Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of major parameters of fibrinolysis were measured in 50 normal human fetuses between 19 and 39 weeks of gestation and compared to those of 50 healthy normal pregnant women and 30 adult controls. In fetuses, euglobulin clot lysis time (ECLT) was significantly shortened, plasminogen level was low and histidine-rich glycoprotein undetectable. While t-PA and u-PA levels were slightly lower than in adult controls, a significant decrease in PAI activity was demonstrated and no PAI-2 could be detected in fetal plasma. In contrast with these findings, the fibrinolytic equilibrium of pregnant women exhibited a prolonged ECLT and a strong increase in both PAI activity and PAI-2 antigen levels, while only a moderate elevation in u-PA and t-PA levels was measured.
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PMID:Comparative study of the fibrinolytic system in human fetuses and in pregnant women. 202 51

Plasmin and kallikrein but not thrombin cleave purified histidine-rich glycoprotein (HRG), and heparin binding inhibits the proteolysis of HRG. To assess the proteolysis of HRG in plasma, immunoaffinity chromatography was used to isolate HRG from human plasma samples and the extent of protein cleavage was determined after electrophoresis under reduced, denaturing conditions. In blood drawn into streptokinase or into urokinase, HRG (78 kDa) was degraded producing peptides ranging in apparent molecular weight from 67 to 9 kDa. In patients undergoing thrombolytic therapy almost no intact HRG remains after 30 minutes, but the levels of circulating HRG are unchanged, indicating that cleaved HRG is not quickly or extensively removed from the circulation.
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PMID:Proteolysis of histidine-rich glycoprotein in plasma and in patients undergoing thrombolytic therapy. 293 71

Thrombospondin (TSP) is a multifunctional platelet alpha-granule and extracellular matrix glycoprotein that binds specifically to plasminogen (Plg) via that protein's lysine-binding site and modulates activation by tissue activator (TPA). In this study we report that the plasminogen activators, TPA and urokinase, greatly influence the binding of Plg to TSP. Using an enzyme-linked immunosorbent assay and a TSP-Sepharose affinity bead-binding assay we have found that Plg-TSP complex formation was markedly enhanced (up to 5-fold) when catalytic concentrations of Plg activators were included in the reaction mixtures. The enhancement was dependent upon the generation of small amounts of active plasmin and was duplicated by pretreatment of the immobilized TSP with plasmin prior to addition of the Plg. The enhancement effect was associated with selective proteolysis of the immobilized TSP. Purified Lys-Plg (the plasmin modified form of native Glu-Plg) bound to TSP to a greater extent than Glu-Plg, and binding of both forms was augmented by Plg activators. The apparent KD values of complex formation were unchanged in the presence of Plg activators suggesting that the enhancement effect was due to the generation of additional binding sites. The increased amount of bound Plg was demonstrated to result in a similar increase in the amount of plasmin generated from the complexes by TPA. Plg activators did not influence binding of Plg to histidine-rich glycoprotein or of histidine-rich glycoprotein to TSP, demonstrating specificity. In addition when TSP was treated with other proteases (human thrombin or human leukocyte elastase) no augmentation of Plg binding was seen. Thus, the initial production of small amounts of plasmin from Plg immobilized on TSP in fibrin-free microenvironments could generate a positive feedback loop by enzymatically modifying both TSP and Plg, resulting in an increase in TSP-Plg complex formation leading to the localized production of substantially more plasmin.
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PMID:Tissue plasminogen activator and urokinase enhance the binding of plasminogen to thrombospondin. 294 36

Like a number of the components of the fibrinolytic and coagulation systems, plasminogen (plgn) is a multifunctional molecule. As a proenzyme, a number of its activities such as its binding to fibrin, histidine-rich glycoprotein (HRGP) and alpha 2-antiplasmin (AP) are expressed while its major enzymatic activity remains unexpressed. This latter activity has been used as a yardstick of plasminogen potency, despite the fact that no such activity resides in the native plasminogen molecule. Assay procedures usually involve the activation of the plasminogen to plasmin using an activator such as streptokinase (SK) or urokinase (UK) and a major problem involves the establishment of a properly-timed plasminogen-activator ratio to fully express the plasminogen as the active enzyme plasmin (Gaffney, P.J. et al. Activation of plasminogen as a feature of its assay. Haemostasis 1977, 6, 72-78). Substrates such as casein, fibrinogen and fibrin have been used to assess the plasmin activity developed while more recently the tripeptide chromogenic substrate S-2251 has been successfully used. These assays have been standardised using a reference preparation of the active enzyme, plasmin, and both a 1st and 2nd International Reference Preparation (IRP) have been established. These IRP's differed in that the fibrin binding kringle-structures were missing in the 1st IRP yielding differing fibrinolytic and chromogenic activities (Philo, R.D. and Gaffney, P.J. Plasmin potency estimates. Influence of substrate used in assay. Thrombosis and Haemostasis 1981, 45, 107-109). Activation procedures of plasminogen and subsequent assays of plasmin using a variety of substrates have been recently superseded by an assay which involves the formation of a plgn-SK complex which complex has an active site which hydrolyses the chromogenic substrate S-2251. This avoids the problems highlighted above involved in measuring plasminogen activity at the optimum stage during activation. While plasmin standards have been suitable for the standardisation of plasminogen when it is measured by activation-based procedures, a British Standard for glutamic acid-plasminogen has now been established in order to standardise the plgn-SK assay (Gaffney, P.J. and Curtis, A.D. The establishment of a standard for plasminogen (glu-type). Thrombosis and Haemostasis 1984, 51, 376-378). The calibration of this standard using the 2nd IRP for plasmin and the value of this standard in the measurement of plasminogen in plasma is discussed.
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PMID:Standardization of plasminogen assays. 328 Apr 25

