Studies on fibrinolysis in urinary tract disease and its treatment with epsilon-amino-caproic acid.
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Amino Acids↗
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On the inhibiting effect of 6-amino caproic acid upon the fibrinolytic system during "spontaneous activation".
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Amino Acids↗
[CORRELATIONS BETWEEN CONSTITUTION AND ACTIVITY IN THE CASE OF FIBRINOLYSIS INHIBITORS].
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4-Aminobenzoic Acid↗
[The treatment of meningococcemia by preserving immune homeostasis].
A study is presented of the cellular-humoral immunity in patients with typical meningococcemia complicated by infectious-toxic shock. Obtained data evidence significant changes of the cellular-humoral immunity in meningococcemias, especially those accompanied by infectious-toxic shock along with traditional methods the authors propose immunoregulatory and pathogenetic treatment: human immunoglobulin, aminocaproic acid, sodium, ethamsilate or dicinon, thymalin or T-activin, dopamin, rifampycin. The dosage of these drugs should be individual. The indications and efficiency should be controlled immunologically.
Antibody Formation↗
Mechanism of enhanced kinin release from high molecular weight kininogen by plasma kallikrein after its exposure to plasmin.
When purified high molecular weight kininogen was incubated with streptokinase-activated plasmin and kallikrein, a larger amount of kinin was released than would have been predicted from the effect of either enzyme alone. To determine the mechanism of this enhancement, high molecular weight kininogen was digested sequentially with these enzymes, and the rates of kinin release and sites of cleavage were determined. Conversion of 133 kd native high molecular weight kininogen to two-chain 112 kd or 102 kd derivatives by plasmin more than doubled the rate of kinin release by kallikrein. Conversely, digestion of high molecular weight kininogen by kallikrein and then plasmin did not enhance the rate of kinin release. The kallikrein cleavage points that provided 112 kd and 102 kd two-chain high molecular weight kininogen were after residues 437 (Arg-Lys) and 389 (Arg-Ser), whereas those for plasmin were after 438 (Lys-His) and 389 (Arg-Ser). epsilon-Aminocaproic acid, which competes for lysine residues that are critical to the binding of plasminogen or plasmin to substrates, inhibited the digestion of high molecular weight kininogen by plasmin, which is consistent with the evidence that the 438-439 Lys-His was a primary site of plasmin attack on high molecular weight kininogen. Furthermore, this cleavage was observed when plasminogen activation was induced in normal and in prekallikrein or Hageman factor-deficient plasmas. We suggest that the generation of fibrinolytic activity in blood could result in enhanced kinin release by kallikrein in regions of inflammation as a result of the collaborative actions of plasmin and kallikrein on high molecular weight kininogen.
Amino Acids↗
Effect of fibrin matrix on growth of glomerular cells.
Rat glomerular cells were grown either in or on fibrin clots prepared from rat plasma to assess the effect of native fibrin on the growth of glomerular epithelial and mesangial cells. Progressive fibrinolysis was observed in glomerular explant cultures without epsilon-aminocaproic acid (EACA), an inhibitor of plasminogen activation. The lytic areas extended as the cell number of glomerular explant outgrowths increased. Glomerular cultures containing 0.5% EACA showed complete inhibition of fibrinolysis. Under this condition, the glomerular outgrowths developed only when the glomerular explants were seeded on the surface of fibrin matrix. While the explants were embedded in the fibrin matrix, few cells could grow out of explants. The more prosperous growth of glomerular epithelial cells in the lytic areas and the lack of intimate binding of glomerular epithelial cell membrane with fibrin fibers implied that fibrin might hinder the outgrowth of glomerular epithelial cells. The mesangial cells, whether growing on the surface of or embedded in the fibrin matrix, showed no fibrinolytic activity. Inhibition of fibrinolysis did not alter the growth pattern of mesangial cells. In addition, mesangial cells exhibited extensive binding of fibrin fibers on their cell surface and developed conspicuous arborization of their cell processes. These features suggested a close affinity between mesangial cells and fibrin matrix. These experiments have addressed our attention to the particular roles of the visceral epithelial cells and mesangial cells in the pathogenesis of fibrin-related glomerulonephritis.
Animals↗
[The use of protease inhibitors in the treatment of burn wounds].
