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PubMed1996

Integrin alpha v beta 3 and phospholipase C regulate prostacyclin formation of endothelial cells caused by ancrod-generated fibrin.

Ancrod-generated fibrin has been shown to stimulate prostacyclin synthesis of human umbilical vein endothelial cells (Chang et al., 1994, Biochem. Biophys. Res. Commun. 203, 1920). We further investigated its mechanism of action. The increment of 6-keto prostaglandin F1 alpha stimulated by ancrod-generated fibrin was almost completely inhibited when endothelial cells were either pretreated with 50 microM 8-(N,N'-diethylamino)octyl-3,4,5- trimethoxybenzoate (TMB-8) or preloaded with 15 microM 1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). 6-Keto prostaglandin F1 alpha production during 2 and 10 h incubation period was also inhibited by 1.2 mM ethyleneglycol-bis-(beta-aminoethylether)-N,N,N',N'-tetraace tic acid (EGTA) (41 +/- 12 and 53 +/- 17% inhibition, respectively). Further, ancrod-generated fibrin caused a rapid-onset increase in [3h]inositol monophosphate (IP1) formation in endothelial cells. This increase in IP1 was significantly inhibited by 1 mM Gly-Pro-Arg-Pro, 1 mM neomycin or 100 ng/ml pertussis toxin. At the same time, neomycin and pertussis toxin also significantly inhibited 6-keto prostaglandin F1 alpha synthesis of endothelial cells stimulated by ancrod-generated fibrin. Additionally, the increment of IP1 production as well as prostacyclin production were significantly inhibited by monoclonal antibodies directed against alpha v beta 3. These results suggest that intra- and extra-cellular Ca2+ participate in prostacyclin synthesis stimulated by ancrod-generated fibrin. Ancrod-generated fibrin stimulates pertussis toxin-sensitive G-protein regulated phosphoinositide breakdown, which is responsible for prostacyclin synthesis. This augmentation in prostacyclin synthesis and phosphoinositide breakdown caused by ancrod-generated fibrin area, at least in part, mediated by fibrin binding to integrin alpha v beta 3 on endothelial cells.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Comparison of fibrin networks in plasma and fibrinogen solution.

Mass-Length ratio of fibrin fibres (microT and microP) derived independently from turbidity and permeability respectively, in networks made in fibrinogen solution and plasma, have been compared under similar conditions of clotting. Amount of fibrinogen conversion to fibrin was similar in both systems when high thrombin concentrations were used. But networks in plasma had significantly thicker fibres (higher microT and microP) than those in fibrinogen solution. This difference arises from differing kinetics of fibrin assembly in the two systems. When lower thrombin concentration is used, fibrin fibre thickness (as indicated by microP and microT) is increased in fibrinogen solution but the fibrin content of the network remains unaltered. In plasma, on the other hand, the fibrin content of the network is decreased, microT remains relatively unchanged while microP increases. The thrombin concentration dependence of the fibrin content of the network in plasma and the bimodal distribution of fibrin fibre thickness explain the breakdown in correlation between microP and microT.

Blood Coagulation↗
PubMed1988

Fibrin activatable urokinase (FA-UK): a latent form of UK found in urine related to a complex with an inhibitor/fibrin-interacting cofactor.

