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PubMed2001

Fibrinogen: a vascular risk factor, why? Contributing effect of oncostatin M on both fibrinogen biosynthesis by hepatocytes and participation in atherothrombotic risk related to modifications of endothelial cells.

Fibrinogen is a vascular risk factor. We suggest that it is a marker of cytokine secretion that simultaneously stimulates fibrinogen biosynthesis and vascular modifications responsible for atherothrombosis. Among these cytokines, oncostatin M (OSM) is the most potent cytokine for inducing fibrinogen biosynthesis by hepatocytes, and it could contribute to endothelial cell anomalies involved in the atherothrombotic process. Here we show that OSM acts (1) by inducing the secretion involved in invasion of the vessel wall by monocytes; (2) by inducing angiogenesis it promotes plaque destabilization, rupture, and consequently thrombosis; and (3) by decreasing fibrinolysis on macrovascular endothelial cells.

Arteriosclerosis↗
PubMedDate not supplied

[Influence of end products of plasmin-mediated hydrolysis of fibrinogen and fibrin (EF and Ef fragments) on fibrinogen cross-linking].

We studied the influence of the end products of plasmin-mediated hydrolysis of fibrinogen and nonstabilized fibrin (EF and Ef fragments) on covalent cross-linking of fibrinogen molecules catalyzed by a fibrin-stabilizing factor (factor XIIIa). The data on elastic and dynamic light scattering reveal no difference in the spatial structure of covalently linked fibrinogen molecules in the presence of the hydrolysis end products EF and Ef. In contrast to the inactive fragment EF, fragment Ef significantly accelerates the enzymatic reaction. This is also confirmed by electrophoresis of the reduced samples indicating a relatively fast accumulation of gamma-dimers and A alpha-polymers as compared to the control samples. Possible molecular mechanisms of this effect are discussed.

Animals↗
PubMed1987

Deposition of fibrin-stabilizing factor (F XIIIA and S), fibrinogen-related antigens, fibrinogen degradation products (FDPd and FDPe) and antihemolytic factor (F VIII) in renal disease: analysis of 161 cases by immunofluorescence microscopy.

To see whether or not the fibrin-stabilizing factor is involved in the pathogenesis of renal damage, we analyzed by IF the glomerular deposition of factor XIII (subunits A and S) in 161 patients with various renal diseases. In 4 out of 5 cases of thrombotic microangiopathy (80%), F XIII deposits were found in a continuous subendothelial pattern, in association with deposition of fibrinogen and FDP, suggesting the occurrence of intraglomerular coagulation. In 22 out of 45 patients with membranous GN (idiopathic or SLE-associated), F XIII deposits were found along the capillary walls in a subepithelial location. These findings were not correlated with the presence of particular histological or clinical features, nor with IF positive for fibrinogen, FDP and factor VIII, suggesting alternative pathways of fibrin formation or local collagen synthesis. Finally, in proliferative GN, either idiopathic (acute post-infectious and membranoproliferative) or systemic (SLE and vasculitis), as in other glomerular and non-glomerular diseases, the presence of F XIII deposits was negligible, even in cases positive for fibrinogen, FDP and factor VIII.

Antigens↗
PubMed1984

Preparation and characterization of NH2-terminal fibrinogen B beta fragments from N-DSK of human fibrinogen.

In order to investigate the early release of NH2-terminal plasmic fragments from the B beta chain of fibrinogen, substantial quantities of B beta 1-42 and B beta 1-21 are required as immunogens, as radioimmunoassay standards and for infusion into human volunteers to determine the half-lives of these peptides. Towards this end methods that employ selective proteolytic cleavage of these fragments from fibrinogen have been developed. Both the N-DSK fragment, produced by CNBr cleavage of fibrinogen, and B beta 1-118 were employed as substrates for plasmin with the finding of higher yields from N-DSK. B beta 1-42 and B beta 1-21 were purified by gel filtration and ion-exchange chromatography on SP-Sephadex using volatile buffers. When the purified preparation of B beta 1-42 was chromatographed on reverse-phase high performance liquid chromatography, two peaks of identical amino acid composition were separated, presumably due either to pyroglutamate or to amide differences.