The results of experimental and clinical studies of the effect of contrykal and aminocaproic acid on tissue regeneration in deep burns are presented. In the experiment, by means of planimetric, histologic, histochemical and biochemical methods of investigation, the positive effect of inhibitors on healing of the burn wounds is shown. In treatment of 272 patients with deep burns, it was established that use of protease inhibitors at the phase of regeneration contributed to 2-fold acceleration of marginal epithelization, shortening of time of would preparation to autodermoplasty by 3-4 days, increase in effectiveness of survival of the cutaneous flaps. A possibility of wide clinical use of proteolysis inhibitors predominantly in combination with antibiotics is shown.
Animals↗
Identification of the rat Heymann nephritis autoantigen (GP330) as a receptor site for plasminogen.
Previous results have demonstrated the binding of a 76- and 80-kDa serum protein to the Heymann nephritis autoantigen, gp330. This 76-kDa serum protein was purified by column chromatography and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A rabbit polyclonal antibody for the serum protein was produced and used to screen a rat liver cDNA expression library. Sequence analysis of an isolated clone identified the serum protein as plasminogen. Plasminogen was isolated from rat serum by standard techniques, and the binding of plasminogen to gp330 was confirmed by Western analysis. Enzyme-linked immunosorbent assay results demonstrated a time-dependent, saturable, and specifically inhibitable binding of plasminogen to gp330. There was no significant difference in the binding of the two carbohydrate forms of plasminogen to gp330. Plasminogen binding to gp330 could be completely inhibited by the addition of exogenous gp330. This binding could also be partially inhibited by benzamidine but only slightly by the lysine analogue, epsilon-aminocaproic acid. However, even a combination of these two inhibitors could not completely block the binding of plasminogen to gp330 indicating that gp330 may be binding to plasminogen through some other unknown interactions. These results demonstrate that gp330 is a receptor site for plasminogen.
Amino Acid Sequence↗
The endothelial cell tissue plasminogen activator receptor. Specific interaction with plasminogen.
Human endothelial cells (EC) assemble plasmin-generating proteins on their surface. We have previously identified an EC membrane protein (Mr approximately 40,000) which specifically binds tissue plasminogen activator (t-PA) but not urokinase (Hajjar, K.A., and Hamel, N. M. (1990) J. Biol. Chem. 265, 2908-2916). In the present study, t-PA receptor protein (t-PA-R) was purified to apparent homogeneity from a detergent extract of human placental tissue by diisopropyl fluorophosphate-t-PA affinity chromatography and preparative gel electrophoresis. In a solid phase binding assay wells coated with t-PA-R bound both 125I-t-PA and 125I-Lys-plasminogen (PLG), but not 125I-urokinase in a specific, reversible, and noncompetitive fashion. Binding of 125I-Lys-PLG, but not 125I-t-PA, to t-PA-R was 80% inhibited by a 20-100-fold molar excess of the PLG-like lipoprotein(a), or by the lysine analog, epsilon-aminocaproic acid (50 mM). A polyclonal anti-t-PA-R antibody inhibited 66 and 79% of the specific 125I-t-PA and 125I-Lys-PLG binding, respectively, to EC monolayers. Biosynthetically labeled 40-kDa protein coprecipitated with t-PA- or Lys-PLG-Sepharose beads, but not with unconjugated Sepharose. In a functional assay, t-PA associated with immobilized t-PA-R generated 6.4 times more plasmin than an equivalent amount of t-PA in the fluid phase. These results suggest that t-PA-R can bind both t-PA and Lys-PLG in a manner that mimics the EC surface. This protein may play a role in modulating plasmin generation on cell surfaces.
Binding, Competitive↗
Enhancement of tissue plasminogen activator-catalyzed plasminogen activation by Escherichia coli S fimbriae associated with neonatal septicaemia and meningitis.
The effect of Escherichia coli strains isolated from blood and cerebrospinal fluid of septic infants on plasminogen activation was studied. These strains typically carry a filamentous surface protein, S fimbria, that has formerly been shown to bind to endothelial cells and interact with plasminogen. The bacteria effectively promoted plasminogen activation by tissue plasminogen activator (t-PA) which was inhibited by epsilon-aminocaproic acid. A recombinant strain expressing S fimbriae accelerated t-PA-catalyzed plasminogen activation to a similar extent as did the wild-type strains whereas the nonfimbriate recipient strain had no effect. After incubation with t-PA and plasminogen, the S-fimbriate strain displayed bacterium-bound plasmin activity whereas the nonfimbriate strain did not. Bacterium-associated plasmin generation was also observed with a strain expressing mutagenized S fimbriae that lack the cell-binding subunit SfaS but not with a strain lacking the major subunit SfaA. Both t-PA and plasminogen bound to purified S fimbriae in a lysine-dependent manner and purified S fimbriae accelerated t-PA-catalyzed plasminogen activation. The results indicate that E. coli S fimbriae form a complex with t-PA and plasminogen which enhances the rate of plasminogen activation and generates bacterium-bound plasmin. This may promote bacterial invasion and persistence in tissues and contribute to the systemic activation of fibrinolysis in septicaemia.
