and the C beta H protons of Ala(10) and between the ring protons of Phe(8) and the C gamma H protons of Val(12) and Val(15) in complexes of thrombin with both tF16 and tF17. A strong TRNOE, in peptides tF16 and tF17, between the C beta H protons of Glu(11) and the backbone NH proton of Val(12) was also observed. However, TRNOE's between the ring protons of Phe(8) and the C alpha H protons of Gly(14) and between the C alpha H proton of Glu(11) and the NH proton of Gly(13), previously observed in the complex of thrombin with FpA, were absent in both peptides tF16 and tF17. From incorporation of TRNOE information into distance geometry calculations, Val(12) was found to disrupt the type II beta-turn involving Glu(11) and Gly(12) that is present in complexes of thrombin with normal fibrinogen-like peptides. The positions of Gly(13) and Gly(14) in the complex are also displaced, relative to the aromatic ring of Phe(8), by the Val(12) substitution. This altered geometry presumably affects the positioning of the Arg(16)-Gly(17) bond in the active site of thrombin.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1972

Molecular events responsible for modulation of neoantigenic expression: the cleavage-associated neoantigen of fibrinogen (blood coagulation-fibrinogen cleavage products-fibrinolysis-molecular conformation).

Molecular events responsible for modulation of neoantigenic expressions of a defined molecule have been explored in relation to three hypothetical molecular models (see below). Fibrinogen and its cleavage-associated neoantigen have been used as a prototype system. Physicochemical and enzymatic factors influencing neoantigenic expression were evaluated. The cleavage-associated neoantigen was not only exposed by plasmin and enzymes of similar specificity, but also in a qualitatively and quantitatively deficient fashion by enzymes of differing specificities. Denaturation of fibrinogen via reduction or pH alteration did not induce the neoantigen, but oxidation of the native fibrinogen molecule did elicit this neoantigenic expression. The neoantigen, once exposed on the D-fragment, was relatively stable to physical and chemical denaturation. These results are inconsistent with proposed cleavage site specific and neoconformational determinant models and are consistent with a steric model, which postulates that the cleavage-associated neoantigenic determinant is buried in native fibrinogen but is exposed in certain altered molecular species. The importance of molecular conformation in the exposure of antigenic expressions of a molecule and in modulation of the binding affinity of a neoantigen for specific antibody is demonstrated.

Acrylamides↗
PubMed1996

Association of genetic variation at the beta-fibrinogen gene locus and plasma fibrinogen levels; interaction between allele frequency of the G/A-455 polymorphism, age and smoking.

The beta-fibrinogen G/A-455 polymorphism genotype along with plasma fibrinogen levels was determined in 482 healthy middle-aged men, of whom 231 were smokers. Smokers had the highest plasma fibrinogen levels (2.92 g/l), ex-smokers the next (2.73 g/l), and never-smokers the lowest levels (2.66 g/l, P < 0.001). Those with one or two A-455 alleles had significantly higher plasma fibrinogen levels in never-smokers and ex-smokers (8.2% and 9.0%, respectively, P < 0.05), and the effect was larger in younger men (45 < 55 years, 11.6%, P = 0.002) than older men (> 65 years, 4.5%, NS), and was not significant in smokers (2.4%, P > 0.05). Allele frequencies were calculated and compared across age groups and between smokers and non-smokers. The difference in frequency of the A-455 allele between smokers and non-smokers varied significantly with age (P < 0.01), with the frequency of the A-455 allele being significantly lower in smokers than in non-smokers in subjects aged > 65 years (P < 0.05), but not in younger men. This demonstrates an interaction between age, smoking and allele frequency of the G/A-455 polymorphism in this population-based sample.

Age Factors↗
PubMed1984

The platelet-fibrinogen interaction. Evidence for proximity of the A alpha chain of fibrinogen to platelet membrane glycoproteins IIb/III.

