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PubMed1985

Fibrinogen Seattle II: defective release of fibrinopeptide A in a slow clotting fibrinogen.

A functionally abnormal fibrinogen was detected in a 27-year-old woman with no prior history of bleeding. Investigation of the defect revealed abnormal release of fibrinopeptide A and incomplete polymerization of fibrin monomers. Crosslinking of polymerized fibrin by Factor XIII was normal. To further characterize the dysfibrinogen, the increase in mechanical impedance during clot development was measured. Fibrinogen Seattle II showed several differences from normal fibrinogen: delayed onset of clotting, decreased rate of clot formation, and lower final clot impedance. Taken cumulatively, these data are consistent with an amino acid substitution at or near residue 16 in one of the A alpha chains, the point at which thrombin cleaves.

Adult↗

PubMed1991

Fibrinogen degradation product-D, fibrinogen, and serum change polymorphonuclear granulocyte activity--possibly important post-trauma?

Severe trauma favors the susceptibility of patients to infection. It has been shown that proteins or protein fragments are responsible for an endogenous immunodepression. After trauma a coagulopathy accompanied by increased serum levels of fibrinogen degradation products (FDP) is often found. Therefore, we examined whether FDP-D can influence the activity of polymorphonuclear neutrophils (PMN). PMN-activation was measured by two different superoxide-specific methods (Cytochrome-C-test, INT-test). With both methods we found a decrease of PMN activity by FDP-D compared to fibrinogen. Albumin, which was used as a control protein, only influenced PMN activity in unphysiologically high concentrations. The third method used to quantify PMN activity was chemiluminescence, which is a more unspecific method since it is developed not only by oxygen radical species but also by activating the lipoxygenase pathway. In contrast to the superoxide specific tests we found an inhibitory effect of fibrinogen and also serum compared to FDP-D using chemiluminescence.

Cytochrome c Group↗

PubMed1985

Thrombin-induced fibrinopeptide release from a fibrinogen variant (fibrinogen Sydney I) with an Aalpha Arg-16----His substitution.

Fibrinogen, purified from a recently identified case of dysfibrinogenaemia, fibrinogen Sydney I, was shown by thrombin digestion, high-performance liquid chromatography (HPLC) and amino acid analysis to be a heterozygous case of an A alpha Arg-16----His substitution. Kinetic studies have been carried out on the thrombin-induced release of fibrinopeptide A (FPA), fibrinopeptide B (FPB) and the variant peptide [His16]FPA. When thrombin was added to fibrinogen Sydney I at a concentration of 0.2 U/ml release of FPA was rapid and there was a 79-fold reduced rate of release of [His16]FPA, but the rate of release of FPB was not appreciably reduced. In contrast, at lower thrombin concentrations the rate of FPB release was reduced in proportion to the rate of total FPA release, supporting the view that release of fibrinopeptides is a sequential process. The second-order kinetic constant kcat/Km for hydrolysis of the abnormal A alpha chain by thrombin was calculated from Lineweaver-Burk plots to be 16-30-fold less than that for the normal A alpha chain. Molecular modelling studies, using a refined model of the trypsin-pancreatic-trypsin-inhibitor complex have been used to suggest how the histidine at the P1 site can be accommodated within the enzyme hydrophobic active-site pocket.

Amino Acids↗

PubMed2004

The effects of additional carbohydrate in the coiled-coil region of fibrinogen on polymerization and clot structure and properties: characterization of the homozygous and heterozygous forms of fibrinogen Lima (Aalpha Arg141-->Ser with extra glycosylation).