Amino Acid Sequence↗
PubMed1997

Fibrinogen Poissy I: a new case of the A alpha Arg 16His fibrinogen variant.

A fibrinogen variant was identified in a patient with disseminated intravascular coagulation and in one member of her family. Coagulation studies showed marked prolongation of both the thrombin and reptilase times and discrepancy was noted between the levels of plasma fibrinogen, determined by a kinetic vs immunological determination or light scattering assay. Studies on purified fibrinogen revealed an impaired release of fibrinopeptides by thrombin. DNA sequencing revealed a heterozygous A to G point mutation in exon 2 of the A alpha chain, which substituted Arg for His at position 16. This mutation creates a Nla III cleavage site which was used to confirm the mutation.

Adult↗
PubMed1976

The sulphite precipitation method for fibrinogen measurement; its use on small samples in the presence of fibrinogen degradation products.

A technique based on precipitation by sodium sulphite (Na2SO3) has been developed for measuring the fibrinogen concentration of small (100 mul) samples. This technique offers technical advantages over the thrombin-clotting method, especially when measuring dilute solutions. Measurements made with the sulphite technique on fibrinogen solutions on plasma samples were not significantly different from those obtained with the thrombin-clotting method.

Fibrin Fibrinogen Degradation Products↗
PubMed1996

Interaction of heparin with fibrinogen using surface plasmon resonance technology: investigation of heparin binding site on fibrinogen.

Heparin is widely used as an antithrombotic drug, having excellent anticoagulant properties. However in certain clinical situations heparin's efficacy seems to be somewhat limited. Despite the administration of heparin there is a high incidence of reocclusion of coronary arteries following thrombolytic therapy, and it has been observed that a significant number of patients receiving heparin treatment still exhibit thrombus extension. Although it is well established that the in vitro and in vivo anticoagulant activities of heparin is mediated via the potentiation of the major coagulation inhibitor, antithrombin III (ATIII), some in vivo antithrombotic mechanisms are not fully understood. There is poor correlation between the anticoagulant activity of heparin as measured by in vitro assays and their in vivo antithrombotic efficacy. This may be due to heparin being targeted to many blood constituents whose resultant activities on the coagulation system have not been measured as yet. The antithrombotic activity of heparin as well as the pathogenesis of bleeding complications during heparin treatment cannot be completely explained by the inhibition of blood coagulation factors. Platelet dysfunction and acceleration of fibrinolytic process have been implicated as additional factors involved. Recently a number of reports have suggested that the inhibition of the antithrombotic activity of heparin in these clinical situations may be due to the interaction of heparin with other plasma proteins specifically with fibrin(ogen) present in the thrombus. Despite the possible pathophysiological significance of heparin-fibrin(ogen) interaction, little is known about the physicochemical aspects of this reaction. In this study an attempt was made to locate where heparin binds to fibrin(ogen), using various isolated structural domains from the plasmin-mediated digests of fibrinogen and the individual chains of fibrinogen. The BIALITE system (Pharmacia Biosensor AB, Uppsala, Sweden) was employed for such a study. This utilises the Surface Plasmon Resonance (SPR) phenomenon and allows a direct quantitative analysis of the label-free molecular interaction, in real-time, from which association and dissociation rate constants can readily be obtained.

Animals↗
PubMed1998

Postoperative plasma interleukin-6 in patients with renal cancer correlates with C-reactive protein but not with total fibrinogen or with high molecular weight fibrinogen fraction.

