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At least 595 records · Page 33Linked to original sources
PubMed1992

Fibrin clot lysis by thrombolytic agents is impaired in newborns due to a low plasminogen concentration.

Although thrombolytic drugs have been extensively used in adults, there is sparse information on their effectiveness in newborns whose fibrinolytic system differs significantly from adults. The purpose of this study was to determine if low plasma levels of plasminogen in cord plasma limited the therapeutic effectiveness of thrombolytic agents. Urokinase (UK), streptokinase (SK) and tissue plasminogen activator (TPA) were compared for their ability to lyse washed 125I-labelled adult or cord fibrin clots suspended in cord or adult plasma. 125I-labelled fibrin clots were prepared by recalcifying cord or adult plasma spiked with labelled fibrinogen and then placed into cord or adult plasma which contained either saline or differing amounts of a specific thrombolytic agent. After a 60 min incubation, the remaining 125I-fibrin in clots released 125I-fibrin fragments, and concentrations of fibrinogen, alpha 2-antiplasmin, and plasminogen in the bathing plasma were measured and compared to starting values. Cord fibrin clots were more resistant than adult fibrin clots to all thrombolytic drugs tested (p less than 0.001). On average, the cord system retained 27% more 125I-fibrin in clots, and released 32% less 125I-fibrin fragments into plasma. Fibrinogenolysis was also decreased in cord plasmas compared to adult plasmas. The degree of fibrinolysis and fibrinogenolysis in cord plasma increased to adult values when plasminogen concentrations were increased in the bathing plasma. Thus, cord fibrin clots have an impaired response to thrombolytic agents secondary to low levels of plasminogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Therapeutic angiogenesis for patients with limb ischemia by utilization of fibrin meshwork. Pilot randomized controlled study.

AIM: The aim of this paper is to assess the feasibility and efficacy of fibrin in inducing neovascularization as an angiogenic substance and/or carrier for vascular endothelial growth factor (VEGF) in patients with limb ischemia. METHODS: Twenty-three patients with limb ischemia and referred for below the knee amputations were randomized for treatment: group 1, 7 patients received only a saline injection; group 2, 9 received intramuscular injection of fibrin and group 3, 7 received the fibrin composition with deferoxamine and added VEGF(165). The fibrin meshwork was introduced into the popliteal area of the diseased limbs using a dual syringe system (1 contained thrombin solution [1 mg, 5000 U] and 1 contained fibrinogen [1 mg, Baxter Hyland Immuno] solution). In group 3, Deferoxamine (100 microg) and 500 microg of VEGF(165) were added to the fibrinogen solution. RESULTS: In the control group 5 patients had undergone below the knee amputation at the 3-6 month follow-up. Only 1 patient from Group 2 had below the knee amputation 5 months following Fibrin only administration. Clinical improvement was noted in all 8 patients following fibrin administration and in all 7 patients injected with the fibrin meshwork, deferoxamine and VEGF combination. CONCLUSION: IM injection of fibrin is safe and appears to be an efficient method to treat limb ischemia. These findings indicate that use of fibrin may be a novel and simple method for inducing therapeutic angiogenesis.

Adult↗
PubMed1991

Fibronectin dependent macrophage fibrin binding.

Plasma fibronectin has been shown to increase the binding of fibrin monomer to macrophages in vitro. In the present study we began characterization of the mechanism underlying this fibronectin activity. Fragments of fibronectin containing the amino terminus enhanced macrophage fibrin binding to the same extent as intact fibronectin on an equimolar basis. However, fibronectin fragments containing the gelatin-binding domain or the cell-binding domain, but lacking the amino terminus, had no effect on fibrin binding. Fibronectin enhanced fibrin binding was not affected by the addition of synthetic peptides containing the RGD adhesion sequence. The ability of fibronectin to augment fibrin binding remained after paraformaldehyde fixation of macrophage monolayers. Fixation did not alter the basal levels of fibrin binding by macrophages. Preincubation of macrophages with exogenous fibronectin did not increase the binding of fibrin. Fibronectin enhanced fibrin binding remained unaltered after the removal of endogenous cell surface fibronectin by capping with F(ab')2 fragments of antibodies to fibronectin. These results suggest that the amino terminus of fibronectin supports the attachment of fibrin to macrophages by an initial fluid-phase interaction that precedes cellular binding and does not require a cellular response.

