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Nihon Rinsho. Japanese Journal of... Sep 1999
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Nihon Rinsho. Japanese Journal of... Mar 1995
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Bailliere's Best Practice & Research.... Sep 1999The fibrinolytic system generates plasmin, which dissolves fibrin in haemostatic plugs and in thrombi. It is often regarded simply as a secondary phenomenon responsive... (Review)
Review
The fibrinolytic system generates plasmin, which dissolves fibrin in haemostatic plugs and in thrombi. It is often regarded simply as a secondary phenomenon responsive to the generation of thrombi but it is, rather, in dynamic balance with fibrin formation, such that abnormalities in either can lead to thrombosis. This chapter summarizes the fibrinolytic system and its regulation. It considers the components of the system in blood, both in plasma and in circulating cells, with emphasis on protease-inhibitor balance. It goes on to discuss local fibrinolytic potential in thrombi, both venous and arterial, and in the diseased vessel wall, presenting evidence that increased local inhibition of fibrinolysis by PAI-1, PAI-2 and alpha2-antiplasmin is intimately involved in thrombus stability and in the generation of fibrin-rich vessel wall lesions. Finally, it reviews the evidence that defective plasma fibrinolysis has a causal role in venous and arterial thrombosis.
Topics: Animals; Blood Platelets; Fibrin; Fibrinolysin; Fibrinolysis; Humans; Serine Proteinase Inhibitors; Thrombosis
PubMed: 10856979
DOI: 10.1053/beha.1999.0034 -
Journal of Biomedicine & Biotechnology 2012Fibronectin and laminin are clinically relevant plasmin receptors in the eye. Located at the vitreoretinal interface, they are cleaved by ocriplasmin (Microplasmin,... (Review)
Review
Fibronectin and laminin are clinically relevant plasmin receptors in the eye. Located at the vitreoretinal interface, they are cleaved by ocriplasmin (Microplasmin, ThromboGenics, Iselin, NJ), a novel ophthalmic medication. A series of clinical trials to study ocriplasmin for the treatment of vitreoretinal diseases such as vitreomacular traction, macular hole, and exudative age-related macular degeneration are underway. The results are promising and may impact patient care.
Topics: Animals; Drug Approval; Fibrinolysin; Humans; Peptide Fragments; Randomized Controlled Trials as Topic; Retinal Diseases; Vitreous Body
PubMed: 23193358
DOI: 10.1155/2012/354979 -
Thrombosis Research Jun 1989The basis for specific binding of plasmin to alpha 2-antiplasmin (AP) was analyzed by preparing overlapping synthetic peptides of 11, 17, 18, 19, 26, 33, and 40 amino...
The basis for specific binding of plasmin to alpha 2-antiplasmin (AP) was analyzed by preparing overlapping synthetic peptides of 11, 17, 18, 19, 26, 33, and 40 amino acid residues corresponding to the carboxy-terminal sequence of AP. Affinities of the peptides for plasmin were estimated by competitive inhibition of the association of AP with plasmin. Dissociation constants with increasing peptide length were: 200, 54, 19, 18, 9.8, 4.7, and 2.8 microM, respectively. Peptides blocked binding sites on plasmin, not the catalytic site, as evidenced by lack of effect on the hydrolysis of chromogenic substrates. Substituting arginine for lysine at the carboxy-terminus or the 17th residue from the carboxy-terminus decreased the affinity of peptides for plasmin 9-fold and 5-fold, respectively, implicating these lysine residues of AP as major ligand sites for plasmin. Several stepwise increases in affinity of peptides for plasmin as peptide length increased up to 40 residues suggest contributions by additional sites, possibly other lysine residues. A potential plasmin binding site in fibrin, analogous to that in AP, is identified by affinity for plasmin of synthetic peptides corresponding to part of the alpha-chain ending with residue 207. To explain these data, we propose that plasmin recognizes physiological ligands by binding two or more lysine residues which are optimally presented to favor simultaneous interaction with separate lysine-binding site in plasmin.
Topics: Arginine; Binding Sites; Fibrin; Fibrinolysin; Ligands; Lysine; Peptide Mapping; Peptides; Phosphoric Monoester Hydrolases; Protein Binding; alpha-2-Antiplasmin
PubMed: 2551057
DOI: 10.1016/0049-3848(89)90128-x -
Clinical Science (London, England :... Apr 1987Plasmin was recently reported to inhibit platelet aggregation. We report here on the interaction of plasmin with the adenylate cyclase system of human platelets. Human...