Fibrinogen Lima is an abnormal fibrinogen with an Aalpha Arg141-->Ser substitution resulting in an extra N-glycosylation at Aalpha Asn139, which seems to be responsible for the impairment of fibrin polymerization. We have studied the polymerization and properties of clots made from both plasma and purified fibrinogen of both the homozygous and heterozygous forms. The clot permeation studies with both plasma and purified protein revealed a normal flux through the network for the heterozygous form but very decreased permeation in the homozygous form. Consistent with turbidity results, the clot network of the homozygous form, seen by scanning electron microscopy, was tight and composed of thin fibers, with many branch points, while the appearance of clots from the heterozygous form was similar to that of control clots, but in both cases the fibers were more curved than those of control clots. The rheological properties of clots from the homozygous form were also altered, with rigidity being increased in plasma clots, but decreased in the purified system, a consequence of the balance between numbers of branch points and fiber curvature. From these results it seems that the extra carbohydrate moiety, located in the alpha coiled-coil region close to the betaC domains, impairs the protofibril lateral association process, giving rise to thinner, more curved fibers, with the structural anomalies being most pronounced in the clots from the homozygous plasma. These studies support a model for fibrin polymerization in which the betaC-betaC interactions are involved in lateral aggregation.

Blood Coagulation↗

PubMed1983

Fibrinogen "Haifa" - a new fibrinogen variant. A case report.

A 30-year-old female presenting with arterial occlusions of the lower limbs was discovered to have a markedly abnormal thrombin time and reptilase time. Further investigations revealed the presence of a qualitatively abnormal fibrinogen. Two other family members who were completely asymptomatic had similar defects. The abnormal fibrinogen has been characterized and found to be a new variant and as such designated fibrinogen 'Haifa'.

Adult↗

PubMed1993

Beta 3 integrin derived peptide 217-230 inhibits fibrinogen binding and platelet aggregation: significance of RGD sequences and fibrinogen A alpha-chain.

beta 3 Integrin derived peptides 217-230 (DAPEGGFDAIMQAT) and 217-231 (Y) (DAPEGGFDAIMQATVY) at 100 microM inhibited 125I-fibrinogen binding to ADP-stimulated platelets and platelet aggregation. Peptide 217-231 (Y) (100 microM) significantly inhibited the binding of 125I-albolabrin (a disintegrin with a single RGD sequence) to ADP- and thrombin-activated platelets while it had only a slight effect on albolabrin binding to resting platelets. The 125I-beta 3 217-231 (Y) cross-linked selectively to the fibrinogen A alpha-chain. The interaction of the RGD sequence in the A alpha-chain of fibrinogen with beta 3 217-231 sequence appears to play a significant role in the events leading to platelet aggregation.

Adenosine Diphosphate↗

PubMed1977

[Fibrinogen "Hannover", a further abnormal fibrinogen].

Another abnormal fibrinogen--"fibrinogen Hannover"--is reported. As known from most dysfibrinogenemias the clottability is poor, while immunologic test, heat precipitating test and the staphylococcal clumping test give normal fibrinogen concentrations. The clotting time when using thrombin or thrombin like enzymes is prolonged, it can be corrected with high thrombin concentration or thrombin combined with calcium inons, but not with thrombin like enzymes combined with calcium ions. The mild bleeding diathesis was first noted when the patient underwent an operation.

Adult↗

PubMed1981

Direct determination of plasma fibrinogen levels by heat precipitation. A comparison of the technique against thrombin clottable fibrinogen with spectrophotometry and radial immuno-diffusion.

We have studied the Thorp method for precipitation of fibrinogen from diluted plasma, using a specific buffer (pH 6.3) at 56 degrees C, and the preferred anticoagulant (EDTA). Nephelometric or turbidimetric measurements of the precipitate were compared with the results obtained by radial immunodiffusion, or by thrombin clotting, of fibrinogen. In the absence of prior proteolysis (as indicated by the presence of fibrinogen and fibrin degradation products), correlations between the methods were excellent (r > 0.99). We conclude that the method of heat precipitation, which is simple to operate and inexpensive, gives results equally as good as the more difficult and time-consuming techniques.

Bilirubin↗

PubMed1989

Dephosphorylation of human fibrinogen, previously phosphorylated in vitro by protein kinase C, by whole blood or intestinal alkaline phosphatase. Effects on thrombin-induced gelation of in vitro dephosphorylated human fibrinogen.