Amino Acid Sequence↗
PubMed1991

Fibrin- and fibrinogen-related antigens in patients with venous disease and venous ulceration.

Abnormalities in systemic fibrinolysis have been implicated in the pathogenesis of venous ulceration. Patients with venous disease have a prolonged euglobulin lysis time and elevated plasma fibrinogen levels, yet little is known about the metabolism of fibrinogen and fibrin in such patients. In this study, we have used a technique that involves electrophoresis and densitometric analysis of captured fibrin-related antigens to measure the concentration and proportions of the individual fibrin and fibrinogen degradation products in patients with venous disease of the lower extremity. As a group, patients with venous disease had markedly elevated levels of total fibrin-related antigen and D-dimer, the terminal degradation product of cross-linked fibrin. Levels of D-monomer, the breakdown product of fibrinogen and non-cross-linked fibrin monomer, and a measure of fibrinogenolysis were normal in all patients. In patients with ulcers, the levels of D-dimer were disproportionately higher than expected from fibrin monomer levels. On an individual basis, significant elevations of D-dimer were present in six (55%) of the 11 patients with venous disease with ulcers and in three (43%) of the seven patients with venous disease without ulcers. We conclude that patients with venous disease have uniform evidence for enhanced fibrin formation, as evidenced by elevated levels of total fibrin-related antigen and D-dimer. This is regardless of whether the venous disease is accompanied by ulceration.

Antigens↗
PubMed1991

On the mechanism of fibrin-specific plasminogen activation by staphylokinase.

The mechanism of plasminogen activation by recombinant staphylokinase was studied both in the absence and in the presence of fibrin, in purified systems, and in human plasma. Staphylokinase, like streptokinase, forms a stoichiometric complex with plasminogen that activates plasminogen following Michaelis-Menten kinetics with Km = 7.0 microM and k2 = 1.5 s-1. In purified systems, alpha 2-antiplasmin inhibits the plasminogen-staphylokinase complex with k1(app) = 2.7 +/- 0.30 x 10(6) M-1 s-1 (mean +/- S.D., n = 12), but not the plasminogen-streptokinase complex. Addition of 6-aminohexanoic acid induces a concentration-dependent reduction of k1(app) to 2.0 +/- 0.17 x 10(4) M-1 s-1 (mean +/- S.D., n = 5) at concentrations greater than or equal to 30 mM, with a 50% reduction at a 6-aminohexanoic acid concentration of 60 microM. Staphylokinase does not bind to fibrin, and fibrin stimulates the initial rate of plasminogen activation by staphylokinase only 4-fold. Staphylokinase induces a dose-dependent lysis of a 0.12-ml 125I-fibrin-labeled human plasma clot submersed in 0.5 ml of citrated human plasma; 50% lysis in 2 h is obtained with 17 nM staphylokinase and is associated with only 5% plasma fibrinogen degradation. Corresponding values for streptokinase are 68 nM and more than 90% fibrinogen degradation. In the absence of a fibrin clot, 50% fibrinogen degradation in human plasma in 2 h requires 790 nM staphylokinase, but only 4.4 nM streptokinase. These results suggest the following mechanism for relatively fibrin-specific clot lysis with staphylokinase in a plasma milieu. In plasma in the absence of fibrin, the plasminogen-staphylokinase complex is rapidly neutralized by alpha 2-antiplasmin, thus preventing systemic plasminogen activation. In the presence of fibrin, the lysine-binding sites of the plasminogen-staphylokinase complex are occupied and inhibition by alpha 2-antiplasmin is retarded, thus allowing preferential plasminogen activation at the fibrin surface.

Antifibrinolytic Agents↗
PubMed1990

von Willebrand factor competes with fibrin for occupancy of GPIIb:IIIa on thrombin-stimulated platelets.