Fibrinogen participates in platelet aggregation via specific inducible receptors on the cell surface. We have used a photoactivable bifunctional reagent, N-succinimidyl-6-(4'-azido-2'-nitrophenylamino)hexanoate, SANAH, to derivatize 125I-labeled-fibrinogen (125I-Fg) and crosslink it to ADP-stimulated platelets. Binding experiments established that 125I-Fg and 125I-Fg-SANAH interacted with platelets with the same kinetics and affinity as unlabeled fibrinogen. After photoactivation of the platelet-bound 125I-Fg-SANAH, polyacrylamide gel electrophoresis under reducing conditions revealed formation of a high molecular weight covalent complex with coordinate loss of the A alpha chain. 125I-Fg-SANAH missing the extreme carboxy-terminal region of the A alpha chain failed to crosslink to the platelets under similar conditions. Crosslinked 125I-Fg-SANAH was extracted from the cells in 1% Triton X-100, and immunoprecipitation with antibodies specific for platelet membrane glycoproteins was used to identify components of the complex. With antibodies to the glycoprotein IIb/III complex (anti-GP IIb/III), 40 +/- 9% of the extracted 125I-Fg-SANAH was immunoprecipitated. Omission of photoactivation, platelets, or ADP from the reaction or use of unmodified 125I-Fg resulted in less than 5% immunoprecipitation by the anti-GP IIb/III. As controls for specificity, anti-(glycoprotein Ib) or anti-IgG immunoprecipitated less than 5% of the extracted 125I-Fg-SANAH. Under similar conditions, 45% of the GP IIb/III from surface-labeled platelets was recovered in the anti-GP IIb/III immunoprecipitate. These results indicate that the A alpha chain of fibrinogen comes in close proximity to GP IIb/III when the molecule is bound to its platelet receptor.

Azides↗
PubMed1995

European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment interaction.

The European Atherosclerosis Research Study (EARS) compares genetic and environmental factors in the offspring of fathers with myocardial infarction before the age of 55 years (designated cases) and control subjects from five different regions of Europe. Genotype was determined for a G-A polymorphism 455 bp upstream from the start of transcription of the beta-fibrinogen gene. In 585 cases and 1106 control subjects, the relative frequency of the A allele was similar (0.223 and 0.217, respectively), with small and nonsignificant differences in frequency observed among the five regions. Because of evidence for an interaction between a number of factors and genotype in the determination of plasma fibrinogen levels (in particular among female cases who reported use of oral contraceptives), the data were analyzed without adjusting for covariates except for age and region, and analyses were carried out excluding women taking oral contraceptives (n = 297). In agreement with previous reports, in all regions the A allele was associated with elevated plasma fibrinogen levels, with the strongest and most consistent effects being seen in men. In nonsmokers, after adjusting for the effects of age and region, male cases and control subjects with genotype A/A had mean fibrinogen levels 0.49 and 0.33 g/L higher, respectively, than those with genotype G/G, whereas those with genotype G/A had intermediate levels (P < .01). In female nonsmokers there was a similar but smaller and nonsignificant effect (A/A levels higher than G/G by 0.12 and 0.07 g/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

Fibrinogen degradation by two neutral granulocyte proteinases. Influence of calcium on the generation of fibrinogen degradation products with anticlotting properties.

Degradation of human fibrinogen by elastase-like proteinase, chymotrypsin-like proteinase and plasmin, was done in the presence and absence of calcium ions, respectively. The resulting fibrinogen degradation products were tested for their coagulant and anti-coagulant properties. The results show that 1. fibrinogenolysis is delayed in the presence of calcium ions. Higher enzyme concentrations are required to get unclottable split products when calcium ions are present. 2. The fibrinogen fragments obtained in the presence of calcium are different in their molecular weights and anticoagulant activities compared to those obtained in the absence of calcium ions. This effect of calcium is most striking during fibrinogen cleavage by chymotrypsin-like proteinase. Elastase and plasmin-induced fibrinogenolysis was substantially influenced by calcium only at a late degradation stage.

Blood Coagulation↗
PubMed1999

Crotalase, a fibrinogen-clotting snake venom enzyme: primary structure and evidence for a fibrinogen recognition exosite different from thrombin.

Crotalase, a fibrinogen-clotting enzyme isolated from the venom of Crotalus adamanteus, and its overlapping fragments were subjected to Edman degradation. The resulting amino acid sequence [see text] characteristic of a serine proteinase. Comparison with thrombin, the physiological fibrinogen-clotting enzyme, showed that thrombin's fibrinogen-recognition exosite (FRE) is poorly represented in crotalase. Hirudin, a FRE-dependent inhibitor, had no effect on crotalase. Spatial modeling of crotalase yielded a possible alternative fibrinogen-recognition site comprised of Arg 60F, Lys 85, Lys 87, and Arg 107 (underlined in the sequence above). Crotalase also lacks thrombin's YPPW loop, as well as its functionally important ETW 146-148, and its heparin-binding site. The enzyme contains a single asparagine-linked glycosylation site, NFT, bearing neutral and amino sugars that account for 8.3% of the enzyme's total molecular weight of 29,027. The calculated absorbance of crotalase at 280 nm, 1%, cm(-1) is 15.2.

Amino Acid Sequence↗
PubMed2001

Fibrinogen Longmont. A heterozygous abnormal fibrinogen with B beta Arg-166 to Cys substitution associated with defective fibrin polymerization.