Activation of human Glu-plasminogen, Lys-plasminogen and low-Mr plasminogen (lacking lysine-binding sites) by pro-urokinase (pro-UK), obtained from a human lung adenocarcinoma cell line (Calu-3, ATCC), obeys Michaelis-Menten kinetics. Activation occurs with a comparable affinity (Km 0.40-0.77 microM), while the catalytic rate constant (kcat) is comparable for Glu-plasminogen (0.0022s-1) and low-Mr plasminogen (0.0034 s-1), but is somewhat higher for Lys-plasminogen (0.0106 s-1). The rate of activation of plasminogen by pro-UK is not significantly influenced by the presence of 6-aminohexanoic acid, purified fragments LBS I or LBS II or histidine-rich glycoprotein, indicating that the high affinity of pro-UK for plasminogen is not mediated via the high-affinity lysine-binding site of plasminogen located in kringles 1-3 (LBS I) nor via the low-affinity lysine-binding site comprised within kringle 4 (LBS II). The site(s) in plasminogen involved in the high-affinity interaction with pro-UK thus appear to be located within the low-Mr plasminogen moiety.
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PMID:Characterization of the high-affinity interaction between human plasminogen and pro-urokinase. 392 92

Fibrinolytic factors were assessed during L-asparaginase administration, to study whether their changes may predispose to a haemorrhagic or thrombotic diathesis. The total level of alpha 2-antiplasmin declined, as well as the ratio of the plasminogen-binding form of alpha 2-antiplasmin to the non-plasminogen-binding form. After cessation of L-asparaginase administration, the ratio increased to 1.6 times that of the pretreatment value. These data indicate that the plasminogen-binding form of alpha 2-antiplasmin is the form primarily synthesized in vivo. L-Asparaginase therapy reduced plasma levels of plasminogen and histidine-rich glycoprotein ( HRG ) and influenced the equilibrium between HRG , plasminogen and HRG -plasminogen complex, with a more pronounced decrease of plasminogen (62% +/- 8) and HRG (76% +/- 11) in comparison to the free-plasminogen levels (51% +/- 6). alpha 2-Macroglobulin was only slightly influenced by L-asparaginase and may consequently play a more pronounced role in inhibition. This is suggested by moderate declines in functional tests of plasmin, urokinase and tissue activator inhibition by patients plasma, and by the ratio of inhibition of these enzymes over alpha 2-antiplasmin. Thus the bleeding tendency described during L-asparaginase therapy can be ascribed not only to a temporary deficiency of coagulation factors but also to temporary alpha 2-antiplasmin deficiency.
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PMID:The influence of L-asparaginase therapy on the fibrinolytic system. 620 49

It has been shown that physical exercise increases blood fibrinolytic potential, primarily by inducing a release of extrinsic plasminogen activator from the vessel wall. Synthetic estrogens have also been reported to influence fibrinolytic activity. The effect of exercise and the possible additional effect of oral contraceptive agents (OCA) on the fibronolytic system were studied in 20 competitive female rowers. Ten females used OCA (users), and 10 others did not (nonusers). All participants were subjected to standardized exhaustive exercise. Preexercise data revealed higher factor XII, total plasminogen, and free plasminogen levels together with a significantly lower C1-inactivator level in the group of users. No differences were observed in prekallikrein, high-molecular-weight kininogen, alpha 2-antiplasmin, alpha 2-macroglobulin, antithrombin III, and histidine-rich glycoprotein plasma levels. The factor XII-dependent fibrinolytic activator activity and the extrinsic (tissue-type) plasminogen activator were significantly higher; however, the urokinase-like fibrinolytic activator activity was significantly lower. These observations suggest a greater susceptibility to activation of the fibrinolytic pathways during OCA medication. Exercise resulted in a decrease of all factors under study but an increase in all fibrinolytic activities. No differences were observed between the two groups in the percentages of change that occurred with exercise.
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PMID:Effect of exercise and oral contraceptive agents on fibrinolytic potential in trained females. 672 68

