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

"Hemorrhage in the newborn" has long been recognized as merely a result of vitamin K deficiency. However, it is also recognized that fibrinolysis, especially the correlation between the plasminogen-activator and plasmin-inhibitors, play an important role in this disease during the neonatal period. With this in mind, we compared thromboelastograms (TEG) from samples with and without urokinase (plasminogen-activator). In 13 out of 15 newborn infant blood-samples (prior to and after addition of urokinase) the thromboelastogram showed the pattern of a consumption coagulopathy. The change in the concentration of plasmin-inhibitor during the neonatal period was also measured using alpha2-macroglobulin, alpha1-antitrypsin and antithrombin III with M-partigen-plates. The value of alpha2-macroglobulin showed normal adult levels but the value of alpha1-antitrypsin and antithrombin III did not even reach half of the adult level. During the newborn period, the plasmin-inhibitor shows a remarkable lowering tendency and it may be surmised that with such a lowering tendency plasmin-inhibitor may constitute an exceptionally large handicap when the activator is working. This is especially true in the case of lung hemorrhage since the activator arises from a severe pathological state in the lungs and in addition because this is complicated by the lowering of plasmin-inhibitor. These results indicate that the low level of plasmin-inhibitors work synergistically with the high value of activator. The low level of antithrombin III could be the reason for coagulation disorders such as disseminated intravascular coagulation, (DIC).
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PMID:New neonatal problems of blood coagulation and fibrinolysis. I. The change of plasmin inhibitor levels in the newborn infant. 6 4

Fresh plasma was seeded with trace amounts of highly purified biologically intact iodine-labelled plasminogen and the plasmin-inhibitor complexes formed after activation with streptokinase or urokinase separated by gel filtration. Two radioactive peaks were observed, the first one eluted in the void volume and the second one just before the 7-S globulin peak. In incompletely activated samples, the second peak was always predominant over the first one. Both components were purified with high yield by a combination of affinity chromatography on lysine-agarose and gel filtration, and investigated by dodecylsulphate-polyacrylamide gel electrophoresis and immunoelectrophoresis. Neither component reacted with antisera against alpha1-antitrypsin, antithrombin III, C1-esterase inhibitor, inter-alpha-trypsin inhibitor or alpha1-antichymotrypsin. The component of the first peak appeared to be a complex between plasmin and alpha2-macroglobulin which reacted with antisera against human plasminogen and against alpha2-macroglobulin. The component of the second peak had a molecular weight (Mr) of 120000-140000 by dodecyl-sulphate-polyacrylamide gel electrophoresis and lpon reduction displayed a doublet band with an Mr of 65000-70000 and a band with Mr 11000. It reacted with antisera against plasminogen and with antisera raised against this complex and absorbed with purified plasminogen. The latter antisera reacted with a single component in plasma which is different from the above-mentioned plasma protease inhibitors. Specific removal of this component from plasma by immuno-absorption resulted in disappearance of the fast-reacting antiplasmin activity whereas alpha2-macroglobulin was found to represent the slower-reacting plasmin-neutralizing activity. In the presence of normal plasma levels of these proteins, the specific removal or absence of alpha1-antitrypsin, antithrombin III or C1-esterase inhibitor did not alter the inactivation rate of plasmin when added to plasma in quimolar amounts to that of plasminogen. It is concluded that only two plasma proteins are important in the binding of plasmin generated by activation of the plasma plasminogen, namely a fast-reacting inhibitor which is different from the known plasma protease inhibitors and which we have provisionally named antiplasmin, and alpha2-macroglobulin, which reacts more slowly.
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PMID:Identification and some properties of a new fast-reacting plasmin inhibitor in human plasma. 13 45

