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PubMed1990

Bipartite mRNA for chicken alpha-fibrinogen potentially encodes an amino acid sequence homologous to beta- and gamma-fibrinogens.

Overlapping cDNAs derived from the chicken alpha-fibrinogen mRNA have been sequenced, beginning from within the coding region for the signal peptide of this subunit and terminating within the poly(A) extension. The predicted size of chicken alpha-fibrinogen is 54,187 daltons, which is the smallest of any alpha chain reported; the oligopeptide repeats that characterize the central regions of the other alpha subunits were conspicuously absent. A further unexpected finding was the presence on the mRNA of a separate, long open reading frame (752 nucleotides), beginning 312 nucleotides downstream from the alpha-fibrinogen coding sequence and containing intron-like features near its 5' end. The protein sequence predicted from this second open reading frame lacks an initiating methionine but is homologous to the C-terminal regions of all known beta- and gamma-fibrinogens as well as the C termini of two nonfibrinogen proteins: cytotactin (tenascin), an extracellular matrix protein, and pT49, a putative protein specific to cytotoxic T cells. The intron-like features of the second open reading frame immediately precede the region of common homology, and the beginnings of the corresponding homologous segments in the beta- and gamma-fibrinogen sequences are marked by aligned intron positions. Based on these findings, it is proposed that fibrinogen gene evolution included a fusion of two distinct ancestral genes.

Amino Acid Sequence↗
PubMed1998

Multiple binding sites in the interaction between an extracellular fibrinogen-binding protein from Staphylococcus aureus and fibrinogen.

Efb (previously Fib) is a fibrinogen-binding protein secreted by Staphylococcus aureus. It has previously been shown that it plays a role in a wound infection model in the rat and that antibodies against Efb reduce the number of recovered bacteria from the mammary glands in a mouse mastitis model. Efb binds to the alpha-chain of fibrinogen and does not participate in bacterial adherence to fibrinogen. The binding of Efb to fibrinogen is divalent, with one binding site within the two repeat regions in Efb at the N terminus and one binding site at the C terminus. The divalent binding nature leads to precipitation of Efb-fibrinogen complex when the proteins are added to each other at a 1:1 molar ratio. The interaction between Efb and fibrinogen is strongly enhanced by Ca2+ or Zn2+ but not by Mg2.

Animals↗
PubMed2004

A novel mutation (deletion of Aalpha-Asn 80) in an abnormal fibrinogen: fibrinogen Caracas VI. Consequences of disruption of the coiled coil for the polymerization of fibrin: peculiar clot structure and diminished stiffness of the clot.

An abnormal fibrinogen was identified in a 10-year-old male with a mild bleeding tendency; several years later, the patient developed a thrombotic event. Fibrin polymerization of plasma from the propositus and his mother, as measured by turbidity, was impaired. Plasmin digestion of fibrinogen and thrombin bound to the clot were both normal. The structure of clots from both plasma and purified fibrinogen was characterized by permeability, scanning electron microscopy and rheological measurements. Permeability of patients' clots was abnormal, although some measurements were not reliable because the clots were not mechanically stable. Consistent with these results, the stiffness of patients' clots was decreased approximately two-fold. Electron microscopy revealed that the patients' clots were very heterogeneous in structure. DNA sequencing of the propositus and his mother revealed a new unique point mutation that gives rise to a fibrinogen molecule with a missing amino acid residue at Aalpha-Asn 80. This new mutation, which would disrupt the alpha-helical coiled-coil structure, emphasizes the importance of this part of the molecule for fibrin polymerization and clot structure. This abnormal fibrinogen has been named fibrinogen Caracas VI.

Asparagine↗
PubMed2006

Fibrinogen gamma375 arg-->trp mutation (fibrinogen aguadilla) causes hereditary hypofibrinogenemia, hepatic endoplasmic reticulum storage disease and cirrhosis.

Hypofibrinogenemia is a rare inherited disorder characterized by low levels of circulating fibrinogen, caused by mutations within 1 of the 3 fibrinogen genes. We report here the case of a 61-year-old man with chronic liver function test alterations. Liver biopsy examination revealed chronic hepatitis complicated by cirrhosis and weakly eosinophilic globular cytoplasmic inclusions within the hepatocytes, faintly stained with PAS-diastase. On immunohistochemistry, the inclusions reacted strongly with human antifibrinogen antibodies. Coagulation investigations of the propositus and his 2 sons showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. A liver biopsy performed on the 28-year-old son demonstrated the same globular cytoplasmic inclusions, albeit without associated chronic liver disease. PCR amplification followed by sequencing showed that all 3 were heterozygous for a CGG>TGG mutation at codon 375 of the fibrinogen gamma-chain gene (FGG), corresponding to an Arg>Trp substitution. This is the first in an adult male and the second published case with a discernible hepatic fibrinogen endoplasmic reticulum storage disease due to an FGG Arg375Trp (fibrinogen Aguadilla) mutation. Our results suggest that familial hypofibrinogenemia should be considered in the differential diagnosis of a progressive liver disease associated to hepatocellular intracytoplasmic globular inclusions.

