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PubMed1985

Specific identification of fibrin polymers, fibrinogen degradation products, and crosslinked fibrin degradation products in plasma and serum with a new sensitive technique.

A new method is described for identifying low concentrations of circulating derivatives of fibrinogen and fibrin, even when present in heterogeneous mixtures. This technique is applicable to plasma and serum and uses electrophoresis in 2% agarose in the presence of sodium dodecyl sulfate (SDS) followed by immunological identification of separated derivatives, using radiolabeled antifibrinogen antiserum and autoradiography. Unique electrophoretic patterns distinguish plasmic derivatives of crosslinked fibrin from those of fibrinogen and also identify crosslinked fibrin polymers produced by the combined action of thrombin and factor XIII on fibrinogen. The assay is sensitive to a concentration of 0.1 micrograms/mL of fibrinogen in serum or plasma. Fibrin polymers, plasmic degradation products of fibrinogen, and plasmic degradation products of crosslinked fibrin were detected in the plasma or serum of a patient with disseminated intravascular coagulation. Plasmic derivatives of both fibrinogen and crosslinked fibrin appeared in serum in the course of fibrinolytic therapy for pulmonary embolism, whereas during acute myocardial infarction a marked increase in the proportion of fibrin polymers in plasma was found in comparison with normal controls. Thus, the procedure can distinguish between the simultaneous processes of fibrin polymer formation, fibrinogenolysis, and fibrinolysis, and is sufficiently sensitive to detect relevant quantities of derivatives in pathologic conditions.

Autoradiography↗
PubMed1994

Binding of alpha-thrombin to fibrin depends on the quality of the fibrin network.

Binding of human alpha-thrombin to fibrin was studied in a purified system at pH 7.35, I 0.08 and 37 degrees C. Binding experiments with active thrombin resulted in fibrin clots of variable quality, depending on the thrombin concentration: opaque gels composed of 'coarse' network were produced at low thrombin concentrations, while increasing concentrations of thrombin led to more translucent 'fine' gels. Scatchard analysis showed a non-linear dependence of thrombin binding to fibrin, suggesting the existence in fibrin(ogen) of multiple classes of binding sites for thrombin. Binding of catalytic-site-inhibited thrombin was investigated in clots of defined quality produced with three different concentrations of a thrombin-like enzyme, batroxobin (EC 3.4.21.29). Straight lines of different slopes were established by Scatchard analysis of binding data at each fixed batroxobin concentration. These results favour a model according to which binding affinity for thrombin depends on the thickness of fibrin bundles. Labelled active-site-inactivated thrombin incorporated in batroxobin-induced clots was only sparingly released during incubation for 24 h in the presence of a 200-fold excess of unlabelled thrombin, indicating that thrombin binding to fibrin is not reversible and that Scatchard analysis is not appropriate for quantification of binding parameters. Irreversible binding of thrombin appears to reflect trapping of thrombin molecules within fibrin fibres. The amount of trapped thrombin depends on the quality of the fibrin fibres, which in turn is determined by the concentration of the clotting enzyme.

Amino Acid Chloromethyl Ketones↗
PubMed1970

Subunit structure of human fibrinogen, soluble fibrin, and cross-linked insoluble fibrin.

The three unique polypeptide chains of human fibrinogen differ significantly in molecular weight. Cross-linkage of fibrin by fibrin-stabilizing factor results in the rapid formation of cross-links between gamma-chains and a slower formation of cross-links between alpha-chains. beta-Chains are not involved directly in the cross-linking of fibrin. Reduced, cross-linked fibrin contains uncross-linked beta-chains, dimers of gamma-chain, and higher polymers of alpha-chain. Although it is uncertain whether the gamma-gamma dimers are formed by chains in different molecules of fibrin, the polymers of alpha-chain in fibrin can only be accounted for by cross-linkage of alpha-chains in different molecules. The nature of cross-linkage among the subunits in fibrin can account well for the three-dimensional, covalent structure of cross-linked, insoluble fibrin.