In order to investigate the binding of pro-urokinase (pro-UK) in urine to fibrin/Celite, the property which led to its discovery, the effect of fibrin on the plasminogen activator activity of urine was studied. The plasminogen activator activity in urine was found to be consistently about 2-fold higher when measured by fibrin plate assay than by amidolytic substrate (S-2444), when normalized against the UK reference standard. When the amidolytic activity measurement was preceded by incubation of urine with soluble fibrin, a 2-fold increase in amidolytic activity was also found. Fibrin similarly increased plasmin generation in urine enriched with Glu- or Lys-plasminogen as determined by synthetic substrate S-2251. The observed promoting effect was common to several forms of soluble fibrin and was dose dependent, whereas fibrinogen had little effect. The promoting effect of fibrin was not expressed in the presence of pro-UK or two-chain UK (TC-UK) in buffer and therefore was attributed to another constituent of urine. Since the activity was inhibited by antibodies to UK but not to t-PA, it was called fibrin activatable UK (FA-UK). Gel filtration (Sephacryl-200) of urine revealed FA-UK activity in fractions eluting at a molecular weight of approximately 100K. A 100 K band of activity was also consistently seen when concentrated urine was subjected to zymography. Treatment of concentrated urine with hydroxylamine (1 M) eradicated both these activities and was associated with an increase in baseline amidolytic activity in the urine sample indicative of the release of UK from an inhibitor complex. Moreover, passage of urine over insolubilized monoclonal antibody against UK-inhibitor (PAI-3) complexes resulted in loss of FA-UK activity and of the 100 K band on the zymogram suggesting that the complex responsible for FA-UK was related to a PAI-3 complex. Since the FA-UK activity appeared to bind to fibrin/Celite, attempts were made to investigate complexation with pro-UK. Unfortunately, due to the instability of pro-UK in urine, no reliable data were obtained. It was concluded that PAI-3 may serve as a fibrin-interacting co-factor of UK, and therefore may play a role in fibrinolysis.

Antibodies, Monoclonal↗
PubMed1996

Migration of cultured vascular smooth muscle cells into non-crosslinked fibrin gels.

We evaluated the migration of vascular smooth muscle cells into fibrin gels, using an in vitro assay system. Vascular smooth muscle cells from bovine fetal aorta migrated into fibrin gels and showed a characteristic elongated spindle-shaped appearance with long cytoplasmic processes. Varying the concentration of thrombin (0.05-1 NIHU/ml) used to form the fibrin gel had little effect on cell migration although higher concentrations of thrombin inhibited the migration. Migration of the cells into fibrin gels was dependent on RNA and protein synthesis but not on DNA synthesis. The addition of antithrombin III, hirudin, and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone after gel formation had no effect, suggesting that residual thrombin in fibrin gels had no influence on subsequent cell migration. Neither the factor XIII-induced crosslinking of fibrin nor the fibrinopeptides released during gel formation were involved in the present migration assay system. Tranexamic acid, an inhibitor of plasminogen activator, or aprotinin, a plasmin inhibitor, also had no significant effect, suggesting that fibrinolysis induced by plasmin was not involved in this system. These findings showed that fibrin gels themselves induce the migration of vascular smooth muscle cells (haptotaxis) without other chemotactic or chemokinetic substances, suggesting an important role for fibrin in the development and progression of such vascular diseases as atherosclerosis, thrombosis and the development of restenosis following balloon angioplasty.

Animals↗
PubMed1988

Biochemical study of adduct synthesis between fibrin monomers and elastin.

Monomers of fibrin generated by thrombin from fibrinogen reacted with elastin to give a new addition product or adduct. Adduct formation resulted from a covalent bond between fibrin monomers and elastin. The kinetic studies of this reaction confirmed that the adduct was formed before fibrin precipitated to produce the clot. The reaction depended on elastin, fibrinogen and thrombin concentrations. When thrombin-induced and reptilase-induced fibrin were compared, it became obvious that fibrin monomers did intervene more commonly as Des AA-fibrin than as Des AA.BB-fibrin. The adduct synthesis was completely inhibited by 150 microM of the peptide Gly-Pro-Arg-Pro which was previously known to stabilize the fibrin monomers and consequently to inhibit the polymerization completely. It is shown that FXIII could intervene directly in the reaction where homological quality of elastin (human versus bovine) and purity of thrombin were other important factors.

Animals↗
PubMed1983

Induction of fibrin-specific antibodies by immunization with synthetic peptides that correspond to amino termini of thrombin cleavage sites.