The concentration of fibrinogen (Fb) and its fractions, the levels of interleukin-6 (I1-6), C-reactive protein (CRP), and immunoglobulin G (IgG) were determined in 38 patients operated on because of renal cancer. The increased Fb and I1-6 concentrations were found in approximately one-half of the patients with malignancy. The relations among the high molecular weight (HMW) and two low molecular weight (LMW and LMW') fibrinogen fractions in these patients before surgery did not differ from the corresponding relations in normal subjects. The levels of all (except IgG) compounds studied increased after surgery and the peak of I1-6 was observed on the first postoperative day but that of CRP on the third day. The concentrations of total Fb and of its HMW fraction were the highest also on the third postoperative day and this was in contrast with the decline of low molecular weight fractions at the same time. These variations of estimated variables can be regarded as being relevant to the acute phase response. We have noted a correlation between the maximal concentrations of I1-6 and CRP, but not between the corresponding concentrations of Il-6 and total Fb or HMW Fb; this may suggest that the concentration of Fb is also under the control of a factor other than I1-6.

Adult↗
PubMed1989

High-resolution NMR studies of fibrinogen-like peptides in solution: interaction of thrombin with residues 1-23 of the A alpha chain of human fibrinogen.

The interaction of the following human fibrinogen-like peptides with bovine thrombin was studied by use of one- and two-dimensional NMR techniques in aqueous solution: Ala(1)-Asp-Ser-Gly-Glu-Gly-Asp-Phe(8)-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg(16 )- Gly(17)-Pro-Arg(19)-Val(20)-Val-Glu-Arg (F10), residues 1-16 of F10 (fibrinopeptide A), residues 17-23 of F10 (F12), residues 1-20 of F10 (F13), residues 6-20 of F10 with Arg(16) replaced by a Gly residue (F14), and residues 6-19 of F10 with Arg(16) replaced by a Leu residue (F15). At pH 5.3 and 25 degrees C, the Arg(16)-Gly(17) peptide bonds of both peptides F10 and F13 were cleaved instantaneously in the presence of 0.6 mM thrombin, whereas the cleavage of the Arg(19)-Val(20) peptide bonds in peptides F12, F13, and F14 took over 1 h for completion. On the basis of observations of line broadening, fibrinopeptide A was found to bind to thrombin. While resonances from residues Ala(1)-Glu(5) were little affected, binding of fibrinopeptide A to thrombin caused significant line broadening of NH and side-chain proton resonances within residues Asp(7)-Arg(16). There is a chain reversal within residues Asp(7)-Arg(16) such that Phe(8) is brought close to the Arg(16)-Gly(17) peptide bond in the thrombin-peptide complex, as indicated by transferred NOEs between the aromatic ring protons of Phe(8) and the C alpha H protons of Gly(14) and the C gamma H protons of Val(15). A similar chain reversal was obtained in the isolated peptide F10 at a subzero temperature of -8 degrees C. The titration behavior of Asp(7) in peptide F13 does not deviate from that of the reference peptide, N-acetyl-Asp-NHMe at both 25 and -8 degrees C, indicating that no strong interaction exists between Asp(7) and Arg(16) or Arg(19). Peptides with Arg(16) replaced by Gly and Leu, respectively, i.e., F14 and F15, were also found to bind to thrombin but with a different conformation, as indicated by the absence of the long-range NOEs observed with fibrinopeptide A. Residues Asp(7)-Arg(16) constitute an essential structural element in the interaction of thrombin with fibrinogen.

Amino Acid Sequence↗
PubMed2006

Analysis of fibrinogen variants at gamma387Ile shows that the side chain of gamma387 and the tertiary structure of the gammaC-terminal tail are important not only for assembly and secretion of fibrinogen but also for lateral aggregation of protofibrils and XIIIa-catalyzed gamma-gamma dimer formation.

