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PubMed1988

A new genetic fibrinogen variant (fibrinogen Erfurt I). Structurally characterized by an abnormal B beta-chain and present both in plasma and platelets.

An abnormal fibrinogen was discovered in the plasma of a clinically asymptomatic woman. This fibrinogen variant was analyzed by high resolution two-dimensional gel electrophoresis and its molecular abnormality established consisting in a slight decrease in molecular mass of the B beta-chains. Analysis of fibrin revealed that cleavage of fibrinopeptide B by thrombin is normal, the molecular defect being confined to the beta-portion of the B beta-chain. The same fibrinogen variant was detected in the blood platelets of the proposita. This finding supports the assumption of a common origin of plasma and platelet fibrinogen pools. Family studies revealed the presence of the abnormal fibrinogen in a brother of the proposita, thus confirming the genetic nature of the observed variant. The underlying mutant gene occurs in both carriers in heterozygous state.

Adult↗
PubMed2004

Biophysical characterization of fibrinogen Caracas I with an Aalpha-chain truncation at Aalpha-466 Ser: identification of the mutation and biophysical characterization of properties of clots from plasma and purified fibrinogen.

Fibrinogen Caracas I is a dysfibrinogenemia with a mild bleeding tendency; a novel nonsense mutation, in the gene coding the Aalpha-chain, identified in this study as G4731T, giving rise to a new stop codon at Aalpha-Glu 467. Fibrinogen from two family members, the mother and sister of the propositus, both heterozygous for the mutation were studied, analyzing clots made from both plasma and purified fibrinogen. Clot structure and properties were characterized by turbidity, permeation, scanning electron microscopy and rheological studies. Permeation through Caracas I plasma clots was decreased, consistent with the decreased final turbidity. As shown by scanning electron microscopy, plasma clots from the patients were composed of very thin fibers, with increased fibrin density and reduced pore size. Viscoelastic measurements revealed that fibrinogen Caracas I plasma clots were much stiffer and less subject to compaction. These results demonstrate a key role of the carboxyl-terminal alpha chains of fibrin in lateral aggregation during polymerization and reinforce the utility of studying plasma clots. It is important to point out that the biophysical studies with fibrinogen purified by two different methods yielded contradictory results, which can be accounted for by selective purification of certain molecular species as seen by two-dimensional electrophoresis.

Biomechanical Phenomena↗
PubMedDate not supplied

Comparison of different methods to measure fibrinogen concentration in canine plasma with respect to their sensitivity towards the fibrinogen degradation products X, Y and D.

In this study, fibrinogen measurements according to the Clauss method, photometric method and Jacobsson method have been investigated to find out how they are influenced by adding in vitro the purified canine fibrinogen degradation products (FDP) X, Y and D. Test results according to the Clauss method were found to be underestimated if the fragments X, Y and D were added while measurements according to the Jacobsson method turned out to underestimate the real fibrinogen concentration if the FDP Y and D were added. The Clauss method was particularly sensitive towards FDP. Results were considerably underestimated even with a quantity as little as 0.05 g FDP Y or FDP D/g fibrinogen (p < 0.05). The photometric method was only affected by FDP X leading to false high results. If FDP X was added, fibrinogen values were also overestimated with the Jacobsson method. Our results demonstrate that the photometric method is the most accurate.

Animals↗
PubMed1987

ADP-induced platelet aggregation depends on the conformation or availability of the terminal gamma chain sequence of fibrinogen. Study of the reactivity of fibrinogen Paris 1.

Fibrinogen Paris I contains a mutant gamma chain that is longer than the normal chain, resulting in altered fibrin polymerization and cross-linking. Because these functions involve the carboxy-terminal region of the gamma chain, we decided to determine whether fibrinogen Paris I or the isolated Paris I gamma chain supports normal ADP-induced platelet aggregation, a function that requires the ultimate 12 residues of the normal gamma chain (400 through 411). Aggregation of ADP-stimulated normal platelets was defective with fibrinogen Paris I and markedly depressed with the gamma Paris I chain. These findings prompted us to characterize the carboxy-terminal structure of the region of the gamma Paris I chain responsible for this activity. The carboxy-terminal cyanogen bromide (CNBr) peptide of the normal gamma chain (385 through 411) or that from gamma Paris I was isolated by differential adsorption to triethylene-tetramine resin or by reverse-phase high-performance liquid chromatography (HPLC). The CNBr peptide from the Paris I gamma chain was identical to that of the normal gamma chain in its retention time on HPLC, its amino acid composition, and its sequence. Thus, the primary structure of the gamma Paris I chain from residue 384 through 411 is normal, indicating that a peptide insertion has occurred upstream from residue 384, resulting in an impairment of those physiologic functions attributable to the carboxy-terminal end of the gamma chain from position 384 (ie, cross-linking, ADP-induced platelet aggregation, and at least a portion of the gamma chain polymerization site). These observations demonstrate that the gamma chain platelet recognition site in the fibrinogen molecule is necessary but not alone sufficient to support normal ADP-induced platelet aggregation. There appears to be an additional requirement for normal conformation of the gamma chain or availability of its terminal sequence during the interaction of fibrinogen with platelets.