Fibrin-specific antibodies have been produced in rabbits which were immunized with synthetic peptides. Specificity against human fibrin monomer was achieved because the synthetic peptide haptens were derived from sites unique to fibrin as compared with fibrinogen. Two undecapeptides were chemically synthesized according to the amino acid sequence of the amino termini of human fibrin alpha- and beta-chains which are revealed by thrombin cleavage. Rabbits immunized with either an alpha- or beta-chain peptide conjugate produced anti-peptide sera which reacted with fibrin monomer. Following immunoadsorption of the rabbit sera with human fibrinogen-Sepharose, fibrin-specific antibodies were detectable by solid-phase radioimmunoassay that did not react with fibrinogen. Antisera elicited by clotted human fibrin contained antibodies that reacted with fibrin and fibrinogen when treated in a similar manner.

Amino Acid Sequence↗
PubMed1987

An investigation of fibrin-platelet adhesive interactions by microfluorimetry.

Interactions between human blood platelets and fibrin have been visualized by light microscopy, and quantitative details of the extent, rate and specificity of fibrin-platelet binding obtained by microfluorimetry. Adhesion of fluorescein-labelled fibrin to activated platelets yielded brightly fluorescent fibrin-platelet aggregates, which emitted light at an intensity 4-7-fold greater than that due to nonspecific association of fluorescein-fibrin with unstimulated fixed cells. The intensity of fluorescent light emitted from fibrin-platelet aggregates increased as a function of time, reaching a plateau after about 1 h under physiological buffer and temperature conditions. Two monoclonal antibodies directed against the glycoprotein IIb-IIIa complex, which have been shown to inhibit the binding of fibrinogen and soluble fibrin oligomers to ADP-stimulated platelets, were employed to further probe the specificity of this adhesive interaction. In contrast to the results with the soluble ligands, one of these antibodies (HP1-1D) was capable of fully inhibiting the attachment of fluorescent fibrin to ADP-activated cells while the other (AP-2) was much less effective.

Adenosine Diphosphate↗
PubMed1995

Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm.

Cardioversion of atrial fibrillation carries a serious risk of major thromboembolism and stroke. To determine whether or not the procedure alters plasma levels of fibrin D-dimer (a marker of intravascular fibrin turnover and thrombus formation) and plasma fibrinogen (associated with stroke and thromboembolism), we performed a prospective study in 19 patients with atrial fibrillation in whom cardioversion was attempted: seven patients without prior oral anticoagulant therapy (but with intravenous heparin for 24 h) (Group I), and 12 patients with full oral anticoagulation pre- and post-cardioversion (Group II). Plasma fibrinogen and fibrin D-dimer were measured pre-cardioversion, and at Days 3, 7 and 14 post-cardioversion. In Group I, there was a significant reduction in median plasma fibrin D-dimer levels by 14 days following cardioversion (200 vs. 52 ng/ml; paired Wilcoxon test, P = 0.02). In Group II, there was no change in median plasma fibrin D-dimer levels over the 14 days following cardioversion. There were no significant changes in plasma fibrinogen with cardioversion in either group of patients. The reduction of plasma fibrin D-dimer in Group I suggests a beneficial reduction of intravascular fibrin turnover and thrombogenesis by the cardioversion of patients with atrial fibrillation to sinus rhythm. Furthermore, it strongly suggests that it is atrial fibrillation itself which is the major risk of thromboembolism and that the risk continues for up to 14 days post-cardioversion. In Group II, the low pre-cardioversion fibrin D-dimer levels and lack of change with cardioversion is consistent with the prophylactic effect of warfarin therapy against thromboembolism during the cardioversion of atrial fibrillation.

Adult↗
PubMed1984

Fibrinogen and fibrin interaction with concanavalin A dimer and its influence on coagulation.

