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PubMed2006

A novel fibrinogen variant (fibrinogen Seoul II; AalphaGln328Pro) characterized by impaired fibrin alpha-chain cross-linking.

We report a novel fibrinogen variant (fibrinogen Seoul II), which has a heterozygous point mutation from CAA to CCA leading to AalphaGln328Pro. The mutation site is among several glutamine residues that serve as alpha-chain cross-linking acceptor sites. Fibrinogen Seoul II was found in a 51-year-old male patient and his family in Seoul, Korea. The patient was diagnosed with myocardial infarction at age 43. Eight years later he was admitted to the emergency room due to recurrence of the disease, where he expired under treatment with tissue plasminogen activator (t-PA). Fibrin polymerization curves, made using purified fibrinogen from the patient's relatives, showed a decreased final turbidity, suggesting Seoul II fibrin clots are composed of thinner fibers. This supposition was verified using scanning electron microscopy. Alpha-polymer formation by the mutant fibrinogen upon thrombin treatment in the presence of factor XIII and calcium was distinctly impaired. This result confirms that the residue Aalpha328 plays a pivotal role in alpha-chain cross-linking.

Adult↗

PubMed1980

Fibrinogen Copenhagen; an abnormal fibrinogen with defective polymerization and release of fibrinopeptide A, but normal adsorption of plasminogen.

A qualitatively abnormal fibrinogen was detected in the plasma of a 53 year old woman with severe arterial thrombotic disease. The concentrations of plasma fibrinogen and serum fibrinogen related material were normal. The abnormal fibrinogen was electrophoretically normal. The defects detected were an abnormality of polymerization of fibrin monomers and a decreased rate of release of fibrinopeptide A. The absorption of radiolabelled partially degraded plasminogen on to fibrin prepared from purified fibrinogen Copenhagen was normal.

Adsorption↗

PubMed1999

Fibrinogen Bastia (gamma 318 Asp-->Tyr) a novel abnormal fibrinogen characterized by defective fibrin polymerization.

A new congenital dysfibrinogen, Fibrinogen Bastia, was discovered in a 20-year-old woman with no clinical symptoms. The plasma thrombin-clotting time was severely prolonged. The functional plasma fibrinogen concentration was low (0.2 mg/ml), whereas the immunological concentration was normal (2.9 mg/ml). Purified fibrinogen Bastia displayed a markedly prolonged thrombin-clotting time related to a delayed thrombin-induced fibrin polymerization. Both the thrombin-clotting time and the fibrin polymerization were partially corrected by the addition of calcium ions. The anomaly of fibrinogen Bastia was found to be located in the gamma-chain since by SDS-PAGE performed according to the method of Laemmli two gamma-chains were detected, one normal and one with an apparently lower molecular weight. Furthermore, analysis of plasmin degradation products demonstrated that calcium ions only partially protect fibrinogen Bastia gamma-chain against plasmin digestion, suggesting that the anomaly is located in the C-terminal part of the gamma-chain. Sequence analysis of PCR-amplified genomic DNA fragments of the propositus demonstrated a single base substitution (G-->T) in the exon VIII of the gamma chain gene, resulting in the amino acid substitution 318 Asp (GAC)-->Tyr (TAC). The PCR clones were recloned and 50% of them contained the mutation, indicating that the patient was heterozygous. These data indicate that residue Asp 318 is important for normal fibrin polymerization and the protective effect of calcium ions against plasmin degradation of the C-terminal part of the gamma-chain.

Adult↗

PubMed1991

Fibrinogen Kiel: a congenital dysfibrinogenaemia with (A alpha-16 Arg----His) substitution characterized by HPLC without prior isolation of fibrinogen.

A congenital fibrinogen variant in a German family is described which has been identified as a substitution of His in position 16 of the A alpha-chain for Arg, manifested over three generations in heterozygous form. The characterization is based on the reaction of the variant fibrinogen with thrombin and reptilase, on the HPLC-chromatographic properties and the amino acid composition of the abnormal fibrinopeptide A. Clinical observations in the affected family members (neither haemorrhagic nor thrombophilic tendencies), the results of routine coagulation tests (normal global clotting tests, prolonged thrombin and thrombin-coagulase time, decreased fibrinogen concentration in functional as opposed to immunological tests), and the autosomal co-dominant modus of inheritance of the fibrinogen variant are all in complete agreement with other reports in the literature concerning the same amino acid exchange. The results of our experiments with fibrinogen Kiel allow no definite conclusion regarding the question of whether it consists of pure homodimers or as of a mixture of homo- and heterodimers.