Human fibrinogen, a phosphoprotein, was either left untreated or phosphorylated by protein kinase C. Then both were dephosphorylated by calf intestinal alkaline phosphatase. The dephosphorylated fibrinogen gave an increased fibre thickness during thrombin-induced gelation. Whole blood anticoagulated by heparin, EDTA or sodium citrate, contained dephosphorylating activity against 32P-labeled fibrinogen, although there were significant differences in activity among the three anticoagulants.

Alkaline Phosphatase↗

PubMed1982

Organization of the rat gamma-fibrinogen gene: alternative mRNA splice patterns produce the gamma A and gamma B (gamma ') chains of fibrinogen.

In a variety of species, including rodents and man, the gamma chain of fibrinogen consists of two nonallelic forms, called gamma A and gamma B, or gamma and gamma '. We have found that these two fibrinogen gamma chains in the rat arise by translation of two mRNAs of 1700 and 2200 nucleotides, which are produced from a single gene by alternative splice patterns. The more abundant, gamma A chain mRNA is 1561 nucleotides long, excluding the polyadenylated region, and encodes a protein 83% homologous with the human gamma A chain. A hydrophobic "signal" polypeptide of 25 amino acids is present at the amino terminus. The gamma B (gamma ') mRNA is identical with the gamma A sequence with the exception of a 513 bp insert located 202 bp from the poly(A) extension. This 513 bp insert is identical to the seventh and final intron of the gamma-fibrinogen gene, and is located four codons prior to the termination codon for the gamma A chain. Translation into this sequence produces a unique 12 amino acid carboxylterminus in the rat gamma B (gamma ') polypeptide that is homologous with the known carboxylterminus of the human gamma B (gamma ') chain.

Amino Acid Sequence↗

PubMed2005

The mouse immune response to human fibrinogen reveals an autoimmune component against mouse fibrinogen.

The present experiments were carried out to analyze whether immunization of mice with human fibrinogen would induce autoimmunity like other heterologous proteins such as collagen type II, thyroglobulin or myelin basic protein. Our results demonstrate that human fibrinogen induces very strong immune responses in all mouse strains analyzed. Autoimmune responses with short-term memory to mouse fibrinogen are induced in genetically susceptible mice. These autoimmune Th2-type responses induce splenomegaly, enhanced coagulation times, and production of rheumatoid factors. The short-lived autoimmune memory was not regulated by either suppressor T cells or exhaustion of immune cells; rather this potentially dangerous autoimmune response was regulated by unknown, antigen-specific feedback mechanisms (they do not influence immune responses to proteins like HSA and OA in the same mice). Such feedback mechanisms were not found in the immune responses to other heterologous proteins inducing significant cross-reactive autoimmunity such as collagen type II, thyroglobulin, or myelin basic protein.

Animals↗

PubMed1990

Isolation and partial structural characterization of an equine fibrinogen CNBr fragment that exhibits immunologic cross-reactivity with an A alpha-chain cross-linking region of human fibrinogen.

Immunochemical studies of equine fibrinogen were conducted to characterize the structural basis for the immunologic cross-reactivity observed between human and equine A alpha chains when employing an antiserum to the 26K, human cyanogen bromide (CNBr) fragment, A alpha 241-476 (CNBr VIII). A 38K, equine CNBr fragment that reacts with this antiserum was isolated from CNBr-digested equine fibrinogen by Sephadex G-100 gel filtration. It was further purified by sequential hydrophobic chromatography on phenyl-Sepharose CL-4B, followed by reversed-phased (C-8) high-performance liquid chromatography (HPLC). NH2-Terminal analysis of the purified fragment, designated EqA alpha CNBr, identified one major sequence whose first three residues, E-L-E, were identical with those of human CNBr VIII. Tryptic and staphylococcal protease digests of the equine fragment were resolved by reversed-phase HPLC (C-4, C-18), and the separated components were characterized by amino acid analysis and automated Edman degradation. A total of 34 tryptic and 20 staph protease peptides yielded sequence information that permitted the alignment of 271 equine residues with residues A alpha 241-517 from the COOH-terminal two-thirds of the human A alpha chain so that 63% of the possible matches were identical. Other features of interest included (1) an amino acid substitution in which the methionine residue at A alpha 476 in the human A alpha chain was replaced by a valine residue, thus accounting, in part, for the larger EqA alpha CNBr fragment obtained from the equine molecule, and (2) a region of striking homology in which 36 successive residues, corresponding to A alpha 428-464 in the human A alpha chain, were identical in both species. These findings, together with available structural data for the COOH-terminal portion of the rat and bovine A alpha chains, indicate that the region corresponding to (human) A alpha 240-517 represents a conserved portion of the fibrinogen molecule. This may, in turn, explain the difficulties encountered when trying to raise monoclonal antibodies to cross-linking regions that are contained within the COOH-terminal two-thirds of the human A alpha chain.