Amino Acid Sequence↗
Mechanism of action and some properties of a tissue activator of plasminogen.
Improvements in preparations of tissue activator and plasminogen and termination of activation by epsilon aminocaproic acid have permitted the use of a quantitative caseinolytic assay for the measurement of the plasmin formed. The following data indicate that the activation of plasminogen by tissue activator is catalytic: a) Biphasic curve obtained when velocity was plotted against plasminogen concentration. b) First order kinetics. c) Dependence of the turnover number on tissue activator concentration. The temperature and pH stability of tissue activator were similar to those reported for urokinase. Since both of these enzymes have now been shown to activate plasminogen by a catalytic mechanism, these data support the suggestion that urokinase may be an excretory form of tissue activator which has been released into the circulation.
Animals↗
Haemostasis in oral surgery--the possible pathogenetic implications of oral fibrinolysis on bleeding. Experimental and clinical studies of the haemostatic balance in the oral cavity, with particular reference to patients with acquired and congenital defects of the coagulation system.
Activation and inhibition of the haemostatic system was reviewed including the interaction between the four biological systems involved in haemostasis: the vessel wall, the platelets, the coagulation system and the fibrinolytic system. The haemostatic mechanism is initiated at the site of injury through local activation of surfaces and release of tissue thromboplastin, resulting in formation and deposition of fibrin. The coagulation process is regulated by physiological anticoagulants. Activation of fibrinolysis is triggered by the presence of fibrin, and the role of tissue-type plasminogen activators (t-PA) at the site of fibrin formation in particular is emphasized. The process is regulated by physiological inhibitors, of which alpha 2-antiplasmin, histidine-rich glycoprotein and plasminogen activator inhibitor are reported to be of major physiological significance. The role of fibrinolysis in the regulation of the dynamic haemostatic balance is discussed, elucidated through examples of congenital deficiencies of the coagulation and the fibrinoytic system. Pharmacological inhibitors of fibrinolysis (i.e. epsilon-aminocaproic acid and tranexamic acid) and their possible effect on the haemostatic system are described. The systemic effects on the fibrinolytic system of surgery and oral surgery is reviewed, and it is concluded, that oral surgery has insignificant effects on blood fibrinolysis. In contrast, oral surgery induces changes of fibrinolysis in the oral environment; initially the fibrinolytic activity of saliva is reduced, due to the presence of inhibitors of fibrinolysis originating from the blood and the wound exudate. When bleeding and exudation cease, the fibrinolytic activity of the saliva will increase. Plasminogen and plasminogen activator, identified as t-PA are present in the oral environment under physiological conditions. Plasminogen is secreted in the saliva and the sources of t-PA include oral epithelial cells and gingival crevicular fluid. The presence of plasminogen and t-PA in the oral environment implies that when fibrin is present (i.e. after surgery), fibrinolysis is triggered. Haemorrhagic complications to oral surgery in patients without known defects of the coagulation system is reviewed. It is concluded that the investigations conducted to the present day do not permit final conclusions with respect to the pathophysiological role of defects in the coagulation and the fibrinolytic systems for the development of bleeding after oral surgery. Further investigations are necessary in order to clarify these aspects, and should include extensive laboratory analyses to reveal rare congenital defects such as factor XIII- and alpha 2-antiplasmin deficiencies.(ABSTRACT TRUNCATED AT 400 WORDS)
Anticoagulants↗
Relationship between gender difference in intravascular aggregation of platelets and the fibrinolytic pathway in the rat.