Amino Acids↗

PubMed1995

Calcium ion-dependent monoclonal antibody against human fibrinogen: preparation, characterization, and application to fibrinogen purification.

We have produced a high-affinity monoclonal antibody classified as IgG1 with kappa-type light chains that recognizes the calcium ion(Ca2+)-dependent conformation of the D-domain of human fibrinogen. Binding of fibrinogen in solution to the insolubilized antibody increased in the presence of increasing concentrations of up to 2 mM Ca2+, the half-maximal binding being reached at 130 microM Ca2+. The dissociation constant was estimated to be 1.6 x 10(-8) M at 2 mM Ca2+. The antibody was found also to be dependent on other divalent metal ions including Zn2+, Mn2+, Co2+ and Cu2+, but not Ba2+, Mg2+ or Sr2+. The synthetic Gly-Pro-Arg-Pro-amide peptide, which has recently been shown to bind to close proximity to the calcium binding site in the D-domain, was unable to elicit the conformation for the antigen to be recognized by this antibody. This antibody was found to be a suitable ligand for the immunoaffinity chromatography of normal and abnormal fibrinogens directly from citrated plasma depleted of the vitamin K-dependent proteins or heparinized plasma by eliminating the precipitation procedure widely adopted in conventional techniques of fibrinogen purification. Indeed, fibrinogen Marburg I with the A alpha chains depleted of the carboxy-terminal A alpha(461-610) residue segment has been purified by this technique, although this dysfibrinogen was difficult to purify by conventional precipitation techniques.

Antibodies, Monoclonal↗

PubMed1995

Polymorphisms of the beta fibrinogen gene and plasma fibrinogen concentration in Caucasian and Japanese population samples.

We reported previously that plasma fibrinogen was significantly higher in U.S. Caucasians than in Japanese, which may contribute to the higher mortality rate of coronary heart disease in the United States than in Japan. To examine the contribution of genetic variations to the race difference in plasma fibrinogen levels, restriction fragment length polymorphisms (RFLPs) of the beta fibrinogen gene were examined in 293 nonsmoking Caucasians and Japanese men and women aged 47-69 years. Three RFLPs were detected by digestion of genomic DNA using the BclI restriction enzyme, polymerase chain reaction (PCR) products using HaeIII and HindIII. The alleles B2 (4.2 kb, BclI digestion), H2 (957 b, HaeIII) and Hd2 (465 b. HindIII) were associated with higher fibrinogen concentrations in previous studies. Because of a strong linkage disequilibrium between HaeIII and HindIII polymorphisms, the data of HindIII was presented. The frequency of the B2 allele was 22% (95% Cl: 17-27%) for Caucasians and 13% (10-17%) for Japanese (the difference: p < 0.01). The respective frequency of the Hd2 allele was 26% (21-31%) and 12% (8-16%) (p < 0.001). After controlling for age, body mass index, alcohol intake, triglycerides, fish intake, and for women, menopausal status and hormone replacement therapy, the adjusted mean fibrinogen level among Caucasians was 289 mg/dl for genotype B1B1 and 301 mg/dl for genotype B1B2 or B2B2 combined (p = 0.18), and 285 mg/dl for Hd1Hd1 and 306 mg/dl for Hd1Hd2 or Hd2Hd2 combined (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1976

Purification of rabbit anti-human fibrinogen antibodies cross reactivity of mammalian fibrinogen.

A simple isolation procedure of highly purified and unaltered rabbit antibodies to human fibrinogen is described. The method used is based upon the preferential adsorption of fibrinogen by barium sulfate at acid pH. After redissolution of the specific precipitate and dissociation of the antigen-antibody complexes at pH 2.4, the fibrinogen is removed by adsorption on barium sulfate, while the antibody protein stays in solution. BaSO4 is eliminated by centrifugation and the supernatant is neutralized and concentrated by ammonium sulfate fractionation (40% saturation). A concentrated solution of specific anti-fibrinogen antibodies is thus obtained; the latter can be used to prepare, by selective immunprecipitation, a fibrinogen free plasma, and to analyze precipitin patterns in cross reacting systems.