The effect of orally-administered stanozolol, 5 mg b.d. on fibrinolysis, coagulation and on various haematological and biochemical parameters have been studied in 16 healthy adults, 8 males and 8 females. Statistically significant enhancement of extrinsic (tissue-type) plasminogen activator activity was detected in all subjects studied. This was associated with significant increases in plasma plasminogen and a concomitant reduction in histidine-rich glycoprotein. There were no changes in plasma urokinase activity. Changes in the coagulation system included significant reduction in plasma fibrinogen and elevation of protein C and antithrombin III. Changes in plasma lipids included significant reduction of HDL cholesterol associated with an increase in LDL triglycerides. No change occurred in total cholesterol. There were no major differences between the sexes, nor were there serious side effects. The effects of stanozolol on extrinsic (tissue-type) plasminogen activator activity, "free" plasminogen, protein C and antithrombin III, argue strongly in favour of its therapeutic potential.
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PMID:Stanozolol-induced changes in fibrinolysis and coagulation in healthy adults. 674 May 47

The plasminogen activator systems in the blood, the coagulation system, and the complement pathways are reviewed. The review describes the role of the vascular intima in activation of coagulation and fibrinolysis and the interrelations between the complement system and haemostatic mechanisms. Physiological activation of fibrinolysis may be triggered by and limited to fibrin because of a special affinity of plasminogen and plasminogen activators. The binding of plasminogen to fibrin is regulated by histidine-rich glycoprotein, and the primary physiological inhibitor of generated plasmin is alpha 2-antiplasmin and especially the plasminogen-binding form of this immediate plasmin inhibitor. Plasminogen activator inhibitors in the blood, that is, notably plasminogen activator inhibitor type 1 (PAI-1), bind circulating tissue-type plasminogen activator (t-PA). However, local fibrinolysis in vivo mediated by t-PA may be independent of complex formation between plasminogen activator inhibitors and t-PA in the fluid phase. Circulating plasminogen activator inhibitors might regulate fibrinolysis by increasing the clearance of t-PA from the blood. The urokinase-type and factor XII-dependent fibrinolytic proactivator system can be activated following t-PA-mediated generation of plasmin, and could thus serve as an amplification system of t-PA-induced fibrinolysis. It is claimed that the as yet uncharacterized proactivator is essential for optimal generation of plasminogen activator activity by the factor XII-dependent fibrinolytic system. The normal antithrombotic condition of the vascular intima probably results from lack of tissue factor activity and the presence of significant antithrombotic components comprising, among others, antithrombin III and the protein C-protein S system. A number of pathophysiologic stimuli, notably mediators of the acute phase response such as the cytokines interleukin-1 and tumour necrosis factor-alpha (cachectin), have the potential to induce the vascular endothelium to express procoagulant activity. Vascular endothelium promoting coagulant activity releases increased amounts of t-PA antigen and PAI-1 antigen into the circulation, and elevated levels in the blood of both may be regarded as a marker of a generalized procoagulant condition involving the vascular endothelium. In a prospective study in patients with unstable angina pectoris, patients in whom disease progresses and acute myocardial infarction develops, have increased amounts of t-PA antigen and PAI-1 antigen in the blood. This suggests that the procoagulant potential and atherosclerotic process of the vascular intima is more pronounced in the risk group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Fibrinolysis in patients with acute ischaemic heart disease. With particular reference to systemic effects of tissue-type plasminogen activator treatment on fibrinolysis, coagulation and complement pathways. 822 63

Plasminogen activity and antigen, euglobulin fibrinolytic activity, tissue-type plasminogen activator activity and antigen urokinase-type plasminogen activator antigen, plasminogen activator inhibitor-1 activity and antigen, plasminogen activator inhibitor-2 antigen, tissue-type plasminogen activator/plasminogen activator inhibitor complexes, alpha 2-antiplasmin, histidine-rich glycoprotein, and fibrinogen/fibrin degradation products were measured in blood samples taken from the umbilical vein of 100 healthy full-term newborns. Results were compared with a control group of 30 healthy adults. The overall fibrinolytic activity assessed on fibrin plates was significantly increased (P < 0.002). We also observed high tissue-type plasminogen activator activity levels (P < 0.001), whereas urokinase-type plasminogen activator antigen levels were lower than in adults. There was a significant reduction in plasminogen activity and antigen (P < 0.0001), plasminogen activator inhibitor-1 activity (P < 0.05), alpha 2-antiplasmin (P < 0.0001), and histidine-rich glycoprotein (P < 0.0001), whereas plasminogen activator inhibitor-2, tissue-type plasminogen activator/plasminogen activator inhibitor complexes and fibrinogen/fibrin degradation products did not differ between groups. We conclude that in the newborn there is increased fibrinolytic activity, mainly due to increased plasminogen activators and reduced fibrinolysis inhibition, without systemic fibrinolysis and fibrinogenolysis.
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PMID:Evaluation of the fibrinolytic system in full-term neonates. 856 78


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