Amino Acids↗
PubMed1996

Interactions between staphylokinase, plasmin(ogen), and fibrin. Staphylokinase discriminates between free plasminogen and plasminogen bound to partially degraded fibrin.

Staphylokinase (STA), a protein of bacterial origin, induces highly fibrin-specific thrombolysis both in human plasma in vitro and in pilot clinical trials. Using fluorescence microscopy, we investigated the spatial distribution of fluorescein isothiocyanate (FITC)-labeled STA during lysis of a plasma clot and its binding to purified fibrin clots in the presence or in the absence of plasmin(ogen). STA highly accumulated in a thin superficial layer of the lysing plasma clot following the distribution of plasminogen (Pg) during lysis. Experiments with purified fibrin clots revealed that STA binds to Pg bound to partially degraded fibrin but not to Pg bound to intact fibrin. Binding of FITC-labeled STA to various forms of plasmin(ogen) in a buffer solution was studied by measuring fluorescence anisotropy. The binding constant for Glu-Pg was estimated as 7.4 microM and for Lys-Pg as 0.28 microM; for active-site blocked plasmin the binding constant was less than 0.05 microM. The much lower affinity of STA for Glu-Pg compared with that for active site-blocked plasmin was mainly due to a lower association rate constant, as assessed by real time biospecific interaction analysis. Gel filtration of a mixture of STA with a molar excess of Glu-Pg demonstrated that STA migrated as an unbound 18-kDa protein when activation of Pg into plasmin was precluded by inhibitors of plasmin. When gel-filtered under the same conditions with plasmin, STA migrated in complex with plasmin with an apparent molecular mass of 100 kDa. Confocal fluorescence microscopy finally demonstrated that when FITC-labeled STA was added to plasma before clotting, it did not bind to fibrin fibers during the first minutes (lag phase), although Pg bound to the fibers moderately. Then, both Pg and STA started to accumulate on the fibers progressively, followed by complete lysis of the clot. In conclusion, our results imply that, when STA is added to plasma, only a small percentage associates with Pg. In contrast, STA binds strongly to plasmin and to Pg, which is bound to partially degraded fibrin. These findings add a new mechanism to the known explanations for the inefficient Pg activation by STA in plasma and specify the mechanism for fibrin-dependent activation of Pg.

Chromatography, Gel↗
PubMed1992

Plasminogen activator inhibitor-1 binds to fibrin and inhibits tissue-type plasminogen activator-mediated fibrin dissolution.

Plasminogen activator inhibitor-1 (PAI-1) accumulates within thrombi and forming whole blood clots. To explore this phenomenon at the molecular level, PAI-1 binding to fibrin was examined. The experiments were performed by adding 125I-PAI-1, which retains its complete tissue-type plasminogen (t-PA) inhibitory activity, to fibrin matrices formed in 2-cm2 tissue culture wells. Guanidine HCl-activated PAI-1 binding was reversible and was inhibited in the presence of excess, unlabeled PAI-1. Activated 125I-PAI-1 recognized 2 sites on fibrin: a very small number of high affinity sites (Kd less than 1 nM) and principally a large number of low affinity sites with an approximate Kd of 3.8 microM. Latent PAI-1 bound to fibrin at a site indistinguishable from the lower affinity site recognized by activated PAI-1. Fibrin, pretreated with activated PAI-1, was protected from t-PA-mediated plasmin degradation in a PAI-1 dose-responsive manner (IC50 = 12.3 nM). Clot protection correlated with partial occupancy of the low affinity PAI-1 binding site on fibrin and was due to the formation of sodium dodecyl sulfate-stable, PAI-1.t-PA complexes. Latent PAI-1 (27 nM) did not protect the fibrin from dissolution. The localization of PAI-1 to a thrombus by virtue of its fibrin binding potential could result in significant protection of the thrombus from the degradative effects of the fibrinolytic system.