We have investigated two major questions related to the molecular basis of interactions between the three-dimensional fibrin network and thrombin-stimulated human platelets. First, what are the roles played by glycoproteins (GP) Ib and IIb:IIIa in linking the fibrin clot tightly to the platelet surface? Second, does von Willebrand factor (vWF) modulate the extent of platelet-fibrin interactions? Quantitative fluorescence microscopy (microfluorimetry) has been used to determine the quantity of fluorescein-labeled fibrin bound to the surface of thrombin-stimulated, gel-filtered platelets (the supernatants of which contained small quantities of vWF) in the presence/absence of receptor-specific and vWF-specific monoclonal antibodies (MoAbs), as well as exogenous vWF. A MoAb specific for the GPIIb:IIIa complex exhibited a concentration-dependent inhibition of fibrin binding, whereas a MoAb specific for GPIb was ineffective in this regard. Similarly, a MoAb that recognizes the N-terminal region of vWF involved in GPIb binding did not influence fibrin binding. In contrast, a MoAb that binds to a C-terminal region of vWF involved in GPIIb:IIIa recognition caused a specific, concentration-dependent increase in the quantity of platelet-bound fibrin. We also found that exogenous vWF caused a concentration-dependent decrease in fibrin binding. These results support the hypothesis that vWF and fibrin, both of which are multimeric adhesive ligands, compete for occupancy of the GPIIb:IIIa complex on thrombin-stimulated platelets.

Antibodies, Monoclonal↗
PubMed1988

Detection of soluble fibrin monomer complexes. Comparison of a haemagglutination assay with the ethanol gelation test.

Hypercoagulability and disseminated intravascular coagulation (DIC) are characterized by the presence of circulating fibrin monomer complexes in plasma. In 342 patients with possible DIC fibrin monomers, fibrinogen, Reptilase Time, antithrombin III and other coagulation parameters were determined at frequent intervals. Testing of soluble fibrin monomer complexes was performed using a sensitive and reliable hemagglutation assay with red cells sensitized by fibrin monomers (FM-Test) and the ethanol gelation test (EGT). Method comparison regarding the influence of fibrinogen levels and fibrin degradation products shows that high fibrinogen levels lead to false-positive results with EGT. The same effect is observed for fibrin degradation products and EGT whereas no influence of fibrinogen level and fibrin degradation products on the FM-Test occurs. It is well-known that during DIC AT III level decreases caused by proteolytic activity. In this study it could be shown that fibrin monomer increases parallel to the decrease of AT III. The same effect does not occur due to fibrin degradation products.

Blood Coagulation Tests↗
PubMed1987

Influence of factor XIII and fibronectin on fiber size and density in thrombin-induced fibrin gels.

The possible role of fibronectin as a molecular anchor for fibrin to ground substance, the ability of factor XIII to cross-link fibronectin to fibrin, and the demonstrated differences between purified fibrin and fibrin formed in plasma prompted this study of the effect of both proteins on fibrin assembly and structure. The influences of activated factor XIII (FXIIIa) and fibronectin were studied by use of turbidity techniques. Fibronectin over a concentration range of 0 to 800 micrograms/ml produced no change in either the mass-length ratio or density of fibrin fibers in 1 mg/ml fibrin gels. FXIIIa at concentrations as high as 6.5 mumol/L, although not altering fiber mass-length ratio, caused a 30% increase in fiber density. Gels formed in the presence of fibronectin plus FXIIIa demonstrated increasing fiber mass-length ratios and increasing fiber density with increasing fibronectin concentration. Mass-length ratios for gels formed in the presence of 3.24 mumol/L FXIIIa increased from 3.25 to 5.20 x 10(13) daltons/cm as the fibronectin concentration increased from 0 to 800 micrograms/ml. Fiber density increased from 13.6 to 19.1 x 10(22) daltons/cm3 over the same fibronectin range. These results imply that FXIIIa-induced structural changes such as increased elastic modulus may be mediated in part by increased fiber density. Fibronectin alone has virtually no impact on fibrin assembly, but in the presence of FXIIIa becomes incorporated into fibrin and results in increased fiber size and density.