Adenosine Diphosphate↗
PubMed1983

[Fibrinogen Bern II: hereditary fibrinogen variant with amino acid substitution of arginine replaced by histidine in position 16 of the A alpha chain].

The number of described individuals with congenital dysfibrinogenemia continuously increases, but only a few fibrinogen variants have thus far been characterized with respect to their structural defect. Fibrinogen Bern II is a hereditary fibrinogen variant with impaired release of fibrinopeptide A (FPA) and a markedly prolonged coagulation time. It turned out that only half of the FPA was cleaved off at normal rate while the residual FPA was released much more slowly and incompletely, unless high thrombin concentrations were used. Amino acid analysis of normal and abnormal FPA revealed that the abnormal peptide, in contrast to the normal, contained histidine but hardly any arginine. It is therefore concluded that fibrinogen Bern II undergoes substitution of arginine in position 16 of the A alpha-chain by histidine. Thus, the structural alteration is identical with that of seven other recently described variants. The presence of 50% normal fibrinogen molecules provides the normal hemostasis in the heterozygous carriers of the Bern II-dysfibrinogenemia.

Afibrinogenemia↗
PubMed1978

Fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A in pleural effusions. High turnover of fibrinogen in pleurisy.

Fibrinogen, fibrin(ogen) degradation products (FDP) and fibrinopeptide A (FPA) were analysed in pleural fluids from 20 consecutive patients with major effusions of various aetiology. FPA is a short-lived polypeptide which is split off from fibrinogen, whereafter fibrin is formed. FDP are formed through lysis of fibrin or fibrinogen. In 18 patients no fibrinogen could be detected in pleural fluid, whereas two (both having malignant tumours) had detectable but low concentrations. High FPA concentrations, interpreted as reflecting very recent fibrin formation, were found in all pleural fluids except for one case of empyema and one transudate. Plasma concentrations were low in most cases. The same pattern was found with regard to FDP, i.e. exudates showed high concentrations, whereas plasma concentrations were low. The only patient with a transudate showed absence of fibrinogen and low concentrations of FDP and FPA. We interpret our findings as indicative of a high rate of fibrin formation and degradation in pleural exudates and have not found any differences between various types of pleural exudates. Consequently, the findings may illustrate the close association between the coagulation system and inflammatory reactions which may be common to most pleural diseases.

Adult↗
PubMed1977

[Presence of an active fibrinogen--heparin complex in the total blood plasma fraction of plasma fibrinogen degradation products].

It is found by means of different methods (the administration of 35S-heparin, the determination of fibrinolytic activity of blood plasma fractions containing fibrinogen degradation products and fibrinogen--heparin complex, spectral analysis of fibrinogen--heparin complex etc.), that thrombin injection into animals results in the formation of fibrinogen--heparin complex, which is mainly discovered in the fraction of fibrinogen degradation products.

Animals↗
PubMed1990

Conformational changes in human fibrinogen after in vitro phosphorylation and their relation to fibrinogen behaviour.

The far-ultraviolet circular dichroism spectra of fibrinogens phosphorylated by protein kinase C or casein kinase II indicated a conformational change corresponding to an increase in ordered secondary structure. The spectra of protein kinase A- or casein kinase I-phosphorylated fibrinogens did not differ substantially from the control. Fluorescence studies indicated changes in the tertiary structure around tryptophan residues for protein kinase A- or C-phosphorylated fibrinogens, but failed to show any such change for fibrinogen phosphorylated by either of the casein kinases. This latter result was also confirmed by circular dichroism measurements in the near-ultraviolet region. The apparent increase in ordered structure was proposed as an explanation for the slower rate of plasmin degradation seen in fibrinogens after phosphorylation by protein kinase C [6], and casein kinase II, especially as both spectral changes and plasmin degradation rate were unaffected by alkaline phosphatase.