Concanavalin A dimer interacts with fibrinogen and soluble fibrin at pH 5.2 Analysis of the binding data shows that there are in both cases four binding sites per molecule and that the dissociation constant does not change by removal of fibrinopeptides A and B. Ultracentrifugal studies show that no aggregates of fibrinogen or fibrin are formed through concanavalin A binding and that up to four molecules of concanavalin A dimer can bind to one molecule of fibrinogen or fibrin. These results imply that the four carbohydrate chains in the molecule are accessible to concanavalin A dimer. There is a diminution in the coagulation of fibrinogen by thrombin at low relative lectin concentrations and an increase at high concentrations. However, the lectin always favours the aggregation of fibrin monomers and does not have any inhibitory effect on the release of fibrinopeptides. We conclude that the electric charge in the neighbourhood of the carbohydrate in both chains, B beta and gamma plays an important role in the attraction between monomeric fibrin and fibrinogen-monomeric fibrin. The different effect of concanavalin A on the coagulation, depending on the relative concentration of the lectin, would be the result of the screening of this electric charge favouring either the interaction of fibrinogen-monomeric fibrin or the polymerization of monomeric fibrin.

Blood Coagulation↗
PubMed2005

Micro-architecture of calcium phosphate granules and fibrin glue composites for bone tissue engineering.

Calcium phosphate ceramics are currently used as bone graft substitutes in various types of clinical applications. Fibrin glue is also used in surgery due to its haemostatic, chemotactic and mitogenic properties. By combining these two biomaterials, new composite scaffolds were prepared. In this study, we attempt to analyse whether thrombin concentration in the fibrin glue could influence the properties of the composite. The association between fibrin glue and calcium phosphate ceramic granules was characterized at the ultra structural level. Micro and macroporous biphasic calcium phosphate ceramic granules with a diameter of 1-2mm composed of hydroxyapatite and beta-tricalcium phosphate (60/40) were associated to fibrin glue. The composites were observed by scanning and transmission electron microscopy and microcomputed tomography. Fibre thickness, porosity and homogeneity of the fibrin clot were modified by increased the thrombin concentration. Mixing fibrin glue with calcium phosphate granules (1:2) did not modify the microstructure of the fibrin clot in the composite. Nevertheless, thrombin interacted with the bioceramic by inducing the nucleation of crystalline precipitate at the ceramic/fibrin glue interface. Combining fibrin sealant and calcium phosphate ceramics could lead to new scaffolds for bone tissue engineering with the synergy of the properties of the two biomaterials.

Bone Substitutes↗
PubMed2004

Does fibrin glue sealant decrease the rate of pancreatic fistula after pancreaticoduodenectomy? Results of a prospective randomized trial.

Despite substantial improvements in perioperative mortality, complications, and specifically the development of a pancreatic fistula, remain a common occurrence after pancreaticoduodenectomy. It was the objective of this study to evaluate the role of fibrin glue sealant as an adjunct to decrease the rate of pancreatic fistula after pancreaticoduodenectomy. One hundred twenty-five patients were randomized after pancreaticoduodenal resection only if, in the opinion of the surgeon, the pancreaticojejunal anastomosis was at high risk for development of a pancreatic anastomotic leak. After completion of the pancreaticojejunal anastomosis, the patients were randomized to topical application of fibrin glue sealant to the surface of the anastomosis or no such application. The primary postoperative end points in this study were pancreatic fistula, total complications, death, and length of hospital stay. A total of 59 patients were randomized to the fibrin glue arm, whereas 66 patients were randomized to the control arm and did not receive fibrin glue application. The pancreatic fistula rate in the fibrin glue arm of the study was 26% vs. 30% in the control group (p = not significant [NS]). The mean length of postoperative stay for all patients randomized was similar (fibrin glue = 12.2 days, control = 13.6 days) and the mean length of stay for patients in whom pancreatic fistula developed was also not different (fibrin glue = 18.9 days, control = 21.7 days). There were no differences with respect to total complications or specific complications such as postoperative bleeding, infection, or delayed gastric emptying. These data demonstrate that the topical application of fibrin glue sealant to the surface of the pancreatic anastomosis in this patient population undergoing high-risk pancreaticojejunal anastomosis did not reduce the incidence of pancreatic fistula or total complications after pancreaticodudodenectomy. There seems to be no benefit regarding the use of this substance in this setting.

Administration, Topical↗
PubMed2004

Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium.