Adult↗
PubMed1991

Measurement of fibrinogen adsorption from blood plasma using 125I-fibrinogen and a direct ELISA technique.

A direct enzyme-linked immunosorbent assay (ELISA), using a polyclonal anti-fibrinogen conjugated to horseradish peroxidase, was used to detect fibrinogen adsorption from blood plasma to ten different materials. Adsorption was also measured with [125I]-fibrinogen. The materials studied included glass, Biomer, Immulon I, and a series of hydroxyethylmethacrylate (HEMA) and ethylmethacrylate (EMA) co-polymers. For all the materials studied, the results from the ELISA technique closely paralleled those obtained using [125I]-fibrinogen. The cross-reactivity of the antibody with proteins other than fibrinogen was generally small. Both experimental methods detected the presence of a maximum in fibrinogen adsorption (as a function of the plasma dilution) to the more hydrophobic materials. For all but two HEMA/EMA co-polymers, a linear correlation between the ELISA and [125I]-fibronogen measurements was indicated by inspection of cross plots as well as by a statistical test.

Adsorption↗
PubMed1999

The fibrinogen gamma chain dodecapeptide inhibits agonist-induced aggregation of rabbit platelets and fibrinogen binding to rabbit glycoprotein IIb-IIIa.

The HHLGGAKQAGDV (H12) sequence at the carboxyl termini of the y chains and the RGD sequences in the Aalpha chains of human fibrinogen are potential recognition sites for the binding of soluble fibrinogen to glycoprotein IIb-IIIa (GPIIb-IIIa) on activated human platelets. Thus, addition of either H12 or RGD-containing peptides inhibits aggregation of and fibrinogen binding to human platelets. In contrast, we reported previously that RGDS had relatively little inhibitory effect on these functions of rabbit platelets. In the present study, we found that H12 inhibited ADP- and thrombin-induced aggregation of rabbit platelets in a dose-dependent manner. Specificity was demonstrated by the failure of the variant HHLGGAKQAGEV peptide to inhibit ADP-induced aggregation. Furthermore, flow cytometric analyses demonstrated that H12 inhibited the binding of FITC-fibrinogen to ADP-activated rabbit platelets in a dose-dependent manner. To examine the direct interaction of H12 with rabbit GPIIb-IIIa, we performed affinity chromatography by applying an octylglucoside extract of rabbit platelet proteins onto an affinity matrix containing the fibrinogen gamma chain sequence. Proteins of approximately 135 kDa and approximately 95 kDa were specifically eluted by soluble H12, and the 95 kDa protein band was immunoblotted by anti-LIBS1, a monoclonal antibody against human GPIIIa. In control samples, no detectable protein from rabbit platelet lysates was eluted from an RGD affinity matrix by GRGDSP. Collectively, our results demonstrated that H12 inhibits aggregation of and fibrinogen binding to rabbit platelets by directly interacting with rabbit GPIIb-IIIa. These findings suggest that rabbit platelets would serve as a suitable thrombosis model for testing the efficacy of peptide mimetics derived from H12.

Animals↗
PubMed2000

The RsaI polymorphism in the alpha-fibrinogen gene and response of plasma fibrinogen to physical training--a controlled randomised clinical trial in men.

We have previously reported cross-sectional data on an interaction effect between physical activity and alpha-fibrinogen RsaI polymorphism on fibrinogen in postmenopausal women. In the present controlled randomised study, we investigated the role of the RsaI polymorphism in determining the response of fibrinogen to long-term regular exercise. Middle-aged men (n = 140), randomly selected from the population registry, were randomised into an exercise or a reference group for a 3-year low intensity exercise intervention. Complete data were available in 125 men. The RsaI restriction enzyme detects threonine (Thr) to alanine change in the fibrinogen alpha codon 312. Anaerobic ventilatory threshold increased by 4%, but decreased by 2% in the exercise and reference groups, respectively. Mean fibrinogen did not decrease in either study group. However, in the exercise group, individual changes in anaerobic threshold explained 48% of the variance in fibrinogen changes in the Thr homozygotes. Our data offer a new aspect of beneficial effects of regular physical exercise on risk factors for coronary heart disease.