To examine the role of fibrinogen gamma-chain residue 387Ile in the assembly and secretion of this multichain protein, we synthesized a series of variants with substitution at gamma387 by Arg, Leu, Met, Ala, or Asp. Only the variant gamma387Asp showed impaired synthesis in the cells and very low secretion into the medium. In addition, we performed thrombin-catalyzed fibrin polymerization and factor (F) XIIIa-catalyzed cross-linking of the gamma-chain for 4 variants. The degree of lateral aggregation of protofibrils into fibrin fibers was slightly reduced for gamma387Arg and Ala, and moderately reduced for gamma387Leu and Met. Although the FXIIIa-catalyzed cross-linking for all of the variants was slower than that for gamma387Ile, that of gamma387Arg was much more markedly impaired than that of the others. In summary, our studies demonstrated that the specific residue at gamma387 or the conformation of gamma388-411 residues, but not the length of the gammaC tail, is critical for fibrinogen assembly and subsequent secretion. Moreover, this residue or the conformation is also important for not only the lateral aggregation of fibrin polymers but also the FXIIIa-catalyzed cross-linking of the gamma-chain. Interestingly, our results clearly indicate that the conformations critical for these 2 functions are different from each other.

Amino Acid Substitution↗
PubMed2000

[Changes in fibrinogen, fibrin-fibrinogen degradation products and fibrinolytic activity during pregnancy, labor and the puerperium in pregnant women with chronic hypertension].

In this study 79 pregnant women were analyzed, during the pregnancy, delivery and postnatal period. The control group consisted of 41 healthy women, while in the studied group there were 38 patients with severe chronic hypertension. Analyzed parameters: fibrinogen, fibrinolysis and FDP. Parameters were performed in all cases of pregnancies during third trimester (I), during the first stage of labor (II), immediately after delivery of placenta (III), two hours after placenta was delivered (IV), eight hours (V), 24 hours (VI), 48 hours (VII) and 72 hours (VIII) after placenta was delivered. Comparing certain measures in fibrinogen's value, high statistical significance was obtained for control group (healthy women), ANOVA (F = 5.17; p < 0.001) and for studied group (women for chronic hypertension), (F = 3.17; p < 0.001. Analyses of FDP values showed high statistically significant difference for control group, F = 15.03; p < 0.00001, and for studied group, F = 10.56; p < 0.00001. Statistically significant difference in fibrinolytic activity was obtained for control group, F = 60.72; p < 0.0001 and studied group, F = 5.70; p < 0.0001.

Adult↗
PubMed1987

[Possibilities of using immunoenzyme test systems for determining levels of myoglobin, fibrinogen, fibrin-fibrinogen degradation products and fibronectin in the diagnosis of somatic diseases].

Clinical trials of immunoenzyme test-systems for the quantitative determination of fibronectin, fibrinogen, fibrin/fibrinogen degradation products and myoglobin have been performed on serum and plasma samples obtained from patients and healthy donors. The tests were informative and possessed diagnostic value in the following conditions: fibronectin--in pyogenic septic complications of newborns, burn infections; fibrinogen and fibrin/fibrinogen products--in thrombosis, myocardial infarction and disseminated intravascular coagulation syndrome; myoglobin--in myocardial infarction.

Adult↗
PubMed1979

Adsorption of fibrinogen and fragment D of fibrinogen onto the insolubilized alpha-chain of fibrin.

After thrombin treatment insolubilized fibrinmonomer, which is obtained from insolubilized fibrinogen covalently bound to agarose, adsorbs soluble fibrin and its derivatives from solutions. The immobilized proteins are attached to the agarose by the 'A' alpha-chain. After reduction of the disulfide bridges the beta- and gamma-chains can be removed from the agarose. After thrombin treatment the immobilized alpha-chain adsorbs fibrinogen and fragment D. To some extent the beta- and gamma-chain do not seem necessary for the adsorption. The amount adsorbed increases, when thrombin treatment of the insolubilized protein follows the reduction process. This may indicate that the fibrinopeptides 'A' of the insolubilized alpha-chain are better accessible after the removal of the beta- and gamma-chains.

Adsorption↗
PubMed1988

Clotting of bovine fibrinogen. Kinetic analysis of the release of fibrinopeptides by thrombin and of the calcium uptake upon clotting at high fibrinogen concentrations.