Chemical Phenomena↗
PubMed1988

Fibrinolysis resistant fibrin deposits in lymph nodes with Hodgkin's disease.

Extravasal fibrin deposition is frequently observed within and around tumorous tissues and has been implicated in various aspects of tumor growth. However, no adequate information has been available on the mechanism how intratumoral interstitial fibrin deposits escape a prompt elimination by the fibrinolytic system. In this study we provide immunomorphological evidence showing that fibrin deposits in lymph nodes with Hodgkin's disease are stabilized and made resistant to fibrinolysis by factor XIII (FXIII) of blood coagulation. By double immunofluorescent labelling systems fibrin deposits were simultaneously stained for alpha 2-antiplasmin (alpha 2-AP), the main physiological inhibitor of fibrinolysis and in a number of nodular areas they were also labelled for plasmin(ogen). The detection of alpha 2-antiplasmin-plasmin complex-neoantigen (alpha 2-AP-P-Neo) revealed that alpha 2-AP reacted with plasmin, i.e., alpha 2-AP covalently linked to fibrin indeed inhibited intratumoral fibrinolysis. In addition to fibrin deposits FXIII was also found in cellular elements characterized earlier as tumor associated macrophages. These cells were attached to fibrin strands suggesting that they are involved in the intratumoral fibrin formation and might be a source of fibrin stabilizing factor in the tumor stroma.

Fibrin↗
PubMed1988

Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration.

We investigated the migration of oil-induced, guinea pig peritoneal macrophages in three-dimensional fibrin matrices, with particular attention to variables which modified fibrin gel structure and/or its adhesive properties for cells. The variables studied were fibrin concentration, gel cross-linking, and fibronectin and glycosaminoglycan content. Macrophage migration was an inverse linear function of fibrinogen concentration. Little or no fibrinolysis accompanied macrophage migration; rather, macrophages migrated through fibrin gels by an active process associated with marked distortions of cell shape and specialized plasma membrane contacts with fibrin strands. Fibrin matrices prepared from fibrinogen that had been depleted of clotting factor XIII and/or fibronectin provided a superior matrix for macrophage migration. Both the number of migrating cells and distance of migration were reduced when the gel matrix included fibronectin and was cross-linked by factor XIII. A hexapeptide containing the fibronectin cell-binding RGDS sequence reversed this migration inhibition, suggesting that fibronectin immobilized by cross-linking to fibrin may have bound macrophages and restricted cell migration. Hyaluronic acid, heparin, and heparan sulfate inhibited macrophage migration in cross-linked fibrin-fibronectin gels over a range of concentrations. These data are relevant to an understanding of macrophage migration in vivo where cross-linked fibrin-fibronectin gels containing variable amounts of glycosaminoglycans are deposited in tissues in immunologic reactions and in many other types of pathology.

Animals↗
PubMed1985

[The use of fibrin glue in neurosurgical operations].

Fibrin glue has been used in 22 neurosurgical patients and following five effects which are very much helpful in neurosurgical practice were recognized. Adhesive effect--Dural defect at cranial base was closed with lyophilized dura and fibrin glue. Hemostatic effect--Fibrin glue soaked oxycel was applied for hemostasis of the bleeding from venous sinus, dura, skull edge and cut surface of tumor. Blocking and sealing effects--In cases of craniopharyngioma, cyst wall around the inserted tube was sealed with oxycel and fibrin glue. CSF leakage from open sphenoidal sinus in aneurysmal operation was closed with fibrin glue soaked gelfoam. Covering and wall strengthening effects--Unclippable aneurysms were coated and wrapped with fibrin glue and oxycel. Packing effect--Huge dead space after removal of mucocele was packed with fibrin glue. In trans-sphenoidal operation of pituitary adenoma, fibrin glue soaked muscle pieces and oxycel were packed in the dead space and sphenoidal sinus. Many other possible availabilities in neurosurgical operations were discussed. Fibrin glue is a biological product, so it can be used with more safety and affinity to the local tissue and with less reaction as foreign body than the artificial adhesives. It takes much time for the preparation of this material for the time being. If this can be prepared instantly, usefulness of this glue will be markedly increased. We have had no hepatitis nor inflammatory complications in our limited experience.