Intravascular aggregation of platelets was evaluated in relation to the fibrinolytic system in order to assess the possibility of a "cause-effect" relationship. The spontaneous fibrinolytic activities of the plasma of male rats and of female rats at the various stages of the oestrous cycle were determined. Male rats had higher euglobulin clot lysis time (54.5 +/- 5.3 vs 29.2 +/- 3.1 min; P less than 0.05), higher fibrinogen levels (330.0 +/- 15.8 vs 231.0 +/- 31.1 mg/dl; P less than 0.025) and higher plasminogen activity (8.1 +/- 1.2 vs 6.1 +/- 1.6 plasmin units/ml; P less than 0.05) than female rats. Female rats had higher fibrinolytic index (8.8 +/- 0.8 vs 6.3 +/- 0.3 mg/dl; P less than 0.05) and plasminogen activator activity (99.1 +/- 6.0 vs 76.5 +/- 7.7 Plough units/ml; P less than 0.05) than male rats. The antiplasmin activities were the same in both sexes. During the oestrous cycle in female rats, euglobulin clot lysis time was not significantly different though it was highest during met-oestrous (34.2 +/- 3.6 min). However, pro-oestrous rats had lower fibrinogen (122.9 +/- 5.3 mg/dl; P less than 0.005), higher fibrinolytic index (10.6 +/- 0.8 mg/dl/min; P less than 0.001) and higher plasminogen activator activity (109.4 +/- 7.8 Plough units/ml; P less than 0.05) than rats from the other stages of the oestrous cycle. There were no significant differences in plasminogen content and antiplasmin activity. Using native rats, aggregatory responses to submaximal doses of adenosine diphosphate (20 micrograms/kg) were determined and correlated with the fibrinolytic data in age- and weight-matched rats (of both sexes). Aggregatory responses in all the groups of rats used correlated positively with fibrinogen levels (r = 0.8316; P less than 0.001) and negatively with plasminogen activator activity (r = -0.7839; P less than 0.05). Streptokinase (250-1000 Plough units/kg/hr) and urokinase (1000-4000 Plough units/kg/hr) produced dose-related reductions in intravascular aggregation induced by adenosine diphosphate. The streptokinase effect (but not urokinase effect) was reversed by epsilon-aminocaproic acid. Following the cessation of infusion of streptokinase and urokinase, there was a recovery of the platelets to aggregate to adenosine diphosphate. These observations suggest fibrinolytic pathway-specific effects. However, on its own, epsilon-amino-caproic acid did not affect the aggregatory responses of platelets from pro-oestrous rats. These results suggest that changes in fibrinolytic mechanisms may account for differences observed in intravascular aggregation of platelets of male and female rats and of female rats during the oestrous cycle.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Role of active center and lysine binding sites of plasmin in plasmin-induced platelet activation and disaggregation.
Previous studies have shown that plasmin can activate platelets and can also disperse platelet aggregates by degradation of fibrinogen bound to platelets. In this study, the role of the active center and the lysine binding sites (LBS) of human plasmin in activating platelets and in dispersing platelet aggregates is investigated using aprotinin and the tripeptide Val-Phe-Lys-CH2Cl to inhibit the active center and using epsilon-aminocaproic acid (EACA) to specifically block the LBS. Our results show that the catalytic activity of plasmin is indispensable both for activating platelets and for dispersing platelet aggregates. Binding of plasmin to platelets through the LBS enhances its activating potential, since both EACA (1 mM) and Lys-plasminogen (molar ratio of plasminogen:plasmin at 2:1 to 4:1) inhibit plasmin-induced platelet activation, whereas Glu-plasminogen at a molar ratio of 15:1 had no effect. Furthermore, plasmin which lacks the LBS (miniplasmin), is about 3 fold less effective in activating platelets. However, plasmin binding through the LBS is not absolutely required to disperse platelet aggregates, since EACA at 30 mmol/l was unable to prevent disaggregation by plasmin (half disaggregation time: 40 min in the presence of EACA against 27 min in its absence). It also appeared that fibrinogen receptors on activated platelets are resistant to plasmin degradation, and that disaggregation of plasmin-induced platelet aggregates was much slower than the degradation of fibrinogen by plasmin.
Amino Acid Sequence↗
Actin is a noncompetitive plasmin inhibitor.
Actin, one of the most abundant cellular proteins, circulates at micromolar concentrations in peripheral blood. Because actin released from dying cells may be trapped in fibrin clots that form at sites of tissue injury, we examined the effects of actin upon lysis of fibrin clots in vitro. Incorporation of native rabbit skeletal muscle actin into fibrin clots slowed their rates of lysis for periods of up to 24 h, an effect not seen when comparable concentrations of human IgG or bovine serum albumin were added instead. Actins isolated from a variety of sources inhibited plasmin's hydrolysis of the synthetic substrate S-2251 in a noncompetitive manner, with a Ki of a 0.6-3.1 microM. Inhibition was rapid, but covalent actin-plasmin complexes were not formed. Both epsilon-aminocaproic acid and tranexamic acid prevented actin's inhibition of plasmin, suggesting that accessible lysine residues of actin interact with the kringle (lysine-binding) regions of plasmin. Neither of the high-affinity actin-binding proteins of plasma (plasma gelsolin and vitamin D-binding protein) prevented actin from inhibiting plasmin. These findings suggest that actin released into the extracellular space following cell death may modulate plasmin action, and hence a number of plasmin-dependent biological responses, at sites of inflammation and tissue injury.