Kinetic data on the release of fibrinopeptides A and B from bovine fibrinogen by human thrombin were obtained at high fibrinogen concentrations, within the 0.8-8.8% range (0.227 X 10(-4) to 2.60 X 10(-4) M), at 25 degrees C, pH 7.26, 0.30 ionic strength, and 10(-4) M free Ca2+ concentration. Release of fibrinopeptide A followed strictly first-order kinetics at all concentrations, in spite of the fact that the highest concentration was 26 times larger than the value of KM found in the literature. This behavior can be explained by inhibition of thrombin by the reaction products, with KI = KM. The equation describing the course of the reaction under these conditions can be rearranged into a linear relationship between 1/kobsd and substrate concentration. The slope of the line is equal to 1/kcat and the intercept to KM/kcat. The data points fell accurately on a straight line, and with the parameters of the latter, kcat and KM were calculated as (6.3 +/- 0.11) X 10(-10) M s-1 (unit of thrombin)-1 L-1 and (11.0 +/- 3.0) X 10(-6) M, respectively. These values agree well with those found in the literature. Release of fibrinopeptide B follows complex kinetics. Higgins et al. [Higgins, D. L., Lewis, S.D., & Shafer, J.A. (1983) J. Biol. Chem. 258, 9276-9282] suggested that it can be described as the result of two consecutive reactions, the first one being the release of fibrinopeptide A and the second one of fibrinopeptide B from those molecules that have already lost fibrinopeptide A in the previous step.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

High-resolution NMR studies of fibrinogen-like peptides in solution: resonance assignments and conformational analysis of residues 1-23 of the A alpha chain of human fibrinogen.

The proton resonances of the following synthetic linear human fibrinogen-like peptides were completely assigned with two-dimensional NMR techniques in solution: Ala(1)-Asp-Ser-Gly-Glu-Gly-Asp(7)-Phe-Leu-Ala-Glu-Gly(12)-Gly(13)-Gly(14)- Val(15)-Arg(16)-Gly-Pro-Arg-Val-Val-Glu-Arg (F10), Ala-Asp-Ser-Gly-Glu-Gly-Asp-Phe-Leu-Ala-Glu-Gly-Gly(13)-Gly(14)-Val-Arg (F11), and Gly-Pro-Arg-Val-Val-Glu-Arg (F12). No predominant structure was found in the chain segment from Ala(1) to Gly(6) for F10 in both H2O and dimethyl sulfoxide. The previous suggestion that there is a hairpin loop involving residues Gly(12) to Val(15) in the A alpha chain of human fibrinogen is supported by the slow backbone NH exchange rates of Gly(14) and Val(15), by an unusually small NH chemical shift of Val(15), and by strong sequential NOE's involving this region in F10. This local chain fold within residues Asp(7) to Val(20) may place the distant Phe residue near the Arg(16)-Gly(17) peptide bond which is cleaved by thrombin.

Amino Acid Sequence↗
PubMed1989

High-resolution NMR studies of fibrinogen-like peptides in solution: structure of a thrombin-bound peptide corresponding to residues 7-16 of the A alpha chain of human fibrinogen.