Animals↗

PubMed1993

Effects of hybrid peptide analogs to receptor recognition domains on alpha- and gamma-chains of human fibrinogen on fibrinogen binding to platelets.

We synthesized a series of hybrid peptides that correspond to the gamma-chain dodecapeptide (400-411), variable numbers of glycine residues, and the RGDS peptide [Y-HHLGGAKQAGDV(G)nRGDS] to investigate the relationship of these receptor recognition domains of fibrinogen to platelet membrane glycoprotein IIb/IIIa. The tetrapeptide RGDS, the GRGDSPA peptide and the dodecapeptide inhibited binding of fibrinogen to GPIIb/IIIa by 50% (IC50) at concentrations of 17 +/- 1.6 microM, 15 +/- 2.1 microM, and 87 +/- 6.8 microM, respectively. The inhibitory effect of hybrid peptides increased as the number of glycine residues increased, plateauing with 9-11 glycine residues in hybrid peptide analogs, which had an IC50 of 0.68 +/- 0.14 microM. These hybrid peptides completely inhibited the binding of fibrinogen to activated platelets when used in sufficient concentrations. The peptide Y-HHLGGAKQAGDV(G)9RGDS blocked ADP-induced aggregation in citrated platelet-rich plasma with IC50 of 3.5 +/- 0.6 microM. When the peptide Y-HHLGGAKQAGDV(G)9RGDS was labeled with 125I to quantify its binding to platelets, maximal binding was observed within 30 min. The binding sites of the hybrid peptide were 43,600 molecules/platelet (Kd = 3.1 +/- 0.5 x 10(-7) M) to stimulated platelets and 12,500 molecules/platelet (Kd = 1.4 +/- 0.2 x 10(-7) M) to nonstimulated platelets. The hybrid peptides had the same binding affinity to platelets as fibrinogen and inhibited platelet function. Moreover, anti-GPIIb/IIIa antibody inhibited the binding of the labeled hybrid peptide to stimulated platelets. These results indicate that in the native fibrinogen molecule the presence of both RGD sequence or gamma-chain domain at optimal distances increased the binding affinity to GPIIb/IIIa.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1996

Affinity of Fibrinogen Binding to Platelet Membrane Glycoprotein IIb/IIIa Increases with RGDS and gamma Chain Fibrinogen Peptide Hybrid.

Arg-Gly-Asp (RGD)-containing peptides and the peptide unique to fibrinogen in the C-terminal domain of the gamma chain are important for fibrinogen binding to platelet membrane glycoprotein (GP) II b/III a. We synthesized a unique hybrid peptide of YRGDSPLGGAKQAGDV encompassing the RGD sequence (RGDS) with the gamma chain peptide (LGGAKQAGDV). Maximum binding to thrombin-stimulated platelets was achieved within 40 minutes with the YRGDS peptide and within 20 minutes with the hybrid peptide and native fibrinogen. The platelet binding sites were 58,600 molecules with the hybrid peptide and 52,400 molecules with YRGDS. These peptides inhibited fibrinogen binding to thrombin-stimulated platelets in a dose-dependent manner. The order of inhibitory potency of these peptides was as follows: fibrinogen models R: hybrid peptide > YRGDS > GQQHHLGGAKQAGDV (G15). The RGES peptide had no inhibitory activity. These three peptides inhibited binding of the anti-GP II b/III a monoclonal antibody (LJ-CP8) to platelets. The hybrid peptide showed the most potent inhibitory activity, with an IC50 of 48 µM. These results suggest that the linear combined RGDS and gamma chain peptide created with proline increases the affinity of binding to activated platelets.

Journal Article↗

PubMed1983

Influence of fibrin, fibrinogen and fibrinogen degradation products on cultured endothelial cells.