Plasmin was recently reported to inhibit platelet aggregation. We report here on the interaction of plasmin with the adenylate cyclase system of human platelets. Human plasmin caused a dose- and time-dependent increase in adenylate cyclase activity when added to a crude platelet membrane preparation. Both basal and prostaglandin E1-stimulated adenylate cyclase activity doubled in presence of plasmin. This stimulatory activity was shared by papain and alpha-chymotrypsin, but not by thrombin which displayed a slightly inhibitory effect. Plasmin not only stimulated platelet adenylate cyclase activity, but also suppressed the GTP-dependent alpha 2-adrenergic inhibition, thereby producing a five- to six-fold increased activity measured in the presence of adrenaline and GTP. These effects of plasmin on the adenylate cyclase system were suppressed by the addition of the protease inhibitor leupeptin, and of soybean trypsin inhibitor, indicating that proteolysis mediated these effects. We also examined the adenylate cyclase activity in membranes prepared from intact platelets incubated with increasing doses of plasmin. Incubation of platelets with plasmin concentrations as low as 0.25 mg/ml resulted in an irreversible increase in membrane adenylate cyclase activity and suppression of the adrenaline-mediated inhibition of enzyme activity. These results suggest that the proteolytic stimulating effect of plasmin on the platelet adenylate cyclase system may account for the inhibition of platelet aggregation.
Topics: Adenylyl Cyclases; Blood Platelets; Fibrinolysin; Guanosine Triphosphate; Humans; Peptide Hydrolases
PubMed: 2951052
DOI: 10.1042/cs0720467 -
Journal of Applied Microbiology Jun 1998The binding of plasmin to Streptococcus uberis strain 0140 J was optimal in the pH range 5.0-5.5. Plasmin binding decreased exponentially with increasing NaCl...
The binding of plasmin to Streptococcus uberis strain 0140 J was optimal in the pH range 5.0-5.5. Plasmin binding decreased exponentially with increasing NaCl concentration (0-0.8 mol l-1), reaching a minimum at NaCl concentrations exceeding 0.55 mol l-1. Neither K+, Mg2+ nor the metal chelator EDTA had any effect on the interaction. Plasmin binding was prevented, in a concentration-dependent manner, by the amino acids lysine, arginine and epsilon-aminocaproic acid. Bound plasmin was also eluted from the bacterial cell using the same amino acids. Bound plasmin was lost from the bacterium in a time- and temperature-dependent fashion, the rate of plasmin loss increased with increasing temperature over the range 4-55 degrees C, and the elution of plasmin from live and heat-killed bacteria was similar. Cell-bound plasmin was only partially inhibited by the physiological inhibitor alpha 2-antiplasmin whereas the serine protease inhibitor aprotinin, and the active site titrant p-nitrophenyl-p-guanidiniobenzoate, inhibited the activity of the cell-bound plasmin by more than 95%.
Topics: Aminocaproates; Animals; Arginine; Cattle; Dose-Response Relationship, Drug; Edetic Acid; Fibrinolysin; Hot Temperature; Hydrogen-Ion Concentration; Lysine; Magnesium; Osmolar Concentration; Potassium; Protease Inhibitors; Streptococcus; Temperature; Time Factors
PubMed: 9717296
DOI: 10.1046/j.1365-2672.1998.00452.x -
European Journal of Biochemistry May 1984This study deals with the effect of fibrin on the transformation of Glu-plasminogen to Glu-plasmin during fibrinolysis. It focuses particularly on changes in fibrin...
This study deals with the effect of fibrin on the transformation of Glu-plasminogen to Glu-plasmin during fibrinolysis. It focuses particularly on changes in fibrin effector function caused by plasmin-catalysed fibrin degradation. Conversion of 125I-labelled Glu-plasminogen to Glu-plasmin was catalysed by urokinase or tissue plasminogen activator, in the presence of different preparations of progressively degraded fibrin. Plasmin catalysis of Glu-plasminogen and the fibrin (derivative) effector was inhibited by aprotinin. The presence of intact fibrin enhanced the rate of Glu-plasmin formation catalysed by tissue plasminogen activator, but not by urokinase. The presence of initially plasmin-cleaved fibrin, however, increased the rates of Glu-plasmin formation with both activators, as compared to those found with intact fibrin. The rate enhancements induced by initial plasmin degradation of the fibrin effector were associated with an increase in its affinity to both Glu-plasminogen and tissue plasminogen activator, suggesting causal relationships. The weak binding of urokinase was unaffected by fibrin degradation, indicating that effector function was solely exerted on the Glu-plasminogen moiety of urokinase-activated systems. Further degradation of fibrin decreased the stimulating effect on Glu-plasmin formation. This decrease occurred at an earlier stage of degradation with tissue plasminogen activator than with urokinase, indicating that greater integrity of the fibrin effector is necessary for its optimal interaction with the tissue plasminogen activator than with Glu-plasminogen. Concentrations of tranexamic acid that saturate low-affinity lysine-binding sites nearly completely dissociated the binding of Glu-plasminogen to degraded fibrin, but not to intact fibrin. In analogy with the binding of lysine analogues to these sites, the conformation of Glu-plasminogen may be altered by binding to degraded fibrin, thus giving rise to the increased activation rate.