OBJECTIVES: In this study, we determined whether fibrin glue improves cell transplant retention and survival, reduces infarct expansion, and induces neovasculature formation. BACKGROUND: Current efforts in restoring the myocardium after myocardial infarction (MI) include the delivery of viable cells to replace necrotic cardiomyocytes. Cellular transplantation techniques are, however, limited by transplanted cell retention and survival within the ischemic tissue. METHODS: The left coronary artery of rats was occluded for 17 min followed by reperfusion. One week later, bovine serum albumin (BSA), fibrin glue, skeletal myoblasts in BSA, or skeletal myoblasts in fibrin glue were injected into the infarcted area of the left ventricle. The animals were euthanized five weeks after injection, and their hearts were excised, fresh frozen, and sectioned for histology and immunohistochemistry. RESULTS: After five weeks, the mean area covered by skeletal myoblasts in fibrin glue was significantly greater than the area covered by myoblasts injected in BSA. Myoblasts within the infarct were often concentrated around arterioles. The infarct scar size and myoblasts in the fibrin group were significantly smaller than those in the control and BSA groups. Fibrin glue also significantly increased the arteriole density in the infarct scar as compared with the control group. CONCLUSIONS: This study indicates that fibrin glue increases cell transplant survival, decreases infarct size, and increases blood flow to ischemic myocardium. Therefore, fibrin glue may have potential as a biomaterial scaffold to improve cellular cardiomyoplasty treat and MIs.

Animals↗
PubMed2005

Marked increase of fibrin gel permeability with very low dose ASA treatment.

INTRODUCTION: Previous data from our group show that acetylsalicylic acid (ASA), especially at low dose, alters the network structure of fibrin, rendering it more porous. The present study was performed to extend the dose-response curve for effects of ASA on fibrinogen clotting properties and to examine the variability of these effects during a 24-h dose interval. MATERIAL AND METHODS: Fifteen healthy volunteers received ASA 37.5 mg daily (low dose) for 10 days and, after an interval of 2 weeks, 320 mg daily (medium dose) for 7 days, followed by a single bolus dose of 640 mg (high dose). The plasma fibrinogen concentrations were determined and the permeability of fibrin gels (Ks) was assayed with a recently modified flow measurement technique. Three-dimensional (3D) structure of the fibrin network was studied by confocal microscopy. RESULTS: ASA therapy did not influence fibrinogen concentrations. Compared to baseline, Ks levels were increased by 21% and 31% in samples during medium and high dose ASA treatment (p<0.01) and, even more markedly, by 44% (p<0.0001) with very low dose ASA treatment (p<0.01, compared to the higher doses). The effects of ASA on fibrin gel permeability were stable over a 24-h dose interval. During ASA treatment, thicker fibrin fibers and larger network pores with irregular structure were observed by confocal microscopy. CONCLUSIONS: Acetylation of lysine residues in the fibrinogen molecule may explain the alterations in its clotting property, resulting in altered fibrin gel permeability. The mechanism(s) behind the greater increase in fibrin gel permeability and alterations in 3D structure of the fibrin network observed, and why this phenomenon is more pronounced at low compared to intermediate or high ASA doses, deserve further investigations.

Adult↗
PubMed1998

Alterations in fibrin detected in coronary sinus blood after heparin and coronary angiography with a nonionic contrast agent (iohexol).