Casein Kinases↗
PubMed2002

Fibrinogen in rat gastrointestinal lymph before, during and after intraduodenal administration of emulsified triglyceride: fibrinogen bound to chylomicrons in gastrointestinal lymph is functional.

Samples of gastrointestinal lymph were collected from fasted, male, Sprague-Dawley rats before, during and after intraduodenal administration of either a phospholipid-stabilized, triglyceride-rich emulsion or the dextrose-saline diluent of the emulsion. In lipid-treated rats, the triglyceride, total protein, and functional fibrinogen contents of lymph increased significantly during the 4 h of continuous lipid infusion, with all analytes returning to near baseline values by 20 h later. Levels of the same analytes changed little, if at all, in control animals. As assessed using immunoblotting, chylomicrons in gastrointestinal lymph are coated with fibrinogen. Fibrinogen-coated chylomicrons readily incorporate into solution phase clots and, in the presence of thrombin, adhere in heparin-preventable fashion to each other and to other fibrinogen-coated surfaces. Taken together, these data indicate that lipid feeding creates in gastrointestinal lymph a condition that is conducive temporally to the physical association of fibrinogen with newly ingested lipids before they reach the circulatory system.

Adhesiveness↗
PubMed1976

Reactivity of fibrinogen and fibrinopeptide A containing fibrinogen fragments with antisera to fibrinopeptide A.

Two antisera used in the radioimmunoassay for human fibrinopeptide A (FPA) which appear to have different immunochemical specificities have been tested for cross-reactivity with fibrinogen and with three fragments of fibrinogen which contain the FPA sequence. These fragments were the three-chain, NH2-terminal disulfide knot (N-DSK) produced by CNBr cleavage of fibrinogen, the reduced, carboxymethyl Aalpha chain portion of the N-DSK, and fragment E produced by plasmin digestion of fibrinogen. One antiserum (R-2) showed high specificity for free FPA and less than 2% cross-reactivity with fibrinogen or the FPA-containing fragments. The other antiserum (R-33) possessed a much higher degree of cross-reactivity with the FPA-containing fragments. Synthetic and native fibrinopeptides were found to be indistinguishable in the assay system with either antiserum. As a result of these studies, an hypothesis has been developed concerning the nature of the antigenic determinants on FPA which favor measurement of free FPA and limit cross-reactivity with larger, FPA-containing peptides.

Amino Acid Sequence↗
PubMed2002

Novel fibrinogen gamma375 Arg-->Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia.

The proposita and her sister had chronically elevated liver function test results, and needle biopsy specimens showed scattered eosinophilic inclusions within the hepatocytes. On immunoperoxidase staining, the inclusions reacted strongly with anti-fibrinogen antisera; on electron-microscopic (EM) examination, the material appeared confined to the endoplasmic reticulum (ER) and was densely packed into tubular structures with a swirling fingerprint appearance. Coagulation investigations showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous CGG-->TGG mutation at codon 375 of the fibrinogen gamma chain gene. This novel gamma375 Arg-->Trp substitution segregated with hypofibrinogenemia in 3 family members and was absent from 50 normal controls. When purified plasma fibrinogen chains were examined by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, reverse-phase chromatography, electrospray ionization mass spectrometry, and isoelectric focusing, only normal gamma chains were detected. In conclusion, we propose that this nonconservative mutation causes a conformational change in newly synthesized molecules and that this provokes aggregation within the ER and in turn causes the observed hypofibrinogenemia. Whereas the mutation site, gamma375, is located in the gammaD domain at the jaws of the primary E-to-D polymerization site, purified plasma fibrinogen showed normal polymerization, supporting our contention that molecules with variant chains never reach the circulation but accumulate in the ER.

Afibrinogenemia↗
PubMed2000

Glycoprotein IIb-IIIa-liposomes bind fibrinogen but do not undergo fibrinogen-mediated aggregation.