Adolescent↗
PubMed1984

Association of fibrin with the platelet cytoskeleton.

We have previously postulated that surface membrane proteins become specifically associated with the internal platelet cytoskeleton upon platelet activation (Tuszynski, G.P., Walsh, P.N., Piperno, J., and Koshy, A. (1982) J. Biol. Chem. 257, 4557-4563). Four lines of evidence are in support of this general hypothesis since we now show that platelet surface receptors for fibrin become specifically associated with the platelet Triton-insoluble cytoskeleton. 1) Fibrin was detected immunologically in the washed Triton-insoluble cytoskeletons of thrombin-activated platelets under conditions where fibrin polymerization and resultant precipitation was blocked with Gly-Pro-Arg-Pro, a synthetic peptide that inhibits polymerization of fibrin monomer. 2) Radiolabeled fibrin bound to thrombin-activated platelets and became associated with the cytoskeleton. 3) The amount of radiolabeled fibrin bound to thrombin-activated thrombasthenic platelets and their cytoskeletons amounted to about 20% of the fibrin bound to thrombin-activated control platelets and their cytoskeletons. 4) The association of fibrin with cytoskeletons and with the platelet surface was nearly quantitatively blocked by an antibody prepared against cytoskeletons (anti-C), an antibody against isolated membranes of Pronase-treated platelets (anti-M1), and a monoclonal antibody to the platelet surface glycoprotein complex, GPIIb-GPIII (anti-GPIII). These antibodies blocked ADP and thrombin-induced platelet aggregation as well as thrombin-induced clot retraction. Analysis of the immunoprecipitates obtained with anti-C, anti-M1, and anti-GPIII from detergent extracts of 125I-surface labeled platelets revealed that these antibodies recognized GPIIb-GPIII. These data suggest that thrombin activation of platelets results in the specific association of fibrin with the platelet cytoskeleton, that this association may be mediated by the GPIIb-GPIII complex, and that these mechanisms may play an important role in platelet aggregation and clot retraction induced by thrombin.

Blood Platelets↗
PubMed1980

Electron microscopy of fibrin Paris I.

Fibrinogen Paris I, a congenital fibrinogen abnormality, is characterized by delayed fibrin aggregation and poor clot retraction owing to the replacement of normal gamma-chains by mutant gamma-chains, which are termed gamma-Paris I. Available evidence indicates that the structural abnormality involves the amino acid sequence near the COOH-terminus of the mutant chain and probably includes the region containing the normal gamma-chain crosslinking site. Electron microscopy was carried out on Paris I fibrin. In place of the normally interwoven network of branching cross-striated fibers, negatively or positively contrasted Paris I fibrin was characterized by nonfibrous clumps of material connected by distince fibrous strands tending to be thinner and more irregular in width than normal fibrin. Most Paris I fibrin fibers tended to the aperiodic, although cross-striations were observed occasionally in negatively contrasted specimens and rarely in positively contrasted specimens. In addition, Paris I fibrin frequently showed relatively short, abruptly terminating fibers. The gross ultrastructural differences between normal and Paris I fibrin suggest that for fibrin assembly to take place normally, a region(s) in the fibrin molecule near to or possibly overlapping the COOH-terminal gamma-chain crosslinking site must be preserved or at least not sterically hindered.

Amino Acid Sequence↗
PubMedDate not supplied

Experimental study on bacterial colonization of fibrin glue and its prevention.