Human antithrombin III was purified from fresh human plasma by affinity chromatography on heparin-Sepharose, affinity chromatography on concanavalin A Sepharose, gel filtration on Ultrogel AcA 34, ion exchange chromatography on DEAE A-50 Sephadex and preparative agarose gel electrophoresis. The hydrolytic activity of urokinase (plasminogen activator from urine) on acetyl-glycyl-L-lysine methylester acetate (Ac-gly-lys-OMeAc) was inhibited by antithrombin III in a slow time-dependent manner. Heparin accelerated the reaction between activator and inhibitor. Inhibition of catalytic activity was associated with the formation of an 1:1 molar complex between activator and inhibitor as revealed by sodium dodecyl sulphate polyacrylamide gel electrophoresis. The complex was also demonstrated by crossed immunoelectrophoresis against anti-antithrombin III.
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PMID:Inhibition of urokinase by complex formation with human antithrombin III in absence and presence of heparin. 70 90

1. We describe a patient who developed deep vein thrombosis after commencing treatment with the synthetic androgen, mesterolone (Pro-Viron). 2. To investigate the potential thrombogenic action of this drug, a 21 day course of mesterolone (100 mg/day) was given to nine healthy male volunteers. 3. No significant change after treatment occurred in any of the blood tests performed (clotting times, Factor VIII coagulant activity, Factor VIII related antigen, antithrombin III activity, fibrinogen, fibrinogen-fibrin degradation products, plasminogen, euglobulin lysis time, urokinase sensitivity, platelet count, haematocrit, whole blood viscosity and plasma viscosity). 4. We conclude that in a conventional dose taken for 3 weeks mesterolone does not produce a consistent measurable prothrombotic state, nor does it enhance fibrinolysis.
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PMID:Mesterolone: thrombosis during treatment, and a study of its prothrombotic effects. 76 Jul 33

Plasma contained two inhibitors of plasminogen activation by urokinase when fractioned by gel filtration on Sephadex G-200. The inhibitor in the lower molecular weight fractions was separate from the principal protease inhibitors of plasma: alpha1-antitrypsin, alpha2-macroglobulin, C1 inactivator and antithrombin III, and from factor XIII. This activation inhibitor was present in both plasma and serum and its recovery was not reduced by preincubating the serum for 6 h at 37 degrees C. Its inhibitory activity was stable for several days at 4 degrees C, and was enhanced in the presence of an increased saline concentration. Preparations of the inhibitor, active in a clot lysis system, failed to inhibit the esterase activity of urokinase on N-alpha-acetyl-glycyl-L-lysine methyl ester.
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PMID:Inhibitors of plasminogen activation in human blood. 125 23

20 patients (6 females, 14 males) aged between 47 and and 75 years (mean: 62.6 yrs.) with acute myocardial infarction (onset of symptoms within 6 hours) were treated intravenously with either 200,000 U urokinase (UK) and 4.5 million U pro-urokinase (pro-UK) within 60 min (group I, N = 10), or 2.5 million U UK within 5 min (group II, N = 10). Blood samples for haemostatic and fibrinolytic function tests were taken prior to and repeatedly during the 24 hours following treatment. Peak fibrinolytic activity measured by fibrin plates was equivalent in both regimens. Average decreases, with lowest levels within 60 to 120 min following thrombolytic therapy, were observed of 27% and 70% for plasminogen, of 71% and 91% for alpha-2-antiplasmin, and of 20% and 74% for fibrinogen in group I and II, respectively. The reptilase time reached maximum values of 1.5- and 4.5-fold within 60 to 180 min. Peak levels of D-dimers and thrombin-antithrombin III complexes in group II were 2.6 and 3.2 times those of group I. After 24 hours, in contrast to group I, all these parameters still remained significantly different from pretreatment values in group II. These data indicate that, contrary to high-dose UK, pro-UK in combination with low-dose UK causes minor systemic fibrinolytic effects and is, therefore, assumed to be largely clot-specific, although the fibrinolytic potential is equivalent for both regimens.
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PMID:Fibrinolytic effects of pro-urokinase combined with low-dose urokinase compared to high-dose urokinase in patients with acute myocardial infarction. 127 35