Binding, Competitive↗
PubMed1987

Immunochemical characterization of fibrinogen, fibrin I, and fibrin II in human thrombi and atherosclerotic lesions.

Arterial thrombi and atherosclerotic lesions were analyzed immunochemically and examined histologically. The extent of in vivo proteolytic cleavage of the amino-terminal end of fibrinogen by thrombin and plasmin was determined and quantitated by specific radioimmunoassays. The samples were treated with cyanogen bromide (CNBr), and the total amount of fibrinogen and fibrin-derived protein was determined as NDSK, the NH2-terminal disulfide knot of fibrinogen. Thrombin-releasable fibrinopeptides A and B were used to quantitate fibrinogen and fibrin I. Previous plasmin cleavage of the B beta chain was inferred from the amount of B beta 1-42 and B beta 15-42 in undigested NDSK. The results obtained in both acute and organized thrombi indicate that approximately 60% of the total protein (as determined by amino acid analysis) was fibrinogen-derived and that 70% to 80% of the fibrinogen-derived material was fibrin II. These findings support the hypothesis that fibrin II as distinct from fibrin I is the predominant component in a thrombus. In samples from normal and atherosclerotic aortas, fibrinogen-derived protein comprised less than 10% of the total protein. Samples from grossly normal aortas contained only fibrinogen and fibrin I. Fibrinogen concentration decreased and fibrin II concentration increased with increasing severity of the lesions, suggesting that increased fibrin II formation is associated with progression of atheromas.

Aorta↗
PubMed1988

Influence of the subendothelial basement membrane components on fibrin assembly. Evidence for a fibrin binding site on type IV collagen.

Effective repair of a vascular injury depends on establishment of a stable fibrin patch at the injury site. Data presented in this study demonstrate that structural modification of fibrin occurs as a result of fibrin interaction with naturally occurring components of the vascular basement membrane and subendothelial structures. Of the basement membrane components, type IV collagen produces the greatest structural modification, generating thick fibrin fibers; a 3-fold increase in the fiber mass/length ratio occurs when type IV collagen is increased from 0 to 100 ng/ml. Laminin and dermatan sulfate decrease the fibrin fiber mass/length ratio resulting in thinner fibers. However, the overall effect of the basement membrane on fibrin is to increase the fibrin fiber diameter. Electrophoretic light scattering and the binding of type IV collagen by fibrinogen-Sepharose further establish the interaction between type IV collagen and fibrinogen. Incorporation of laminin with type IV collagen onto coated surfaces decreases the ability of type IV collagen to bind fibrinogen. These studies emphasize that the final fibrin structure is influenced by the milieu in which the clot is assembled.

Basement Membrane↗
PubMed1984

The fibrin-binding site of human plasminogen. Arginines 32 and 34 are essential for fibrin affinity of the kringle 1 domain.

Kringle 1 (Tyr 79/Leu 80-His 167 and Tyr 79/Leu 80-Tyr 173), a chymotryptic fragment of human plasminogen that has high affinity for fibrin and omega-aminocarboxylic acids, has been subjected to modification with 1,2-cyclohexanedione to identify arginine residues essential for ligand binding. Reaction of 1,2-cyclohexanedione with kringle 1 was found to rapidly abolish the fibrin-Sepharose affinity of the fragment, whereas the affinity for lysine-Sepharose was lost at a significantly slower rate. Successive affinity chromatography of modified kringle 1 on fibrin- and lysine-Sepharose was used to separate kringle 1 that lost affinity for fibrin-, but retained affinity for lysine-Sepharose from kringle 1 that lost affinity for both affinants. The modified proteins were subjected to structural studies in order to locate the labeled arginine residues in kringle 1. These studies have revealed that modification of Arg 34 leads to the loss of both the fibrin- and lysine-Sepharose affinities of kringle 1, whereas reaction of Arg 32 abolishes fibrin affinity but leaves lysine-Sepharose affinity unaltered. The results suggest that Arg 32 and Arg 34 are both involved in fibrin binding and that Arg 34 is also involved in binding omega-aminocarboxylic acids. Previous NMR studies on kringles have indeed shown that the segment containing residue 34 is in the proximity of and interacts with the omega-aminocarboxylic acid-binding site. This interaction may explain the influence of omega-aminocarboxylic acids on fibrin binding by kringle 1.