To assess the possibility of bacterial colonization of fibrin glue and the effects of adding local sustained-release antibiotics, we conducted in vivo and in vitro preliminary studies. The in vitro experiments revealed that, although there was no colonization of the fibrin glue plates by the eight strains of bacteria tested, the fibrin mesh can serve as a culture medium when blood mingles with it, as is the case in clinical use. Adding dibekacin sulfate (DKB; 3570 micrograms/mL) to fibrin glue decreased the likelihood of colonization of the fibrin mesh. The pharmacokinetics of the added DKB were investigated by adding DKB-supplemented fibrin glue directly to muscle and vascular tissue in male rats. The DKB rapidly eluded from the fibrin glue (less than 0.2% remained after 24 hours). Because the amount remaining after 7 days (2.03 micrograms/mL) was greater than the minimum inhibitory concentration for most clinical pathogens, a 7-day preventive effect against colonization of the fibrin glue and the surrounding tissue can be anticipated at the concentration used in the present experiments. Experiments using the dermis layer of porcine skin strips showed that the added DKB did not affect the adhesive strength of the fibrin glue.

Animals↗
PubMed1994

Cloning of the complete coding sequence of rat fibrinogen B beta chain cDNA: interspecies conservation of fibrin beta 15-42 primary structure.

After thrombin cleavage, the newly exposed NH2-termini of the beta chains play a role in both fibrin polymerization and fibrin interactions with cells in the process of wound healing. These physiological responses have been shown to be mediated, at least in part, by beta 15-42. To compare the sequence of the beta chain of fibrin across species, the complete coding sequence of the rat fibrinogen B beta chain cDNA was cloned (designated pRB beta 3) and characterized. The sequence newly determined from pRB beta 3 encompassed nucleotides 121-589, encoding residues 9-165 of the mature polypeptide. Significant homology of pRB beta 3 cDNA and deduced amino acid sequences was found when compared with other species' B beta chains. The rat B beta-Arg14-Gly15 thrombin cleavage site is conserved; however, the fibrinopeptide B sequences are only 50% similar when rat is compared with human. In contrast, the beta 15-42 region is 100% similar when allowing for conservative amino acid substitutions. Monoclonal antibodies (MAbs) specific for human fibrinogen B beta 1-21 (1-8C6) and human fibrin beta 15-21 (59D8 and T2G1) failed to cross-react with rat fibrinogen or fibrin by ELISA, respectively, even though thrombin conversion of rat fibrinogen to fibrin was confirmed. MAb 1-8C6 reacted with reduced and denatured human fibrinogen B beta chain by Western blotting, whereas, MAb T2G1 did not blot with reduced and denatured human fibrin beta chain. A comparative analysis of the binding affinity of the human B beta fibrin(ogen) specific MAbs with B beta fibrin(ogen) from several species suggested that amino acid residues preceding and including Arg14-Gly15 are important in the epitope of the B beta 1-21 specific MAb 1-8C6, and that residues Gly15, Leu19 and/or Lys21 play an important role in the epitope shared by the beta 15-21-specific MAbs T2G1 and 59D8.

Amino Acid Sequence↗
PubMed1994

Progressive cross-linking of fibrin gamma chains increases resistance to fibrinolysis.

In the presence of plasma transglutaminase (factor XIIIa) fibrin first undergoes intermolecular covalent cross-linking between its gamma chains to create gamma dimers followed by slower cross-linking among its alpha chains to form alpha polymers. Progressive cross-linking of gamma chain dimers occurs at the slowest rate, resulting in gamma trimers and gamma tetramers ("gamma multimers"). Most studies indicate that cross-linked fibrin clots become resistant to fibrinolysis, but the basis for this event is not clear. In this study, we explored the role of gamma chain multimerization compared with alpha polymerization as causal factors in time-dependent development of resistance to fibrinolysis. Fibrin clots prepared from native (intact) fibrinogen were incubated for up to 120 h at near physiological ionic strength and a factor XIIIa level approximating that in plasma. These clots were lysed by plasmin at rates that were inversely proportional to the level of gamma multimers, which increased progressively with the time of incubation. In contrast, fibrin cross-linked at high ionic strength (a condition under which only gamma dimers and alpha polymers form) or fibrin formed in the absence of factor XIII showed no time-dependent decrease in lysis rates. Fibrin cross-linked for a fixed time period with increasing amounts of factor XIIIa contained gamma multimer levels that were proportional to the factor XIIIa concentration and lysed at rates that were inversely proportional to the gamma multimer level. Furthermore, cross-linked fibrin formed from fibrinogen fraction I-9, which has limited potential for alpha polymerization, showed the same reduction in the lysis rate as native cross-linked fibrin. These findings indicate that development of resistance to fibrinolysis of cross-linked fibrin is not measurably dependent upon gamma dimer or alpha polymer formation but develops solely as a function of gamma multimerization.