We have studied the expression of alpha-smooth muscle actin (alpha sm-1) by mesangial cells, and the expression of Thy-1 glycoprotein, antithrombin III (ATIII), and urokinase by tubular epithelial cells in normal kidneys and dysfunctional renal allografts. Kidney biopsies were studied immunocytochemically for changes in each of these markers and the findings were classified into two groups and compared with creatinine plasma levels at the time the biopsies were taken. In dysfunctional grafts, mesangial alpha sm-1 and tubular epithelial Thy-1 reactivities were greatly diminished, and urokinase and ATIII were missing from proximal renal tubular epithelial cells. Urokinase, which was absent from normal renal glomeruli, appeared in glomeruli of some dysfunctional allografts. The possible usefulness of these markers in patient evaluations was supported by our finding that the distribution of vinculin, fibronectin, myosin, actin B4, desmin, glomerular HLA-DR, and the tubular expression of CD15 remained unchanged. These data prompt us to suggest that the immunocytochemical localization and evaluation of alpha sm-1, Thy-1, ATIII, and urokinase in kidney allografts may be useful adjuncts in the assessment of function in renal allografts.
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PMID:Novel immunohistochemical markers of human renal allograft dysfunction--antithrombin III, Thy-1, urokinase, and alpha-smooth muscle actin. 136 Dec 52

Coronary thrombolysis reduces morbidity and mortality in patients with acute myocardial infarction, however, the exact effects of thrombolytic agents on the status of intrinsic hemostases are not fully understood. In the present study, we examined serial changes in plasma thrombin and protein C activities of 6 patients with acute myocardial infarction treated with urokinase. Fibrinolysis occurred immediately after urokinase injection with an increase in the plasma thrombin-antithrombin III complex, suggesting a subsequent procoagulant state due to thrombin generation. Correspondent increases in plasma protein C activity were observed, however, protein S levels did not change at all. Our findings suggest that urokinase administration for coronary thrombolysis not only causes fibrinolysis, but also induces thrombin activity, which may be antagonized by augmented intrinsic protein C activity.
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PMID:Augmented plasma protein C activity after coronary thrombolysis with urokinase in patients with acute myocardial infarction. 138 46

Oral contraceptives caused increased fibrinogen, FVII, FX, and fibrinolysis. The latter was associated with elevated FXII and PKK, while C1-INH was decreased, ATIII and alpha 2M were unchanged; it could not be accounted for by changes in t-PA, u-PA, PAI, plasminogen, alpha 2-AP, proteins C or S. HCII and alpha 1-PI were increased and may regulate the availability of thrombin and FXIa. The increased FXII/PKK dependent fibrinolytic potential and HCII may offset any increase in thrombin generation, while alpha 1-PI limits intrinsic coagulation.
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PMID:Procoagulant changes induced by oral contraceptives are balanced by an increased fibrinolytic tendency. 146 38

In this report, we investigated the expression and activation of proteolytic enzymes by mouse T-lymphoma cell lines of differing metastatic potential. In contrast to the low metastatic Eb line, the metastatic variants ESb and ESb-MP secreted urokinase-type plasminogen activator (u-PA), which was present in the culture supernatant predominantly in the active form (ESb, 96%; ESb-MP, 80%). All three T-lymphoma variants expressed a mainly cell surface-associated proteinase, which proved to be immunologically and enzymatically related to the murine T-cell-associated serine proteinase-1 (MTSP-1). Intact lymphoma cells were able to activate the recombinant human proenzyme of u-PA (pro-u-PA) by a plasmin-independent mechanism, because plasmin contamination of the cells was not detectable. When ESb-MP cells were cultured in the presence of inhibitors of MTSP-1, such as antithrombin III, Pro-Phe-Arg-chloromethylketone, or aprotinin, the ratio of endogenously activated murine u-PA to inactive pro-u-PA in conditioned medium was significantly reduced (from 80% to 15%). The most potent inhibitor, antithrombin, did not inhibit plasmin-catalyzed pro-u-PA activation. These results suggest a novel autocrine mechanism of plasmin-independent pro-u-PA activation for metastatic T lymphomas by the production of an MTSP-1-related proteinase. The ability to initiate the proteolytic cascade of plasminogen activation in the absence of plasmin might contribute to the metastatic behavior of these cells observed in vivo.
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PMID:A T-cell-related proteinase expressed by T-lymphoma cells activates their endogenous pro-urokinase. 156 36


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