Amino Acid Sequence↗
PubMed1982

Fibrin in peritonitis. III. The mechanism of bacterial trapping by polymerizing fibrin.

We have previously shown that fibrin can act to contain microorganisms and prevent early septic death in experimental peritonitis. However, this trapping eventuates in abscess formation. Fibrinogen, the precursor molecule of fibrin, is known to possess binding structures for some pathogenic organisms. We compared the extent of incorporation of various aerobic and anaerobic bacteria as well as polystyrene latex microspheres into fibrin clots. Similar numbers of organisms and microspheres were incorporated into either noncontracted or contracted fibrin clots. Detailed comparisons of the binding of Escherichia coli or Staphylococcus aureus to human fibrinogen were then made. The addition of 111:B4 lipopolysaccharide did not inhibit incorporation of E. coli 0111:B4 into either type of fibrin clot. With initial inoculum sizes of 10(6) to 10(8) colony-forming units (CFU)/ml, S. aureus was better incorporated into contracted fibrin clots (P less than 0.01) than was E. coli, possible evidence for an easily saturable receptor mechanism. We concluded that microorganisms are incorporated into the polymerizing fibrin matrix in the same fashion as are inert particles of similar size, irrespective of external chemical structure. Adherence of bacteria to fibrinogen or polymerizing fibrin did not appear to represent a specific bacterial virulence factor, more likely representing an effective host defense mechanism of broad specificity.

Abscess↗
PubMed1993

Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure.

Fibrinogen Dusart is a congenital dysfibrinogenemia (A-alpha 554 Arginine-->Cysteine) associated with severe thrombotic disorder, high incidence of thrombotic embolism, and abnormal fibrin polymerization. This thrombotic disorder was attributed to an abnormal clot thrombolysis with reduced plasminogen binding to fibrin and defective plasminogen activation by tissue plasminogen activator. The purpose of this work was to assess whether clot architecture could be involved in the thromboresistance of the fibrin Dusart and the high incidence of embolism. An important change in Dusart fibrin clot structure was identified with dramatic decrease of gel porosity (Ks), fiber diameters (d), and fiber mass-length ratios (mu) derived from permeation analysis. In addition, rigidity of the Dusart clot was found to be greatly increased compared with normal fibrin. We provide evidence that both thrombolysis resistance and abnormal rigidity of the fibrin Dusart are related to this abnormal architecture, which impairs the access of fibrinolytic enzymes to the fibrin and which is responsible for a brittle clot that breaks easily, resulting in a high incidence of embolism. Indeed, when restoring a normal clot structure by adding dextran 40 (30 mg/mL) before coagulation, clot thrombolysis and clot rigidity recovered normal values. This effect was found to be dose-dependent. We conclude that clot architecture is crucial for the propensity of blood clot to be degraded and that abnormal clot structure can be highly thrombogenic in vivo. The alpha-C domains of fibrinogen are determinant in fibrin clot structure.

Dextrans↗
PubMed1980

The structure of soluble fibrin complexes and fibrin degradation products after Echis carinatus bite.