Chromatography, Affinity↗
PubMed1995

Characterization of endothelial cell differential attachment to fibrin and fibrinogen and its inhibition by Arg-Gly-Asp-containing peptides.

We investigated the adhesion of human umbilical vein endothelial cells (HUVECs) to fibrin(ogen) molecule of varying structure for identifying sites that mediate cell attachment. Fibrin was prepared either with ancrod which liberates only FPA from fibrinogen, or with thrombin, which liberates both FPA and FPB. Both fibrin preparations equally supported HUVEC attachment. GRGDS, RGD-containing peptides of snake venoms, and monoclonal antibodies against alpha v beta 3 (23C6 and 7E3) inhibited the attachment of HUVECs to fibrin by 65-75%. In contrast, the attachment of HUVECs to fibrinogen was less effective and was almost completely inhibited by both RGD-containing peptides and by antibodies against integrin alpha v beta 3 (85-95% inhibition). The C-terminal dodecapeptide of fibrinogen gamma chain (residues 400-411) inhibited minimally the attachment of HUVECs to fibrin. Additionally, the binding of RGD-containing snake venom peptides to HUVECs was both RGD- and divalent-cation-dependent. The IC50S for inhibition of HUVEC attachment to fibrin were 0.09 microM (rhodostomin), 1.54 microM (trigramin) and 1.64 microM (halysin). These results indicate that fibrin mediated support of cell attachment is independent of the cleavage of FPB from fibrinogen. HUVEC attachment to fibrinogen was almost completely inhibited by RGD-containing peptides and by antibodies against alpha v beta 3. In contrast, the attachment to fibrin was partially resistant to RGD-containing peptides and to the monoclonal antibodies against integrin alpha v beta 3. However, alpha v beta 3 is the major receptor mediating HUVEC attachment to fibrin.

Amino Acid Sequence↗
PubMed1996

A gamma Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I.

A new type of gamma Gly-268 (GGA) to Glu (GAA) substitution has been identified in a homozygous dysfibrinogen by analyses of the affected polypeptide and its encoding gene derived from a 58 year-old man manifesting no major bleeding or thrombosis. The functional abnormality was characterized by impaired fibrin assembly most likely due to failure to construct properly aligned double-stranded fibrin protofibrils. This presumption was deduced from the following findings: (1) Factor XIIIa-catalyzed cross-linking of the fibrin gamma-chains progressed in a normal fashion, indicating that the contact between the central E domain of one fibrin monomer and the D domain of another took place normally; (2) Nevertheless, factor XIIIa-catalyzed cross-linking of the fibrinogen gamma-chains was obviously delayed, suggesting that longitudinal association of D domains of different fibrin monomers, ie, D:D association was perturbed; (3) Plasminogen activation catalyzed by tissue-type plasminogen activator was not as efficiently facilitated by polymerizing fibrin monomer derived from the patient as by the normal counterpart. Therefore, gamma Gly-268 would not be involved in the 'a' site residing in the D domain, which functions as a complementary binding site with the thrombin-activated 'A' site in the central E domain, but would be rather involved in the D:D self association sites recently proposed for human fibrinogen. Thus, the gamma Glu-268 substitution newly identified in this homozygous dysfibrinogen seems to impair proper alignment of adjacent D domains of neighboring fibrin molecules in the double-stranded fibrin protofibril, resulting in delayed fibrin gel formation.

Afibrinogenemia↗