Although platelet cross-bridging is mediated primarily by the binding of fibrinogen to its activated membrane receptor, glycoprotein (GP) IIb-IIIa*, such an interaction may not be sufficient to support the aggregation process. As this question could potentially be answered by reconstituting GPIIb-IIIa* into a non-platelet environment such as liposomes, a protocol was developed for the generation of large lipid vesicles containing purified GPIIb-IIIa*. Flow cytometric techniques confirmed that the receptor was present in the lipid bilayer and were used to evaluate the characteristics of fibrinogen binding to the liposomes, which like fibrinogen-platelet interactions exhibited specificity, saturability, time dependence and calcium dependence. No fibrinogen-specific aggregation of GPIIb-IIIa* liposomes with stir or shear was observed, as determined by flow cytometric cell counting and microscopic examination of particles. In contrast, activated platelets rapidly bound Fg and rapidly formed large aggregates. The Fg associated with GPIIb-IIIa* in liposomes was 'normally' recognized by two fluorescently labelled antibodies: 4A5, which interacts with the Fg gamma chain C-terminus (residues 400-411) required for Fg-mediated cross-bridging of activated platelets in platelet aggregation (Shiba E, Lindon JN, Kushner L, Matsueda GR, Hawiger J, Kloczewiak M, Kudryk B, Salzman EW. Antibody-detectable changes in fibrinogen adsorption affecting platelet activation on polymer surfaces. Am J Physiol 1991; 260: C965-74), and anti-Fg-RIBS-I, which associates with an epitope on Fg (residues 373-385) expressed upon binding to GPIIb-IIIa. These data suggest that the Fg gamma-terminus is sterically accessible for particle cross-bridging and that an identical conformational change occurs for receptor-bound Fg on both liposomes and platelets. It thus appears that cellular elements aside from GPIIb-IIIa, such as cytoskeletal proteins proposed to be necessary for receptor 'anchoring', play a necessary role in flow-associated platelet aggregation.

Acetates↗
PubMed1995

Comparison of the kinetic fibrinogen assay with the von Clauss method and the clot recovery method in plasma of patients with conditions affecting fibrinogen coagulability.

A Kinetic Fibrinogen Assay (KFA), a method based on the kinetic reaction of the developing fibrin clot, was used to determine fibrinogen concentration in plasma. Two other methods employing different quantification principles were used for comparison: the von Clauss method and the procedure measuring protein concentration in an isolated and washed plasma clot (World Health Organization [WHO] method). All three methods quantified functional thrombin-coagulable fibrinogen. Plasma specimens were obtained from three groups of patients: those with liver disease and those taking either coumarin derivative or heparin. In all of these conditions, there are deviations from the normal process of fibrin clot formation. The KFA method yielded results that were consistent and provided excellent precision and accuracy allowing quantification of plasma fibrinogen in the range of 70-800 mg/dL (2-23.5 microM). The determination of fibrinogen by the KFA method was not adversely affected using plasma from patients treated with heparin and those undergoing coumarin therapy. Statistical analysis of the results indicated that the KFA method compared very favorably with the von Clauss and WHO methods. In assessing the clinical utility of each method, the WHO method was found to be labor intensive and time consuming; therefore, not suitable for routine use in a clinical laboratory. The von Clauss method required a trained laboratory technician and some laboratory manipulations. The KFA method was not only reliable and accurate, but also fully automated, making it the easiest and the fastest to perform routinely.

Anticoagulants↗
PubMed2002

Fibrinogen Saint-Germain I: a case of the heterozygous Aalpha GLY 12 --> VAL fibrinogen variant.

A fibrinogen variant was suspected based on the results of routine coagulation tests in a 2-year-old asymptomatic child. Coagulation studies showed marked prolongation of both the thrombin and reptilase times, and discrepancy was noted between the level of plasma fibrinogen as measured by a kinetic versus immunological determination. Family studies revealed that the father beared the same abnormality. Studies of purified fibrinogen revealed an impaired release of both fibrinopeptides by thrombin. Fibrin monomer polymerization and fibrin stabilization were normal. DNA sequencing revealed a heterozygous G --> T point mutation in exon 2 of the gene coding for the Aalpha chain, which substituted a Gly for Val at position 12. Although the mutation is the same as in fibrinogen Rouen, fibrinogen Saint-Germain I shows a different fibrinopeptide release pattern and a mild factor V deficiency.

Amino Acid Substitution↗
PubMed2005

The binding of fibrin sealant to collagen is influenced by the method of purification and the cross-linked fibrinogen-fibronectin (heteronectin) content of the 'fibrinogen' component.