Amino Acid Substitution↗
PubMed2000

A case of congenital afibrinogenemia: fibrinogen Hakata, a novel nonsense mutation of the fibrinogen gamma-chain gene.

Congenital afibrinogenemia due to a novel homozygous nonsense mutation of the fibrinogen gamma-chain gene, fibrinogen Hakata, was found in an 18-year-old Japanese girl who had received supplemental fibrinogen therapy since she was 4 months old. The plasma fibrinogen concentrations of the proband were measured as less than 10 mg/dl by a functional method and less than 17 mg/dl by an immunological method. Fibrinogen concentrations of her family were in the range of 94-164 mg/dl. The proband and her family had no other clinical symptoms. Genomic DNA of the proband and her family was isolated from leukocytes, and all exons of fibrinogen subunits and their intron/exon boundaries were analyzed. A genetic mutation, a guanine-to-thymine (G-to-T) transversion at the nucleotide position of 5860, was identified on exon 7 of the gamma-chain gene. This mutation changed the codon for the 231st residue of the gamma-chain from GAG (Glu) to TAG (stop). No other mutation was observed. Aalpha, Bbeta and gamma chains were observed in plasma of the heterozygous family members. However, only a trace amount of Aalpha chain and no gamma chain was detected in the plasma of the proband.

Afibrinogenemia↗
PubMed2000

[The study of beta-fibrinogen gene - 455 G/A, - 148 C/T, 448 G/A polymorphisms and their association with plasma fibrinogen levels].

OBJECTIVE: To analyze the frequency of beta-fibrinogen (beta-Fg) gene - 455 G/A, - 148 C/T, 448 G/A polymorphisms and their association with plasma fibrinogen levels in Han nationality in Guangdong Chinese. METHODS: The beta-Fg gene - 455 G/A, - 148 C/T, 448 G/A polymorphisms of 156 individuals were analyzed by restriction fragment length polymorphism (RFLP). Plasma fibrinogen levels were determined by turbidimetry. RESULTS: The frequencies of A(- 455), T(- 148) and A(448) allele were 0.276, 0.285 and 0.272, respectively. There were strong linkages of G(- 455), C(- 148) and G(448), and of A(- 455), T(- 148) and A(448), the correspondence was more than 97%. The plasma fibrinogen levels in the presence and absence of A(- 455) allele were (3.13 +/- 0.74) g/L and (2.89 +/- 0.57) g/L (P < 0.05); of T(- 148) allele were (3.12 +/- 0.73) g/L and (2.89 +/- 0.58) g/L (P < 0.05); and of A(448) were (3.13 +/- 0.74) g/L and (2.89 +/- 0.57) g/L (P < 0.05), respectively. The plasma fibrinogen levels of the three polymorphisms with the mutant gene are significantly higher than that in the wild type. CONCLUSION: The three polymorphisms loci are strong linkage disequilibrium. It suggests that beta-Fg gene - 455 G/A, - 148 C/T, 448 G/A polymorphisms are associated with plasma fibrinogen levels.

Adult↗
PubMed1992

[Formation of left ventricular thrombus in acute myocardial infarction: significance of the determination of fibrinogen, of products of fibrinogen degradation, and of plasminogen].

OBJECTIVE: To evaluate the significance of the fibrinogen, the plasminogen and the fibrinogen degradation products levels as marks of left intraventricular thrombosis (LIVT) in acute myocardial infarction (AMI). METHODS: 219 consecutive patients of AMI admitted in a Coronary Care Unit of an University Hospital, were prospectively studied. All protocols included a clinical evaluation, an M-mode and 2D echocardiographic study and blood samples, at day 1, 3, 7 and at hospital discharge. In the intraventricular thrombus evaluation just the 4 Asinger grade was considered. In the laboratory evaluation we used: the Clauss chronometric method for the fibrinogen, the colorimetric method for the plasminogen and the agglutination in plaque for the FDP. The patients with ECO in the 2 or 3 Asinger grades and those in which ECO and laboratory study were not performed in the same day, were excluded. 101 patients remained on the study, and they were divided in two groups: 53 patients with LIVT and 48 patients without it. RESULTS: In both groups the fibrinogen raised along the first six days of the AMI, however in the group with LIVT this level didn't raise as high as in the group without LIVT (p < 0.001). In the FDP evaluation two peaks were found, one at 48 hours and another on the 6 th day, but there were no differences between the two groups. The plasminogen values raised along the first week of AMI, in a similar way in both groups. CONCLUSIONS: a) Fibrinogen levels raises in AMI, but this elevation is significantly smaller in the group with LIVT, which suggests fibrinogen consume in fibrin formation of the thrombus. b) FDP and plasminogen levels raise along the first week of AMI, but in a similar way in the two groups. c) None of these parameters permitted to individualize patients with thrombus formation.