B beta Arg166 to Cys substitution was identified in an abnormal fibrinogen named fibrinogen Longmont. The proband, a young woman, and her mother were heterozygous; both experienced episodes of severe hemorrhage at childbirth. The neo-Cys residues were found to be disulfide-bridged to either an isolated Cys amino acid or to the corresponding Cys residue of another abnormal fibrinogen molecule, forming dimers. Thrombin and batroxobin induced fibrin polymerization were impaired, despite normal release of fibrinopeptides A and B. Moreover, the polymerization defect was not corrected by removing the dimeric species or adding calcium. Fibrinogen Longmont had normal polymerization site a, as evidenced by normal GPRP-peptide binding. Thus, the sites A and a can interact to form protofibrils, as evidenced by dynamic light scattering measurements. These protofibrils, however, do not associate laterally in a normal manner, leading to an abnormal clot formation.

Biopolymers↗
PubMed2002

A performance evaluation of commercial fibrinogen reference preparations and assays for Clauss and PT-derived fibrinogen.

The wide availability of fibrinogen estimations based on the prothrombin time (PT-Fg) has caused concern about the variability and clinical utility of fibrinogen assays. In a multi-centre study, we investigated fibrinogen assays using various reagents and analysers. Clauss assays generally gave good agreement, although one reagent gave 15-30% higher values in DIC and thrombolysis. Two commercial reference preparations had much lower potencies than the manufacturers declared, and plasma turbidity influenced parallelism in some Clauss assays. PT-Fg assays gave higher values than Clauss and showed calibrant dependent effects, the degree of disparity correlating with calibrant and test sample turbidity. Analyser and thromboplastin dependent differences were noted. The relationship between Clauss and PT-Fg assays was sigmoid, and the plateau of maximal PT-Fg differed by about 2 g/l between reagents. ELISA and immunonephelometric assays correlated well, but with a high degree of scatter. Antigen levels were higher than Clauss, but slightly lower than PT-Fg assays, which appeared to be influenced by degraded fibrinogen. Clauss assays are generally reproducible between centres, analysers and reagents, but PT-Fg assays are not reliable in clinical settings.

Blood Coagulation Tests↗
PubMed1981

The binding of fibrinogen and fibrinogen degradation products to the erythrocyte membrane and its relationship to haemorheology.

A study has been made of the binding of fibrinogen to erythrocyte membranes. The amount of fibrinogen bound is found to be proportional to the concentration in the suspending phase (up to 10 g/l) and to be unaffected by other plasma proteins or calcium ions (up to normal concentrations). The binding is also unaffected by temperature (between 4 and 37 degrees C). However it is sensitive to both pH and ionic strength variation. A similar study of the major fibrinogen degradation products (FDP) produced by plasmin shows that these all bind to red cell membranes but by different amounts. A model based on these data is suggested for the positions of the binding regions on the fibrinogen and FDP molecules and is used to explain their influence on rouleaux formation and on the flexibility of the erythrocyte.

Anticoagulants↗
PubMedDate not supplied

[Immunoelectrophoretic and functional evidence in various infants of a transient variant of the fibrinogen (fetal fibrinogen?)].

In 21 out of 466 full term newborn babies (4.5%) and in 5 out of 50 prematures (10%) a transient fibrinogen electrophoretic abnormality, anodic and cathodic, was found. The observation that the thrombin time in full term newborn babies is prolonged, compared with the adult levels, was confirmed (p less than 0.0005). The difference between the thrombin time in full term newborn babies without fibrinogen electrophoretic abnormalities and those who had them, was statistically significant (p = 0.005) suggesting that the abnormality is associated with the protein function. The normal electrophoretic component could be the "adult" equivalent of the protein and the cathodic variant, the "fetal" type of fibrinogen. This hypothesis could explained why the thrombin time of plasma in newborn normal babies is enriched with the "fetal" fibrinogen in variable proportion, and is delayed compared with that of the adults.

Electrophoresis↗
PubMed1994

Both fish oil and olive oil lowered plasma fibrinogen in women with high baseline fibrinogen levels.

This double-blind, cross-over study with olive oil as placebo, examined the effect of a daily dosage of 6 g fish oil on cardiovascular risk markers of 20 healthy young volunteers (10 men, 10 women). Serum lipids and lipoproteins, and plasma coagulation and fibrinolytic enzymes, including fibrinogen concentrations and plasminogen activator inhibitor-1 (PAI-1) activity were measured at baseline and after 6-week supplementation of either fish or olive oil. The results showed that fish oil had an independent lowering effect on triglycerides and coagulation factors Vc and VIIc. Both fish and olive oil significantly raised PAI-1 levels and lowered plasma factor Xc and fibrinogen levels in the women, who had higher initial levels than the men. Mean fibrinogen levels of the women were lowered from 3.23 +/- 0.98 to 2.64 +/- 0.55 g/l and from 3.19 +/- 0.72 to 2.66 +/- 0.49 g/l by fish and olive oil respectively. This study raises the question whether a particular fatty acid or group of fatty acids, or another constituent of the oil such as vitamin E may be responsible for the fibrinogen lowering effect.