Topics: Catalysis; Electrophoresis, Polyacrylamide Gel; Feedback; Fibrin; Fibrinolysin; Fibrinolysis; Humans; In Vitro Techniques; Kinetics; Plasminogen Activators; Protein Binding; Thrombin; Tranexamic Acid
PubMed: 6233145
DOI: 10.1111/j.1432-1033.1984.tb08132.x -
Archives of Dermatological Research 1987Addition of human plasminogen to three different pemphigus plasma samples showed a synergistic effect on acantholysis in the skin organ culture model. Human plasmin...
Addition of human plasminogen to three different pemphigus plasma samples showed a synergistic effect on acantholysis in the skin organ culture model. Human plasmin itself, without addition of pemphigus plasma, induced typical acantholytic changes in the skin explants, causing different types of acantholysis in a dose- and time-dependent manner: in the presence of 3 CU plasmin per ml culture medium, focal suprabasilar acantholysis of pemphigus vulgaris type could be detected after 72 h incubation, whereas 15 CU/ml caused extended acantholysis of pemphigus foliaceus type in the upper epidermal layers after 24 h, and extended acantholysis of benign chronic pemphigus (Hailey-Hailey disease) type comprising all layers of the epidermis after 48 h incubation. Plasminogen activator levels (Mr 55,000 urokinase type) in tissue extracts of skin explants and in culture media were reduced after 24 and 48 h incubation with pemphigus IgG as compared to control experiments with normal human IgG; this probably resulted from urokinase inactivation by reaction with inhibitors. These results lend support to the hypothesis proposed by Hashimoto et al. in 1983 that the plasminogen activator-plasmin system could play an essential role in the protease mechanisms of pemphigus acantholysis.
Topics: Acantholysis; Fibrinolysin; Humans; Organ Culture Techniques; Pemphigus; Plasminogen; Plasminogen Activators; Skin; Skin Diseases
PubMed: 2957965
DOI: 10.1007/BF00431228 -
Biophysical Journal Mar 2024We modify a three-dimensional multiscale model of fibrinolysis to study the effect of plasmin-mediated degradation of fibrin on tissue plasminogen activator (tPA)...
We modify a three-dimensional multiscale model of fibrinolysis to study the effect of plasmin-mediated degradation of fibrin on tissue plasminogen activator (tPA) diffusion and fibrinolysis. We propose that tPA is released from a fibrin fiber by simple kinetic unbinding, as well as by "forced unbinding," which occurs when plasmin degrades fibrin to which tPA is bound. We show that, if tPA is bound to a small-enough piece of fibrin that it can diffuse into the clot, then plasmin can increase the effective diffusion of tPA. If tPA is bound to larger fibrin degradation products (FDPs) that can only diffuse along the clot, then plasmin can decrease the effective diffusion of tPA. We find that lysis rates are fastest when tPA is bound to fibrin that can diffuse into the clot, and slowest when tPA is bound to FDPs that can only diffuse along the clot. Laboratory experiments confirm that FDPs can diffuse into a clot, and they support the model hypothesis that forced unbinding of tPA results in a mix of FDPs, such that tPA bound to FDPs can diffuse both into and along the clot. Regardless of how tPA is released from a fiber, a tPA mutant with a smaller dissociation constant results in slower lysis (because tPA binds strongly to fibrin), and a tPA mutant with a larger dissociation constant results in faster lysis.
Topics: Fibrinolysis; Fibrinolysin; Tissue Plasminogen Activator; Fibrin; Kinetics; Plasminogen
PubMed: 38356261
DOI: 10.1016/j.bpj.2024.02.002