Although heparin and some radiographic contrast agents inhibit coagulation, thrombi can still form in their presence. The chemical environment in which a thrombus forms affects fibrin structure that may alter the ability of the thrombus to be lysed. Therefore, we assessed changes in fibrin structure in 13 patients referred for coronary angiography. Blood was obtained from the femoral vein, femoral artery, ascending aorta, left main coronary artery (LMCA), and coronary sinus (CS) before, during, and after coronary angiography was performed with iohexol. The number of fibrin monomers per fiber cross section was determined by turbidity measurements of fibrin gels formed from plasma samples. At baseline there was no difference in the number of fibrin monomers per fiber cross section in plasma gels generated from the different sampling sites. After iohexol administration, there was a significant decrease in the number of fibrin monomers per fiber cross section at the sampling sites ranging from - 13% to -25% compared with the respective baseline values with the largest change in the LMCA CS (51+/-16 to 38+/-15, p <0.025). Transcardiac (LM - CS value) changes in the number of fibrin monomers per fiber cross section were dependent on the timing of the sample collection in the CS. In 7 patients, the CS sample was collected approximately 2 minutes after injection of contrast material and there was no transcardiac difference. When the CS sample was obtained during contrast injection (n=6) a large transcardiac change occurred (44+/-10 to 32+/-14, p=0.01). These data show transient changes in fibrin structure during coronary angiography with iohexol. The thinner fibers formed in the presence of iohexol were more resistant to fibrinolysis.

Anticoagulants↗
PubMed1985

Hemostatic effectiveness of fibrin glue derived from single-donor fresh frozen plasma.

Fibrin glue derived from pooled human blood is an effective sealant for high-porosity vascular grafts and a valuable topical hemostatic agent in heparinized patients. Use of this agent in the United States is prohibited because of potential transmission of hepatitis B, acquired immunodeficiency syndrome, and other serologically transmitted illnesses. We have developed a cryoprecipitation technique that allows preparation of fibrin glue from single-donor fresh frozen plasma. Use of this agent presumably entails no greater risk of disease transmission than intravenous administration of single-unit fresh frozen plasma. This report describes our early clinical experience with this material. Fibrin glue was used as a sealant for porous woven Dacron tubular prostheses and cardiovascular patches in 19 patients. The fibrin glue sealant has also been employed to control bleeding from needle holes and small anastomotic tears in 22 patients. No patient in this series had a bleeding complication from a suture line or graft treated with fibrin glue. This experience indicates that like fibrin glue from pooled blood, fibrin glue from single-donor plasma is effective as a graft sealant and topical hemostatic agent. Preparation of fibrin glue from single-donor plasma is simple and economical, and may provide cardiothoracic surgeons in the United States with a widely available, valuable hemostatic adjunct.

Blood Donors↗
PubMed1997

Fibrin-glue assisted vasoepididymostomy: a comparison to standard end-to-side microsurgical vasoepididymostomy in the rat model.

PURPOSE: The use of fibrin glue for vasovasostomy has produced high patency rates in animal models. Vasoepididymostomy is a microsurgical technique that might be made easier if fibrin glue could substitute for microsutures. We evaluated the efficacy of a new vasoepididymostomy technique using fibrin glue. MATERIALS AND METHODS: Bilateral vasoepididymostomies were performed in 24 male Sprague-Dawley rats using a conventional microsurgical technique on one side and a fibrin-glue assisted technique on the other. The rats were sacrificed 30 days after surgery and anastomotic patency was assessed by examining the vasal fluid for sperm, injecting methylene blue dye into the vas deferens and observing backflow into the epididymis by gross inspection and histological studies. Additionally, the incidence of granuloma formation was compared between the two techniques. RESULTS: Fibrin-glue anastomoses showed a patency rate of 79% (n = 19), compared with 63% (n = 15) for the conventional suture anastomoses (p = 0.29). Among the patent anastomoses, the incidence of sperm granuloma formation between the sutured (12, 50%) and the fibrin glue anastomoses (16, 67%) did not differ significantly (p = 0.36). Morphological tissue changes were similar for the two techniques. The time required for anastomosis using fibrin glue was significantly shorter than the conventional suture technique (p < 0.001). CONCLUSIONS: Conventional suturing techniques for vasoepididymostomy require advanced microsurgical skills. The use of fibrin glue simplifies this procedure and provides patency rates comparable to microsutured, end-to-side anastomoses.

Animals↗
PubMed2001

Method to measure in vivo blood fibrinolytic activity with a (125)I-fibrin coated aorta loop validated with agents which affect blood fibrinolytic activity.