Studies on the concentration and structure of fibrinogen, fibrinogen-fibrin soluble complexes, and fibrinogen-fibrin degradation products were made on 11 patients in Nigeria who suffered defibrination following Echis carinatus bite. Following admission, before treatment with antivenom, all patients had reduced or zero fibrinogen levels, and increased concentrations of soluble complexes and degradation products. The fibrin component of the soluble complexes, separated by fibrinogen-sepharose chromatography, consisted of both intact fibrin and fibrin degraded at the alpha-chain. After isolation by Biogel chromatography the soluble complexes were also found to contain gamma-dimer chains. The fibrinogen-fibrin degradation products consisted of several X species, Y, D and D-dimer, as well as fragment E. The major fragment in all patients was D, but a few samples contained significant quantities of D-dimer, indicating in vivo activation of factor XIII. There was evidence of degraded fibrinogen, as well as fibrin, in the soluble complexes and degradation products, suggesting that fibrinogenolysis, in addition to fibrinolysis, had occurred, probably as a result of secondary endogenous activation of the fibrinolytic system in response to defibrination.

Antivenins↗
PubMed1994

Degradation of the alpha-chain of fibrin by human neutrophil elastase reduces the stimulating effect of fibrin on plasminogen activation.

UNLABELLED: The degradation of fibrin by human neutrophil elastase (HNE) and the interference of such degradation on the stimulating effect of fibrin on plasminogen activation by tissue plasminogen activator (t-PA) was studied. By using SDS electrophoresis and Western blotting with subsequent immunostaining with monoclonal antibodies, degradation of the fibrin molecule was monitored. This degradation was related to the stimulating effect on plasminogen activation. Degradation of the alpha-chain was seen to occur before degradation of the beta- and gamma-chains. On the alpha-chain it was found that C-terminal degradation occurred prior to visible degradation of the N-terminal end. This C-terminal degradation was associated with a fall in the stimulation of plasminogen activation, coinciding with a corresponding reduction in the polymerization of fibrin. With further degradation, including N-terminal proteolysis of the alpha-chain, the stimulating effect of fibrin was reduced to that of fibrinogen. CONCLUSIONS: Our results indicate that HNE degradation of the alpha-chain of fibrin occurs initially from the C-terminal end, affecting the polymerization of fibrin. This impaired polymerization may be important for the observed reduction in the t-PA mediated plasminogen activation.

Enzyme Activation↗
PubMed2004

Properties of engineered vascular constructs made from collagen, fibrin, and collagen-fibrin mixtures.

Vascular constructs were formed by embedding rat aortic smooth muscle cells in three-dimensional matrices of Type I collagen, fibrin, or a mixture of collagen and fibrin in a 1:1 ratio, at total matrix protein concentrations of 2 and 4 mg/ml. Morphological and mechanical properties were evaluated after 6 days in culture, and the effect of cyclic mechanical strain on collagen-fibrin mixture constructs was also studied. Constructs made with the lower protein concentration compacted to the greatest degree, and fibrin was found to enhance gel compaction. Each matrix type exhibited a characteristic stress-strain profile. Pure collagen had the highest linear modulus and pure fibrin had the lowest. The ultimate tensile stress was strongly dependent on the degree of gel compaction, and collagen-fibrin mixtures at 2mg/ml total protein content exhibited the highest values. Application of cyclic mechanical strain to collagen-fibrin mixture constructs caused a significant increase in gel compaction and a decrease in cell proliferation. The linear modulus, ultimate tensile stress and toughness of the constructs were all augmented by mechanical strain. These results demonstrate that the properties of engineered vascular tissues can be modulated by the combination of selected extracellular matrix components, and the application of mechanical stimulation.

Animals↗
PubMed2006

A fibrin encapsulated liposomes-in-chitosan matrix (FLCM) for delivering water-soluble drugs. Influences of the surface properties of liposomes and the crosslinked fibrin network.