Aged↗
PubMed1991

[Fibrinogen Bern III: a further case of hereditary fibrinogen variants with substitution A alpha 16 Arg----Cys].

A heterozygous hereditary fibrinogen variant, fibrinogen Bern III, has been characterized. The proposita and her daughter showed prolonged thrombin time and reptilase time, as well as a markedly reduced fibrinogen concentration as determined by functional clotting assay. Fibrinogen was purified from the proposita's plasma and subjected to biochemical characterization. The delayed fibrin formation was shown to result from impaired release of fibrinopeptide A. Thrombin was found to cleave an extended fibrinopeptide A (A alpha 1-19) from the reduced polypeptide chains of the abnormal fibrinogen. Amino acid analysis of this fragment indicated that the arginine residue, located at the physiological thrombin cleavage site, was replaced by cysteine. The functional defect of the fibrinogen variant Bern III is due to the amino acid substitution A alpha 16 Arg----Cys.

Adult↗
PubMed1990

Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen.

Previous studies indicated that synthesis of B beta chain may be a rate-limiting factor in the production of human fibrinogen since Hep G2 cells contain surplus pools of A alpha and gamma but not of B beta chains, and fibrinogen assembly commences by the addition of preformed A alpha and gamma chains to nascent B beta chains attached to polysomes. To test whether B beta chain synthesis is rate limiting Hep G2 cells were transfected with B beta cDNA, and its effect on fibrinogen synthesis and secretion was measured. Two sets of stable B beta cDNA-transfected Hep G2 cells were prepared, and both cell lines synthesized 3-fold more B beta chains than control cells. The B beta-transfected cells also synthesized and secreted increased amounts of fibrinogen. Transfection with B beta cDNA not only increased the synthesis of B beta chain but also increased the rate of synthesis of the other two component chains of fibrinogen and maintained surplus intracellular pools of A alpha and gamma chains. Transfection with B beta cDNA did not affect the synthesis of albumin, transferrin, or anti-chymotrypsin and had a small inhibitory effect on the synthesis of C-reactive protein. Taken together these studies demonstrate that increased B beta chain synthesis specifically causes increased production of the other two component chains of fibrinogen and that unequal and surplus amounts of A alpha and gamma chains are maintained intracellularly.

Blotting, Northern↗
PubMed1977

A method for the measurement of fibrinolytic activity based on one dimensional diffusion using small glass tubes. II. With special reference to the differences between the use of plasminogen-rich fibrinogen and that of plasminogen-free fibrinogen as the substrates.

The optimal conditions for the measurement of the fibrinolytic factors of plasma were examined using human and bovine plasminogen-rich fibrinogen or plasminogen-free fibrinogen as the substrates using the one dimensional diffusion method. The results were as follows: 1. There was no essential difference found between using human or bovine fibrinogen. 2. The levels of proactivator-plasminogen and plasminogen could be measured while using either plasminogen-rich or plasminogen-free fibrinogen. But, in using the latter, the proactivator-plasminogen level could not be measured, if a final concentration of more than 2,000 Christensen units of streptokinase were employed. 3. When using plasminogen-rich fibrinogen, anti-plasmin(s) and anti-activator(s) could be measured while using urokinase and plasmin, but not while using streptokinase. However, further study should be given to the measurement of the inhibitors, when using plasminogen-free fibrinogen.

Animals↗
PubMed1984

Bovine alpha- and beta-thrombin. Reduced fibrinogen-clotting activity of beta-thrombin is not a consequence of reduced affinity for fibrinogen.