Amino Acid Sequence↗

PubMed1980

Mechanism of action of thrombin on fibrinogen. Size of the A alpha fibrinogen-like peptide that contacts the active site of thrombin.

The following peptides were synthesized by classical methods in solution: Ac-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg-Val-Val-Glu-NHCH3 (F-4), Ac-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg-Gly-Pro-Arg-Val-NHCH3 (F-5), and Ac-Phe-Leu-Ala-Glu-Glv-Gly-Gly-Gly-Val-Arg-Gly-Pro-NHCH3 (F-6). The rates of hydrolysis of the Arg-Gly bond in these peptides by thrombin were measured, and the values of the specificity constant, kcat/KM, were all found to be approximately 2 X 10(-7) [(NIH unit/L)s]-1, similar to that for a peptide (F-3) having an additional Arg residue between Glu- and -NHCH3 of F-4. The difference between this value and that for the A alpha chain of bovine fibrinogen is attributed to slight conformational differences arising from long-range interactions present in fibrinogen but not in the synthetic peptides. In addition to the requirement for the Phe residue, demonstrated earlier, it is shown here that no residues on the C-terminal side of Pro are required for interaction between thrombin and fibrinogen. The active site of thrombin thus appears to interact with a peptide of the size of F-6, with the Phe residue possibly being in close spatial proximity to the Val-Arg-Gly moiety.

Amino Acid Sequence↗

PubMed2003

Novel Aalpha chain truncation (fibrinogen Perth) resulting in low expression and impaired fibrinogen polymerization.

A young woman with a history of menorrhagia and easy bruising presented with a functional fibrinogen concentration of 1.8 mg mL(-1), a gravimetric concentration of 3.3 mg mL(-1) and a prolonged thrombin clotting time of 32 s. Both reverse phase analysis and reducing SDS-PAGE revealed a normal profile of Aalpha, Bbeta, and gamma chains. However, non-reducing gels revealed a broadened 340-kDa band, while the 305-kDa band was normal, suggesting a C-terminal truncation of the Aalpha chain. DNA sequencing of all exons and intron boundaries revealed a single heterozygous cytosine deletion at nucleotide 4841 of the Aalpha gene predicting a frameshift and the incorporation of 23 new residues (LMKLPSSTLPQLEKHSQVSSHLC) before termination after residue 517. In agreement with a predicted mass decrease of 9953 Da, the measured mass of the Aalpha(Perth) chain was 56 242 Da, while that of the normal Aalpha(A) chain was 66 189 Da. Tryptic mapping of isolated Aalpha chains revealed a new [M + 2H] ion at 607 m z(-1), corresponding to the predicted penultimate peptide LPSSTLPQLEK. The variant chain was poorly incorporated into plasma fibrinogen at a ratio of Aalpha(Perth)/Aalpha(A) of 0.15 : 1, suggesting the Aalpha(Perth) chain might be out-competed by normal chains during molecular assembly in the hepatocyte. Despite the low expression, polymerization curves showed a decreased V(max) and final turbidity, suggesting the fibrinogen Perth clots are composed of thinner fibers. However, the fibrinolytic rate was very similar to that of the control.

Adult↗

PubMed2005

Japanese collaborative study for fibrinogen assay: variability of the fibrinogen assay between different laboratories does not improve when a common calibrator is used.