A depot drug delivery system, fibrin encapsulated liposome-in-chitosan matrix (FLCM), has been developed to deliver a water-soluble drug which is configured by a porous chitosan matrix containing a bovine fibrin network encapsulated different surface properties of liposomes. Quinacrine (QR), a water-soluble, low-molecular weight fluorescent marker, is used as a model drug to evaluate the delivery characteristics of the system. The SEM photographs show that the fibrin network adheres to the surfaces and pores of the chitosan matrix of a FLCM system. The QR release periods of the FLCM are sustained for about four times longer than those of QR encapsulated into the liposomes. However, the QR release periods and profiles of the FLCM are influenced by the surface properties of liposomes. The release of QR from FLCM is sustained for 9 days for neutral liposomes and only 5 days for PEG modified liposomes (PEG-liposome). After crosslinking the fibrin network of the FLCM with 0.5% of glutaldehyde, the release of QR is further sustained for 17 days with good linear profiles (e.g., 13 days) and with 50% of reduced burst release compared with those of without crosslinking, indicating that the stability of the fibrin network plays an important role on QR release of the system. More interestingly, the release periods and profiles of QR of the FLCM system are highly similar to those of Tirofiban, low-molecular weight of a water-soluble clinical cardiovascular drug, although the study has been done by human platelet poor plasma instead of bovine fibrinogen as a source of fibrin network. It suggests that the QR is a suitable model for investigating the drug delivery behaviors for water-soluble, low-molecular weight drugs of the FLCM. In conclusion, with QR as a model drug, FLCM with crosslinked fibrin network can effectively sustain the release of QR for 17 days but the release profiles are influenced by the surface properties of encapsulated liposomes. This study suggests that FLCM may have the potential as a depot drug delivery system for water-soluble drugs.

Amines↗
PubMed1988

Molecular morphology of fibrin monomers and early oligomers during fibrin polymerization.

The structural features of early fibrin oligomers produced during the initial stages of polymerization were investigated by rotatory shadowing after cryotechnical preparation. The building blocks of polymerization, namely fibrin monomer units (in analogy to fibrinogen itself), were found to exhibit a high degree of flexibility which is independent of fibrinopeptide A and B removal. Early polymers exhibited directed longitudinal growth and were frequently branched. Along the main oligomer axis, fibrin monomer units were randomly orientated. Within early oligomers, a given fibrin monomer unit was found to establish a single contact with each of its two neighbors, suggesting that during the early stages of polymerization, only one polymerization and one binding site are activated per fibrinogen molecule (becoming an AB2 fibrin monomer unit). This morphological feature was corroborated by the finding that early oligomer fractions are deficient in only 50% of releasable fibrinopeptide A. Early associations between AB2 fibrin monomer units were demonstrated to be reversible and to occur in the absence of direct domainal contact; interactions thus presumably occur via fine molecular protrusions on either D or E domains. The arrangement of AB2 fibrin monomer units within early oligomers suggests that, with respect to their structural organization, fibrinogen molecules are radially symmetrical through the E domain (implying an antiparallel organization of polymerization and binding sites). This pattern is inconsistent with a "top-bottom" model, and thus with "half-staggered double-stranded" polymer growth. The methodological problems responsible for the apparent conflict with previous morphological findings are discussed.

Fibrin↗
PubMed1988

Isolation of a fibrin-binding fragment from blood coagulation factor XIII capable of cross-linking fibrin(ogen).

Purified platelet Factor XIII was radioiodinated and then partially degraded by thrombin or trypsin, and a fibrin-binding fragment was identified by autoradiography and immunoblotting following separation by SDS/polyacrylamide-gel electrophoresis. Limited proteolysis of 125I-Factor XIII by thrombin or trypsin produced an 125I-51 kDa fragment and an unlabelled 19 kDa fragment. The 51 kDa fragment was purified by h.p.l.c. on a TSK-125 gel-filtration column. Partial amino acid sequence analysis of the 51 kDa fragment indicated that it was similar in sequence to the Gly38-Lys513 segment in placental Factor XIII a-chain. More than 70% of the 51 kDa fragment bound to fibrin, whereas the 19 kDa fragment did not bind. The active site was localized to the 51 kDa fragment since this fragment expressed transglutaminase activity, cross-linked fibrin and fibrinogen and incorporated iodo[14C]acetamide into the active-site cysteine residue. Isolation of a fibrin-binding fragment expressing transglutaminase activity demonstrates that each a-chain of the dimeric Factor XIIIa could function independently to cross-link fibrin. The fibrin-binding site could play an important role in localizing Factor XIIIa to the fibrin clot.