Thin films of a fibrin-agar mixture induced significant morphological changes in porcine aortic endothelial cells in vitro. The cells became spindle shaped, piled up and consequently the intercellular spaces widened. These morphological changes became more significant with higher concentrations of fibrin. Films of fibrinogen-agar or thrombin-agar mixtures induced no such morphological changes thereby suggesting that fibrin itself injures the endothelial cells. Despite the lack of morphological effects of fibrinogen degradation product D or E on cultured endothelial cells, lower molecular weight fibrinogen degradation products separated by Sephadex G-25 chromatography did induce injury in the endothelial cells. As damage to the endothelium is a key event in initiation of atherosclerosis, fibrinogen and its metabolites probably play important roles.

Animals↗

PubMed2003

Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk).

Two siblings with hypofibrinogenemia have lifelong trauma-related bleeding. Recently, the brother experienced recurrent thrombosis after cryoprecipitate infusions following surgery. The sister had 6 miscarriages. Plasma clots in each were resistant to compression and fibrinolysis and were soluble in 5 M urea. Examination by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed only the presence of crosslinked gamma-gamma fibrin chain dimers without high polymers of alpha n. Fibrin clots contained an abnormal 35-kDa constituent recognized by an antibody to the mature fibrinogen Aalpha-chain residues 241-476 but not by antibodies to Aalpha219-348 or Aalpha349-406. DNA analysis revealed a heterozygous CAA-->TAA mutation at the codon for amino acid 328 of the Aalpha gene in these siblings and 2 asymptomatic family members. The Gln328stop mutation (fibrinogen Keokuk) predicted a 46% truncation and the production of a 35-kDa Aalpha chain. Analysis of purified fibrinogen revealed expression of the abnormal Aalpha chain in 4 family members but found no normal fibrinogen in the 2 hypofibrinogenemic patients. This paradox was resolved when they and their asymptomatic mother were found to be heterozygous for a second Aalpha mutation, a GT-->TT splice site mutation in intron 4 (IVS4 + 1 G> T). However, compound heterozygosity for both mutations was required for the expression of severe hypodysfibrinogenemia and for clinical symptoms.

Blood Coagulation Disorders↗

PubMed1983

Novel structure elucidation strategy for genetically abnormal fibrinogens with incomplete fibrinopeptide release as applied to fibrinogen Schwarzach.

A novel and simple strategy was developed for the structure elucidation of those genetically abnormal fibrinogens in which thrombin is unable to release fibrinopeptide A from the abnormal molecules. The method provides evidence for the Arg leads to Cys exchange at the C-terminus of the fibrinopeptide A sequence. The abnormal fibrinogen was mercaptolysed and then S-amino-ethylated. Upon thrombin digestion, the modified fibrinogen released new peptides, as shown by high-performance liquid chromatography. The amino-acid analysis proved that these peptides correspond to the expected fibrinopeptide A variants. It was therefore concluded that the analysed case of dysfibrinogenemia, designated Fibrinogen Schwarzach, contains an A alpha 16 Arg leads to Cys exchange in the heterozygous form.

Amino Acids↗

PubMed1979

The accelerating effect of fibrinogen and early fibrinogen degradation products on erythrocyte sedimentation.

The fibrinogen molecule has a number of biological activities and some of these are shared by the larger degradation products. This study was carried out to investigate the erythrocyte sedimentation-accelerating property of fibrinogen and how this property might be modified by proteolytic digestion with plasmin. The sedimentation rate of washed human red cells suspended in saline, was found to be directly proportional to the concentration of added purified human fibrinogen, down to 250 mg%, below which there was no difference from saline controls. Plasmic digestion of fibrinogen yielding fragment X, did not reduce the accelerating affect on erythrocyte sedimentation, indicating that the intact carboxyl terminal end of the A alpha chain is unnecessary for this phenomenon. Further digestion to fragment Y reduced the effect slightly but digestion to fragments D and E abolished the accelerating effect completely.

Blood Sedimentation↗

PubMed1978

Adsorption of plasma proteins on hydrophobic surfaces. II. Fibrinogen and fibrinogen-containing protein mixtures.