The interaction of the following human fibrinogen-like peptides with bovine thrombin was studied by one- and two-dimensional NMR techniques in aqueous solution: acetyl-Phe(8)-Leu(9)-Ala(10)-Glu-(11)-Gly(12)-Gly(13)-Gly(14)-Val(15)-Ar g(16)- Gly(17)-Pro(18)-NHMe (F6), acetyl-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg(16) (tF6), acetyl-Asp(7)-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg(16)-Gly(17)-Pro- Arg(19)-Val(20)-NHMe (F8), and acetyl-Asp-Phe-Leu-Ala-Glu-Gly-Gly-Gly-Val-Arg(16) (tF8). At pH 5.3 and 25 degrees C, the Arg(16)-Gly(17) peptide bonds in both F6 and F8 were cleaved instantaneously in the presence of 0.5 mM thrombin, producing truncated peptides tF6 and tF8 and other peptide fragments. On the basis of observations of line broadening, thrombin was found to bind to the cleavage products, tF6 and tF8, of peptides F6 and F8. Peptide tF8 may have a higher affinity for thrombin than peptide tF6, as suggested by the more pronounced thrombin-induced line broadening on the proton resonances in peptide tF8. Transferred NOE (TRNOE) measurements were made of the complexes between thrombin and peptides tF6 and tF8. Medium- and long-range NOE interactions were found between the NH proton of Asp(7) and the C beta H protons of Ala(10), between the C alpha H proton of Glu(11) and the NH proton of Gly(13), and between the ring protons of Phe(8) and the C alpha H protons of Gly(14) and the C gamma H protons of Val(15). Sets of structures of the decapeptide tF8 were deduced by use of distance geometry calculations based on sequential and medium- and long-range TRNOEs from the thrombin-bound peptide. A predominant feature of these structures is the nonpolar cluster formed by the side chains of residues Phe(8), Leu(9), and Val(15) that are directly involved in binding to thrombin. This structural feature is brought about by an alpha-helical segment involving residues Phe(8)-Ala(10), followed by a multiple-turn structure involving residues Glu(11)-Val(15). These results provide an explanation for the observations that Asp(7), Phe(8), and Gly(12) are strongly conserved in mammalian fibrinogens and that the mutations of Asp(7) to Asn(7) and of Gly(12) to Val(12), result in delayed release of fibrinopeptide A, producing human bleeding disorders.

Amino Acid Sequence↗
PubMed1976

Proteolytic fragmentation of fibrinogen. II. kinetic modeling of the digestion of human and bovine fibrinogen plasmin or trypsin.

The kinetic data presented in the previous paper (Mihalyi, E., et al. (1976), Biochemistry 15, preceding paper in this issue), with respect to the fragmentation of human the bovine fibrinogen by either plasmin or trypsin, were compared with several chemical kinetic models. The models were derived mathematically on the basis of the three-nodular structure of fibrinogen (Hall, C.E., and Sayter, H.S. (1959), J. BiophysBiochem. Ctyol. 5, 11) and the asymmetrical cleavage sequence first proposed by Marder, V.J., et. al. ((1969) J. Biol. Chem. 244, 2111). The parameters were determined by nonlinear curve fitting. The whole process could be described accurately by only two rate constants. Several variant models were tested and, although a clear cut choice cannot be made, one of these, the protected three-bonds model, appears to give the best fit in most cases. This model assumes that the chain segment that distinguishes F from X protects certain other chains (the bonds) from proteolytic cleavage.

Animals↗
PubMed1997

Fibrinogen Kaiserslautern (gamma 380 Lys to Asn): a new glycosylated fibrinogen variant with delayed polymerization.

An adult woman diagnosed with cerebral thrombosis following a caesarean section was found to have severely prolonged thrombin and reptilase times. Five other family members also had prolonged, but variable, thrombin and reptilase times. Analysis of purified fibrinogen on reducing SDS-PAGE revealed an additional band, in all family members, which migrated immediately below the normal B beta band. Western blotting indicated that this band was a gamma chain and endoglycosidase-F digestion established that it contained an additional oligosaccharide side chain. Partial acid hydrolysis localized the new oligosaccharide to the C-terminus of the gamma chain. Amplification of this region by PCR and subsequent DNA sequencing demonstrated a single base substitution altering the normal 380 Lys (AAG) codon to Asn (AAT), producing a new Asn-Lys-Thr glycosylation site. The propositus and one other family member were homozygous for this mutation but the remaining four family members were heterozygous. The polymerization of purified fibrin monomers from the propositus was grossly abnormal; however, the polymerization curve was almost normalized by the removal of terminal sialic acid residues. This suggests that the polymerization defect was primarily caused by additional negatively charged sialic acid residues present on the new oligosaccharide. Further analysis of the D domain of purified fibrinogen established that calcium binding to the high affinity site remained unaffected by the bulky carbohydrate side chain or negatively charged sialic acid residues.

Adult↗