Amino Acid Sequence↗
PubMed2001

The fibrin intermediate, its place in the fibrinogen-fibrin transformation.

Our preceding study indicated that, in course of coagulation of human fibrinogen by thrombin, substantial production of the fibrin intermediate (alpha-profibrin) lacking only one fibrinopeptide A (FPA) precedes the formation of alpha-fibrin monomer lacking both FPAs. The plateau concentration of alpha-profibrin (20% of initial fibrinogen) appearing in reactions indicated, however, that the second FPA is released four times faster than the first. The study reported here confirms those findings, and provides new insight into the significance of differing rate constants for the production of alpha-profibrin and its conversion to alpha-fibrin. The intermediate could be isolated in a distinct electrophoretic band by electrophoresing partial thrombin digests at high concentrations. Its identity was verified by digesting it with CNBr and by demonstrating that its N-terminal domain, the NDSK fragment, both lacks an FPA and contains an FPA, unlike the NDSKs of the bands from fibrin which contained no FPA or the fibrinogen band that lacked no FPA. The single step isolation also enabled us to confirm the 15-20% plateau level of alpha-profibrin in course of thrombin reactions, well below the 37% maximum that would be expected if release of the first and second FPA proceeded independently with no difference in rate. The 37% maximum is observed in reactions with atroxin, and it is suggested that the abundant production of alpha-profibrin underlies the therapeutic utility of atroxin as a defibrinating agent. Gel chromatography procedures were optimized for isolation of alpha-profibrin/fibrin mixtures free of fibrinogen, the final step of which involves literal use of agarose gel as a filter to remove fibrin aggregates from the fibrinogen free fractions (aggregates are left behind in gel filtration, rather than their moving ahead in gel chromatography). Unlike human fibrinogen, rabbit fibrinogen does not yield much alpha-profibrin in course of its conversion to fibrin, less than 10% as determined by electrophoresis and comparison with abundant production with atroxin. This low production of alpha-profibrin conformed with conclusions from our early studies on the generalized Shwartzman reaction in rabbits, and we now infer that the low production of alpha-profibrin and rapid conversion to fibrin by rabbit fibrinogen underlies the unparalleled susceptibility of these animals toward fibrinoid formation in the generalized Shwartzman reaction.

Animals↗
PubMed1992

The structure basis of the poor fibrin specificity of urokinase (II)--The inhibition of urokinase A chain 149-157 on the fibrin stimulated activation of plasminogen by tissue type plasminogen activator.

In view of the similarity of the charge distribution between fibrin A alpha 148-161 and A chain 149-157 of urokinase, the latter might compete with fibrin A alpha 148-161 when single chain pro-urokinase is converted to double chain urokinase. To test this, the stretch of urokinase A chain 135-157 was separated from the low molecular weight urokinase, a competitive binding between this stretch and fibrin to tPA kringle-2 was shown by radio-binding assay. The inhibition of the stretch on the fibrin stimulated activation of plasminogen was demonstrated in the caseinolytic system. The synthesized novapeptide urokinase A chain 149-157 (R-peptide) showed a significant inhibition on the activation of plasminogen in the presence of fibrin. By contrasting finely with R-peptide, a synthesized novapeptide in which Arg154 and Arg156 were replaced by Asp (D-peptide) did not show any inhibition effect on the fibrin stimulated activation of plasminogen by tPA. These results suggest that the positively charged residues in the stretch 149-157 of urokinase are crucial for the inhibition of fibrin binding with the kringle domain of urokinase.

Amino Acid Sequence↗