A functional animal model to measure in vivo the blood fibrinolytic activity and pharmacological-induced changes thereof are described. A (125)I-fibrin coated plastic loop is inserted in the rat aorta; the rate of label disappearance (sigmoid curve) is directly registered outside the animal with a gamma scintillation probe. The time needed to let disappear 50% of the removable-labeled fibrin is used as measure for the blood fibrinolytic activity. The direct advantage of this model is the absence of a blood or plasma clot: a thin labeled fibrin layer attached to the inner wall of the loop is in direct contact with the blood and is therefore sensitive to increased or decreased blood fibrinolytic activity. The total experiment needs about 60 min. Experiments with nontreated rats showed that, after an initial lag phase of about 10 min, the labeled fibrin started to disappear from the loop. A sigmoid pattern was obtained showing that about 20-30% of the coated-labeled fibrin is resistant to removal. Registration of the total curve of a nontreated (control or placebo) rat required about 30-40 min. The clinically used thrombolytics (intravenously administered) urokinase and t-PA showed a dose-dependent fibrinolytic activity resulting in increased removal of the bound (125)I-fibrin. Streptokinase was not active, which is in agreement with literature. Tranexamic acid, dexamethasone and endotoxin (inhibitors of fibrinolysis) showed dose-dependent inhibition of removal of the coated fibrin. Retinoic acid was tested as compound, which may enhance the blood fibrinolytic activity; retinoic acid was not found to be significantly active in this model. The disappearance of labeled fibrin is not sensitive to inhibitors of coagulation or platelet aggregation. This technically simple and fast model can thus be used to measure in vivo quantitatively the effects of pharmacological active compounds, which increase or decrease the blood fibrinolytic activity.

Animals↗
PubMed2005

Fibrinogen and fibrin.

Fibrinogen is a large, complex, fibrous glycoprotein with three pairs of polypeptide chains linked together by 29 disulfide bonds. It is 45 nm in length, with globular domains at each end and in the middle connected by alpha-helical coiled-coil rods. Both strongly and weakly bound calcium ions are important for maintenance of fibrinogen's structure and functions. The fibrinopeptides, which are in the central region, are cleaved by thrombin to convert soluble fibrinogen to insoluble fibrin polymer, via intermolecular interactions of the "knobs" exposed by fibrinopeptide removal with "holes" always exposed at the ends of the molecules. Fibrin monomers polymerize via these specific and tightly controlled binding interactions to make half-staggered oligomers that lengthen into protofibrils. The protofibrils aggregate laterally to make fibers, which then branch to yield a three-dimensional network-the fibrin clot-essential for hemostasis. X-ray crystallographic structures of portions of fibrinogen have provided some details on how these interactions occur. Finally, the transglutaminase, Factor XIIIa, covalently binds specific glutamine residues in one fibrin molecule to lysine residues in another via isopeptide bonds, stabilizing the clot against mechanical, chemical, and proteolytic insults. The gene regulation of fibrinogen synthesis and its assembly into multichain complexes proceed via a series of well-defined steps. Alternate splicing of two of the chains yields common variant molecular isoforms. The mechanical properties of clots, which can be quite variable, are essential to fibrin's functions in hemostasis and wound healing. The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active enzyme plasmin, results in digestion of fibrin at specific lysine residues. Fibrin(ogen) also specifically binds a variety of other proteins, including fibronectin, albumin, thrombospondin, von Willebrand factor, fibulin, fibroblast growth factor-2, vascular endothelial growth factor, and interleukin-1. Studies of naturally occurring dysfibrinogenemias and variant molecules have increased our understanding of fibrinogen's functions. Fibrinogen binds to activated alphaIIbbeta3 integrin on the platelet surface, forming bridges responsible for platelet aggregation in hemostasis, and also has important adhesive and inflammatory functions through specific interactions with other cells. Fibrinogen-like domains originated early in evolution, and it is likely that their specific and tightly controlled intermolecular interactions are involved in other aspects of cellular function and developmental biology.

Animals↗