Actins↗
Interactions of plasminogen and tissue plasminogen activator (t-PA) with amphoterin. Enhancement of t-PA-catalyzed plasminogen activation by amphoterin.
The heparin-binding p30 protein amphoterin is proposed to mediate adhesive interactions of the advancing plasma membrane in migrating and differentiating cells. Since the NH2-terminal part of amphoterin is exceptionally rich in lysine residues, we have studied its interactions with plasminogen and tissue plasminogen activator (t-PA). On immunostaining of N18 neuroblastoma cells, amphoterin and t-PA showed a close co-localization in the filopodia of the leading membrane and in the substrate-attached material. In purified systems, both t-PA and plasminogen bound to immobilized amphoterin, and their binding was inhibited by the lysine analogue epsilon-aminocaproic acid. Plasminogen bound to immobilized amphoterin was activated by t-PA, and this resulted in effective degradation of the immobilized amphoterin. Correspondingly, amphoterin-bound t-PA activated plasminogen. In solution amphoterin accelerated t-PA-catalyzed plasminogen activation maximally 46-fold. The results indicate that t-PA and plasminogen form through their lysine-binding sites a complex with amphoterin, which results in acceleration of plasminogen activation and effective degradation of amphoterin. We suggest that local acceleration of t-PA-catalyzed plasminogen activation by amphoterin at the leading membrane enhances the penetration of growing cytoplasmic processes through extracellular materials during cell migration, differentiation and regeneration. The amphoterin-mediated adhesion at the leading membrane may be transient in nature, because the protein also enhances its own breakdown by accelerating t-PA-catalyzed plasminogen activation.
Binding Sites↗
Isolation, molecular cloning, and partial characterization of a novel carboxypeptidase B from human plasma.
A novel plasminogen-binding protein has been isolated from human plasma utilizing plasminogen-Sepharose affinity chromatography. This protein copurified with alpha 2 antiplasmin when the plasminogen affinity column was eluted with high concentrations of epsilon-aminocaproic acid (greater than 20 mM). Analysis by sodium dodecyl sulfate suggests this protein has an apparent Mr of 60,000. The amino-terminal amino acid sequence showed no similarity to other protein sequences. Based on the amino-terminal amino acid sequence, oligonucleotide probes were designed for polymerase chain reaction primers, and an approximately 1,800 base pair cDNA was isolated that encodes this Mr 60,000 protein. The deduced amino acid sequence reveals a primary translation product of 423 amino acids that is very similar to carboxypeptidase A and B and consists of a 22-amino acid signal peptide, a 92-amino acid activation peptide, and a 309-amino acid catalytic domain. This protein shows 44 and 40% similarity to rat procarboxypeptidase B and human mast cell procarboxypeptidase A, respectively. The residues critical for catalysis and zinc and substrate binding of carboxypeptidase A and B are conserved in the Mr 60,000 plasminogen-binding protein. The presence of aspartic acid at position 257 of the catalytic domain suggests that this protein is a basic carboxypeptidase. When activated by trypsin, it hydrolyzes carboxypeptidase B substrates, hippuryl-Arg and hippuryl-Lys, but not carboxypeptidase A substrates, and it is inhibited by the specific carboxypeptidase B inhibitor (DL-5-guanidinoethyl)mercaptosuccinic acid. We propose that the Mr 60,000 plasminogen-binding protein isolated here is a novel human plasma carboxypeptidase B and that it be designated pCPB.
Amino Acid Sequence↗
[A spectrophotometric method for determining the concentration of L-lysine using L-lysine-alpha-oxidase from Trichoderma sp. and 3,3',5,5'-tetramethylbenzidene dihydrochloride].
A simple and relatively sensitive procedure was developed for determination of L-lysine at 3-30 mmole/L concentration. The procedure does not involve the carcinogenic compound o-dianisidine. L-lysine alpha-oxidase catalyzed oxidative deamination of L-lysine with O2 consumption and formation of H2O2, NH3 and alpha-keto-epsilon-aminocaproic acid. Horseradish peroxidase and a non-carcinogenic compound 3,3,5,5'-tetramethylbenzidine dihydrochloride as an electron donor were used in determination of H2O2 formed. The procedure developed enabled also to measure the L-lysine alpha-oxidase activity at the enzyme concentrations of 10-500 ng/ml. The only limitation of the procedure is relatively low pH-values of the reaction medium.
Amino Acid Oxidoreductases↗