beta-Thrombin, a product of the limited proteolysis of alpha-thrombin, is characterized by greatly reduced fibrinogen-clotting activity as compared to alpha-thrombin but with unchanged activity toward ester substrates. The present study was designed to elucidate the basis for the changes in the catalytic activity resulting from the conversion of bovine alpha-thrombin to bovine beta-thrombin. Fibrinogen was utilized as a competitive inhibitor in the hydrolysis of a peptide nitroanilide substrate by bovine alpha- and beta-thrombin. The Ki values obtained for fibrinogen in these experiments were similar for alpha- and beta-thrombin (about 10 microM). Similar values for Ki were obtained when fibrinogen was used to inhibit the inactivation of bovine alpha- and beta-thrombin by diisopropylphosphorofluoridate. These experiments suggested that the conversion of bovine alpha- to beta-thrombin does not affect the fibrinogen-binding site on thrombin. Differences in the reactivity of functional groups at the active site were then explored. beta-Thrombin was observed to undergo modification at the active site histidine at a slower rate than that of alpha-thrombin when reacted with either tosyllysyl chloromethyl ketone or diethyl pyrocarbonate. It is suggested that the difference in the fibrinogen-clotting activity of these two forms of thrombin can result from changes in the reactivity of the active site histidine residue.

Affinity Labels↗
PubMed1976

Human platelet fibrinogen: a protein different from plasma fibrinogen.

Fibrinogen has been purified from normal and dysfibrinogenemia Metz plasmas, and from normal and from the patient's platelets. There are differences in the pattern of disc polyacrylamide gel electrophoresis between normal plasma and normal platelet fibrinogens, but the migration of the A alpha chain is similar. The abnormality of the electrophoretic mobility of the A alpha chain of plasma fibrinogen from Metz dysfibrinogenemia is not found in platelet fibrinogen of this patient. This result clearly establishes that platelet fibrinogen is a different protein from plasma fibrinogen.

Adult↗
PubMed1977

Plasma fibrinogen, cholinesterase activity, and anemia: utility of fibrinogen in multiphasic screening and in assessing the activity of diseases.

I present the general pattern relationship between (a) plasma fibrinogen and cholinesterase activity and (b) plasma fibrinogen and hemoglobin, in 250 and 310 hospitalized adults, respectively. Although responses of cholinesterase were often unrelated to fibrinogen, when its activity in plasma was depressed, above-normal fibrinogen concentrations were present in about 90% of the subjects. Further, despite the observed independence of hemoglobin and fibrinogen concentrations, whenever frank anemia was present (hemoglobin less than 110 to 120 g/liter), hyperfibrinogenemia was also present in about 75-85% of such anemic patients. Thus, these studies affirm that fibrinogen determination would be an appropriate component of tests on hospital admission and also that hyperfibrinogenemia is a very sensitive "acute phase" reactant, and an important reaction for gauging the course of numerous disorders.

Acute Disease↗
PubMed1985

Fibrinogen Kawaguchi: an abnormal fibrinogen characterized by defective release of fibrinopeptide A.

A congenital dysfibrinogenemia was found in a 32-year-old asymptomatic female and her immediate family. The propositus, apparently a heterozygote for the abnormality, characteristically showed defective release of fibrinopeptide A from half of her fibrinogen molecules. No fibrinopeptide A was cleaved off from the isolated abnormal molecule by thrombin or snake venoms (Reptilase and Ancrod) as evidenced by radioimmunoassay, high performance liquid chromatography and determination of the NH2-terminal amino acids. The abnormal fibrinogen formed a solid gel solely by the release of fibrinopeptide B upon incubation with thrombin. We provisionally designate this abnormal fibrinogen as "Fibrinogen Kawaguchi", although possible identity with other abnormal fibrinogens is not excluded.

Adult↗
PubMed1983

"Fibrinogen Tokyo II". An abnormal fibrinogen with an impaired polymerization site on the aligned DD domain of fibrin molecules.

A hereditary dysfibrinogenemia associated with defective aggregation of fibrin monomers was found in a 39-yr-old female and in the members of her immediate family, who had all been asymptomatic. The abnormality was probably due to an impaired polymerization site exposed in the DD domain of two adjacent fibrin molecules, because plasmic fragment DD derived from the propositus' cross-linked fibrin bound far less tightly to insolubilized normal fragment E than that from the normal one. Its complementary polymerization site in the E domain of fibrin, which was exposed by thrombin cleavage, and the polymerization site in the D domain of fibrinogen, which was available without activation by thrombin, were both found to be normal. More anodal migration of the abnormal fragment DD than the normal one, as shown by immunoelectrophoresis, seemed to support our concept that the mutation most likely resides in the D domain of the abnormal fibrinogen molecule at or near a region closely related to the polymerization site that is exposed when two fibrin molecules are linearly aligned. The work of others on the polymerization of normal fibrin with different techniques yielded results consistent with our conclusions. We tentatively designate this type of abnormal fibrinogen "fibrinogen Tokyo II," but its possible identity with other abnormalities of fibrinogen reported heretofore is not excluded.

Adult↗