Several national and local external quality assurance schemes have been developed to improve the plasma fibrinogen assay in Japan over the past 30 years. Now most commercial calibrant plasma may be calibrated against an International Standard preparation, in order to achieve agreement of results obtained by different laboratories. However, we have never achieved satisfactory results, according to an external quality control survey regarding the fibrinogen assay. Therefore, we distributed two kinds of fibrinogen standards to be used as common calibrators, along with three plasma samples, among 183 general laboratories in Japan. The results of this collaborative study showed that the assigned value for the commercially available calibrators remained problematic. Furthermore, it was concluded that the between-laboratory variability could not be improved beyond a certain degree of standardization, even if a common calibrator was used for the Clauss-derived assay carried out by an automatic coagulometer.

Calibration↗

PubMed2001

Genetic and immunological characterization of fibrinogen inclusion bodies in patients with hepatic fibrinogen storage and liver disease.

Fibrinogen storage in liver cells can occur under three different morphological inclusions. Type I contain all three fibrinogen chains (A alpha, B beta, and gamma) as well as D and E fragments, whereas type II and III lack B beta as well as D and E fragments. Patients with type I inclusions carry a point mutation (gamma 284 Gly-Arg). The mutation is not present in patients with type II and III inclusions. These results appear to suggest that the three various phenotypic expressions (i.e., morphological variants) reflect different genetical abnormalities of fibrinogen.

Fibrinogen↗

PubMed2005

Identification and characterization of the fibrinogen-like domain of fibrinogen-related proteins in the mosquito, Anopheles gambiae, and the fruitfly, Drosophila melanogaster, genomes.

BACKGROUND: The fibrinogen-like (FBG) domain, which consists of approximately 200 amino acid residues, has high sequence similarity to the C-terminal halves of fibrinogen beta and gamma chains. Fibrinogen-related proteins (FREPs), which contain FBG domains in their C-terminal region, are found universally in vertebrates and invertebrates. In invertebrates, FREPs are involved in immune responses and other aspects of physiology. To understand the complexity of this family in insects, we analyzed FREPs in the mosquito genome and made comparisons to FREPs in the fruitfly genome. RESULTS: By using the genome data of the mosquito, Anopheles gambiae, 53 FREPs were identified, whereas only 20 members were found in the Drosophila melanogaster genome. Using sequence profile analysis, we found that FBG domains have high sequence similarity and are highly conserved throughout the FBG domain region. By secondary structure analysis and comparison, the FBG domains of FREPs are predicted to function in recognition of carbohydrates and their derivatives on the surface of microorganisms in innate immunity. CONCLUSION: Detailed sequence and structural analysis discloses that the FREP family contains FBG domains that have high sequence similarity in the A. gambiae genome. Expansion of the FREP family in mosquitoes during evolutionary history is mainly accounted for by a major expansion of the FBG domain architecture. The characterization of the FBG domains in the FREP family is likely to aid in the experimental analysis of the ability of mosquitoes to recognize parasites in innate immunity and physiologies associated with blood feeding.

Alternative Splicing↗

PubMed2000

Fibrinogen Caracas V, an abnormal fibrinogen with an Aalpha 532 Ser-->Cys substitution associated with thrombosis.

A new dysfibrinogenemia associated with thrombophilia has been identified in a Venezuelan kindred. Thrombin and Reptilase times were prolonged and the accelerating capacity of the patient's fibrin on the t-PA-induced plasminogen activation was decreased. In addition the affinity of fibrinogen for plasminogen was diminished. Permeability and electron microscopy studies revealed that the abnormal clot was made up of thin and densely packed fibres giving rise to a reduced fibrin gel porosity. This was confirmed by turbidity studies showing a decreased fibre mass/length ratio. Affected members were heterozygous for an Aalpha 532 Ser-->Cys mutation as demonstrated by genetic analyses. This abnormal fibrinogen has been designated as Fibrinogen Caracas V. The family study showed a convincing association between the mutation and thrombotic manifestations. The thrombotic tendency may be ascribed to lack of accelerating capacity of fibrin to induce fibrinolysis caused by an abnormal clot structure with thin fibres and reduced porosity.

Adolescent↗