The adsorption of fibrinogen from single solution and from mixed solution with albumin and gamma-globulin has been followed at the air-buffer, isooctane-buffer, and methylene iodide-buffer interfaces by the pendant drop technique. Fibrinogen is shown to form substantial coherent films on isooctane and methylene iodide, suggesting considerable unfolding and lateral association. From this, a novel hypothesis has been proposed to account for the dominance of fibrinogen adsorption from mixed solutions on certain hydrophobic surfaces, in which the spreading pressure of rapidly unfolding fibrinogen molecules is sufficient to desorb other plasma proteins.

Adsorption↗

PubMed2001

Lack of fbe, the gene for a fibrinogen-binding protein from Staphylococcus epidermidis, reduces its adherence to fibrinogen coated surfaces.

The significance of Fbe, a fibrinogen-binding protein in Staphylococcus epidermidis, was investigated. A fbe mutant was constructed by allelic replacement, where a Gentamicin resistance gene replaced a portion of the A region of fbe. Adherence assay to immobilized fibrinogen on polyethylene surfaces and peripheral venous catheters from patients showed that the fibrinogen binding ability of the mutant was reduced compared to its parental strain. This shows that Fbe is a major factor involved in adherence of S. epidermidis to fibrinogen. No difference was found between the wild-type and mutant in their affinity to immobilized fibronectin.

Alleles↗

PubMed1984

The identification of a DNA polymorphism of the alpha fibrinogen gene, and the regional assignment of the human fibrinogen genes to 4q26-qter.

We have identified a common restriction fragment length polymorphism of the alpha fibrinogen gene with the enzyme TaqI. This polymorphism is probably due to a single base change that creates or destroys a TaqI recognition site about 1000 basepairs from the 3' end of the alpha fibrinogen géne. The frequency of the rare allele in 83 unrelated healthy individuals is 0.33. We have used in situ hybridisation of the alpha fibrinogen cDNA to localise the gene on chromosome 4q29-31. We have confirmed this regional localisation by restriction fragment detection in a human X Chinese hamster somatic cell hybrid which contains a translocated human chromosome 4 with a breakpoint at 4q26. The alpha, beta, and gamma fibrinogen genes are all present on human chromosome 4q26-qter.

Base Sequence↗

PubMed1994

Preliminary observations on plasma fibrinogen and plasma protein concentrations and on plasma protein:fibrinogen ratios in clinically healthy buffaloes.

The plasma fibrinogen concentration, the total plasma protein concentration and the plasma protein to fibrinogen ratio (PP:F) were determined in clinically healthy Nili Ravi buffaloes. The plasma fibrinogen concentrations in calves, lactating and non-lactating buffaloes were 513 +/- 62, 615 +/- 90 and 544 +/- 74 mg/dl, respectively, and were statistically different (p < 0.05). Total plasma protein concentrations in these animals were 7.15 +/- 0.28, 9.32 +/- 0.53 and 8.79 +/- 0.58 g/dl. PP:F for all animals was between 11 and 19. Fibrinogen levels were positively correlated with plasma protein (r = 0.59) and negatively correlated with PP:F (r = -0.59).

Animals↗

PubMed1975

Electron microscopic studies of plasmic degradation products of fibrinogen. Implications for the disulfide structure of fibrinogen.

Fibrinogen, coagulable plasmic derivatives (Fragments X) and Fragments Y, D and E were studied by negative staining electron microscopy. Fragment X obtained from Stage 1 digests and fibrinogen were both globular, while Fragment X of Stage 2 digests appeared as a nodular filament. The Stage 1 and Stage 2 Fragment X preparations had approximately the same molecular weight, but could be differentiated by several subtle differences in polypeptide chain structure. Fragments Y and D were also filamentous, although shorter than Fragment X (Stage 2), and Fragment E appeared as a small, compact or folded filament. These results agree with the concept that fibrinogen consists of a strand of nodules connected by thin strands, folded into a compact, spherical shape. The molecule opens up when stabilizing bonds are disrupted or liberated by plasmin. The data are compatible with a fibrinogen molecule in which the two halves are linked by a single locus of disulfide bonds at the amino terminus and with the asymmetric hypothesis of plasmic degradation to Fragments X, Y, D and E.

Binding Sites↗