Administration, Oral↗
PubMed1994

Fibrinogen New Britain: characterization of an A alpha Arg 16-->His variant human fibrinogen.

Routine laboratory screening identified an abnormal fibrinogen in an asymptomatic patient from New Britain, Connecticut. This paper reports the characterization of the abnormal fibrinogen. Clinical clotting studies showed marked prolongation of both the thrombin and Reptilase times. A discrepancy was noted between the fibrinogen concentration as determined by a rate-dependent clotting assay (0.73 milligrams) vs immunological determination (2.27 milligrams). Polymerase chain reaction (PCR) based DNA sequencing was used to identify the underlying molecular defect. Fibrinogen New Britain was found to have a point mutation in exon 2 of the A alpha chain. This mutation results in the amino acid substitution Arg-->His at position 16 of the A alpha chain, the site of thrombin cleavage. The substitution results in delayed polymerization of fibrin clot due to impaired release of fibrinopeptide A by thrombin. Studies of fibrin fibre dimensions and structure showed New Britain fibrin fibres to have a larger mean diameter and an increased mass/length ratio when compared with normal fibrin fibres formed under the same conditions.

Amino Acid Sequence↗
PubMed1997

[Fibrinogen as an independent cardiovascular risk factor and the question of treatment with fibrinogen-lowering drugs].

The atherosclerotic vascular disease is a progressive condition of multifactorial origin. Among cardiovascular risk factors alterations of lipid metabolism are of central role. But the haemostatic system, first of all the plasmatic fibrinogen is also highly implicated. Increased fibrinogen condition can be regarded as a strong and independent predictor of cardiovascular risk. Total cholesterol, LDL-cholesterol and plasma fibrinogen concentration as risk factors are compared. Fibrinogen lowering treatments are also summarized.

Anticoagulants↗
PubMed1987

Fibrinogen Haifa: fibrinogen variant with absence of protective effect of calcium on plasmin degradation of gamma chains.

The abnormal fibrinogen Haifa is characterized by the fact that calcium present during enzymatic digestion by plasmin does not protect the Haifa D gamma chain against further plasmin attack as it does in normal molecules. Since calcium binding to fibrinogen, ADP--platelet aggregation cofactor activity and gamma dimerization process induced by factor XIIIa are normal for fibrinogen Haifa, the corresponding sequences in the gamma chain are not involved. It seems rather that the anomaly resides near the gamma 302 plasmin cleavage site that is protected when calcium is bound to the gamma chain and that this affects the availability of the polymerization site located in the C terminal part of the chain.

Adult↗
PubMed2000

Antibody responses in patients with staphylococcal septicemia against two Staphylococcus aureus fibrinogen binding proteins: clumping factor and an extracellular fibrinogen binding protein.

We analyzed the serum antibody responses against two Staphylococcus aureus fibrinogen binding proteins, the cell-bound clumping factor (Clf) and an extracellular fibrinogen binding protein (Efb). The material consisted of 105 consecutive serum samples from 41 patients suffering from S. aureus septicemia and 72 serum samples from healthy individuals. An enzyme-linked immunosorbent assay (ELISA) was developed. Healthy individuals showed variable levels of antibodies against the studied antigens, and cutoff levels (upper 95th percentile) against these antigens were determined. No correlation was seen between serum antibody levels against Clf and Efb. In acute-phase samples 27% of patients showed positive antibody levels against Clf and 10% showed positive levels against Efb, while in convalescent-phase samples 63% (26 of 41) showed a positive serology against Clf and 49% (20 of 41) showed a positive serology against Efb. Antibody levels against Efb were significantly lower in the acute-phase sera than in sera from healthy individuals (P = 0. 002). An antibody response against Clf was most frequent in patients suffering from osteitis plus septic arthritis and from endocarditis (80% positive). The antibody response against Efb appeared to develop later in the course of disease. A possible biological effect of measured antibodies was demonstrated with the help of an inhibition ELISA, in which both high-titer and low-titer sera inhibited the binding of bacteria to fibrinogen. In conclusion, we have demonstrated in vivo production of S. aureus fibrinogen binding proteins during deep S. aureus infections and a possible diagnostic and prophylactic role of the corresponding serum antibodies in such infections.

Adolescent↗