Two fibrinogen preparations, each an intermediate in the manufacture of the 'fibrinogen' component of a commercial human tissue sealant, were made from a common cryoprecipitate source. The first preparation, prepared according to the process described by Schwartz et al. had a higher ratio of clottable to total protein than the second preparation, prepared according to that by Martinowitz and Bal but a much lower ratio of fibronectin to fibrinogen. After clotting with thrombin and solubilization and reduction of the clots, sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a much higher content of high molecular weight polymers of fibrin(ogen) in the second preparation than in the first. The second preparation bound to collagen more strongly than did cryoprecipitate and much more strongly than did the first one. Experiments with highly purified proteins showed that fibronectin was essential in promoting progressive binding of fibrinogen to collagen under the action of activated factor XIII (transglutaminase). It was concluded that, because of their method of purification from cryoprecipitate, preparations of fibrinogen differ in their content of fibronectin and heteronectin. The binding of these proteins to collagen may improve the adhesion of tissue sealant clots to the extracellular matrix.

Collagen↗
PubMed1978

Three new cases of an inborn qualitative fibrinogen defect (fibrinogen Oslo II).

An autosomally inherited, qualitative fibrinogen defect is presented. It is associated with prolonged thrombin clotting time, low plasma fibrinogen when assayed by a fibrin polymerization test and large amounts of fibrinogen antigen determinants in the supernatant after clotting. The plasma fibrinogen level was normal when assayed by an immunological technique or by quantitation of insoluble fibrin under conditions in which fibrin polymerization in enhanced. As judged from N-terminal amino acid analyses, fibrinopeptides were split off at normal speed, and the subunit chains of the fibrinogen appeared normal when examined on polyacrylamide gels. The abnormality was not associated with bleeding tendency, and other routine coagulation tests gave normal results. The findings are in accordance with the concept of defective fibrin polymerization.

Adult↗
PubMed1982

An abnormal inherited fibrinogen (fibrinogen Genova) with delayed fibrin aggregation.

A new autosomally inherited dysfibrinogenaemia was recognized in 3 members of an Italian family. No bleeding tendency or thrombotic disease in any of the affected members were demonstrated. Coagulation tests revealed prolonged prothrombin, thrombin and Reptilase times. Plasma fibrinogen levels were normal with immunologic method and slightly reduced with chronometric assay: the other blood coagulation factors were normal. In addition, cross-immunoelectrophoresis performed on patients' plasma was indistinguishable from the normal. Dysfibrinogenaemia was confirmed by studying the purified fibrinogen. The fibrin polymerization curve, measured spectrophotometrically, showed a lower slope than the normal. A delay in fibrin monomer aggregation was revealed when compared to the normal at an equal concentration. The release of fibrinopeptides was normal. SDS polyacrylamide gel electrophoresis, isoelectric focusing and cross-immunoelectrophoresis of purified fibrinogen were not able to demonstrate any structural abnormality. The fibrinogen was named fibrinogen Genova.

Blood Coagulation Disorders↗
PubMed2001

Fibrinogen: evolution of the structure-function concept. Keynote address at fibrinogen 2000 congress.

Coagulation of blood is such an evident phenomenon that its observation can be traced back to earliest historical times. The great philosophers and physicians of antiquity discussed and provided interesting explanations. However, it was not until the end of the seventeenth century that the structural component of the blood clot was described by Malpighi as a white fibrous substance. In the middle of the nineteenth century this was identified as a constituent of pathological thrombi and given the name fibrin. At about that time its precursor in blood, fibrinogen, was isolated in a highly purified form by Hammarsten who suggested that, preceding fibrin formation, activation of fibrinogen by thrombin occurred by limited proteolysis. The activation mechanism was eventually clarified in the 1950s. It was shown to proceed in two discrete steps, by removal of low molecular weight activation peptides. Ferry postulated, based on physicochemical observations, that the activated molecules aligned in a half-staggered fashion to form polymers. The rapid post-war development of biochemical technology permitted evaluation of the primary structure of fibrinogen. With that followed identification of molecular domains in the activated firbinogen molecules that participate in polymer formation, crosslinking of polymeric structures, and domains for cellular attachment. Crystallization of fragments and, recently, of the entire molecule has confirmed and extended this knowledge. Lately, it has also been possible to obtain detailed information on the architecture of the fiber network in the fibrin gel. The gel structure is primarily determined by the initial rate of fibrinogen activation, but without infringement of this primary rule, several factors in blood may modulate the structure. Fibrinogen and fibrin play important roles in normal hemostasis, wound healing, and pathological processes, such as thrombosis and atherosclerosis.

Fibrinogen↗