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)

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 examined the changes in fibrinolysis after urokinase administration for 6 patients with acute myocardial infarction. Patients were treated with urokinase with doses between 960,000 and 1,440,000 units, and fibrinolytic activities were determined by using newly developed molecular markers: alpha 2-plasmin inhibitor (alpha 2-PI), plasminogen, alpha 2-PI plasmin complex (PIC) and FDP D dimer. We also used classical hemostatic tests such as prothrombin time (PT) and plasma fibrinogen level. These tests were measured with 1 to 2 hour intervals, during the first 6 hours of therapy, daily during the next 3 days, and subsequently on day 7 and 14. The initial intravenous administration of urokinase with a dose of 460,000 units produced a significant decrease in alpha 2-PI level, but induced only minimal changes in the level of fibrinogen, FDP-E, and FDP D-dimer, suggesting that enhancement of fibrinolytic activity was less pronounced under such therapy. This might be due to the ability of residual amounts of alpha 2-PI to sufficiently inhibit plasmin generation in the circulating blood. However, a subsequent injection of 960,000 units of urokinase into the coronary artery induced a profound reduction in the alpha 2-PI to an unmeasurable level, and resulted in a marked enhancement of fibrinolytic activity. The elevation of FDP-E and FDP D-dimer was accompanied with this decrease in alpha 2-PI and persisted for more than 6 hours after urokinase injection. Prolongation of PT due to decrease in fibrinogen level was also observed over 6 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Serial changes in hemostatic molecular markers after urokinase therapy of acute myocardial infarction]. 153 65

In a multicenter dose-finding study, the thrombolytic potency of urokinase preactivated pro-urokinase was evaluated. Sixty-two patients were randomly assigned to receive 250,000 U of urokinase plus either 4.5 mega U (group I: n = 33) or 6.5 mega U (group II: n = 29) of pro-urokinase. Patency rates were 36.4% (20.4-54.9%) vs. 54.5% (36.3-71.9%) (n = 27) at 60 minutes and 55.6% (32.5-70.6%) vs. 62.1% (42.3-79.3%) at 90 min into thrombolysis (n.s.). In a third group of 12 patients treated with 500,000 U of urokinase plus 6.5 mega U of pro-urokinase patency was achieved in 33.3% (9.9-65.1%) and 41.7% (15.2-72.3%) at 60 and 90 min, respectively. Patency rates at 24 hr follow-up angiography (n = 35) were 78.6% (49.2-95.3%), 85.7% (57.2-98.2%), and 85.7% (42.1-99.6%). Coagulation analysis in 37 patients revealed similar alterations in the three treatment groups with minor decreases in fibrinogen levels, moderate drops in plasminogen and alpha-2-antiplasmin levels, and moderate increases in the concentrations of the total fibrinogen/fibrin degradation products, the differences between the groups not being significant. Bleeding complications were observed in 12.9%, 13.8%, and 25% of patients in groups I, II, and III, respectively, mainly related to catheter sites. Hence, the safety profile of urokinase preactivated pro-urokinase seems comparable to other thrombolytic regimens. Reopening of occluded coronary arteries, however, is achieved relatively slowly. Thus, in its use for thrombolysis in myocardial infarction, urokinase preactivated pro-urokinase does not seem to offer superior advantages.
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PMID:Multicenter dose-finding trial for thrombolysis with urokinase preactivated pro-urokinase (TCL 598) in acute myocardial infarction. German Preactivated Pro-Urokinase Study Group. 161 8

Fibrin deposition is a prominent finding in the synovium of patients with rheumatoid arthritis (RA). Macrophages are found in increased numbers in RA synovium, and these cells are known to produce a variety of procoagulant and anticoagulant molecules. Using immunohistologic techniques, the content and distribution of several important components of the coagulation system in the synovium of patients with RA, osteoarthritis (OA), or traumatic joint abnormalities requiring surgery were investigated. Samples from 3 patients from each category were examined in detail. RA synovium (compared with that of patients with OA or joint trauma) had increased numbers of macrophages and increased expression/content of fibrinogen, tissue factor, factor XIII, tissue transglutaminase, cross-linked fibrin (fibrin D dimer), urokinase-type plasminogen activator, and alpha 2-plasmin inhibitor. Macrophage content in RA synovium was increased in both the lining cell areas and the interstitial cell areas. Fibrinogen was distributed throughout the tissue in all samples and was greater in RA synovium. In trauma and OA synovia, tissue factor was seen only in association with vessels (endothelial cells), but in RA synovium, it was markedly increased throughout the tissues. While fibrin D dimer was seen in small amounts in synovial lining cell areas of trauma and OA synovia, it was present in increased amounts in the lining cell and interstitial cell areas of RA synovium. Factor XIII and tissue transglutaminase were present in scant amounts in trauma and OA synovia, but there were increased amounts of both (especially tissue transglutaminase) in RA synovium in the vessel, lining cell, and interstitial cell areas. Urokinase and alpha 2-plasmin inhibitor were also markedly increased in RA synovium. These results suggest that in inflamed synovium, there is ongoing extravascular tissue fibrin formation and dissolution that correlates with the degree of inflammation and macrophage content. Extravascular coagulation/fibrinolysis in RA represents a potential target for therapeutic intervention in this disease.
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PMID:Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis. 167 74

A functional assay for equine plasminogen was established, using urokinase as the activator, a synthetic chromogenic substrate, a computer-assisted centrifugal analyzer, and acidified/neutralized plasma. One documented effect of plasma acidification appears to be inactivation of alpha-2-antiplasmin. Intra- and interassay precision testing yielded coefficients of variation of 4.1% (n = 10) and 5.6% (n = 26), respectively. Plasminogen was stable in equine plasma stored up to 1 week at 4 C and up to 5 months at -70 C. Plasminogen in nonacidified equine plasma was not activated by urokinase, streptokinase, tissue plasminogen activator, or tissue plasminogen activator plus soluble fibrin. Streptokinase also failed to activate plasminogen in acidified/neutralized equine plasma.
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PMID:Chromogenic assay for equine plasminogen. 169 46

All the thrombolytic agents currently in clinical use act as plasminogen activators. In this study evidence is presented that also oxidants of the phagocyte type are of fibrinolytic efficiency in vivo. Activated phagocytes participate in physiologic fibrinolysis. The cells generate plasminogen activators and reactive oxidants of the nitrogen-chlorine type. Experimental mimicry of this oxidative inflammatory response induces selective thrombolysis in a rabbit jugular vein model. Intravenous bolus administration of sub-millimolar blood concentrations of chloramine-T resulted in thrombolysis after about 30 min without notable systemic toxicity; the coagulation parameters activated partial thromboplastin time (aPTT), thrombin time, fibrinogen, and alpha-2-antiplasmin were not influenced. Control experiments with 2000 IU of urokinase/kg induced thrombolysis after about 90 min with systemic changes of the hemostatic system. The fibrinolysis promoting effect of the oxidants of the phagocyte type could be inhibited by quenchers of singlet molecular oxygen and was not affected at all by inhibitors of oxygen radicals. The data gives evidence that nonradical excited oxygen species (NEOS) act as powerful pro-fibrinolytic and anti-coagulant agents in vivo. It might be suggested that NEOS could represent a novel class of regulators of the fibrinolytic system. The long lived and hydrophilic chloramine derivatives can either accumulate or diffuse far from their site of generation. Therefore, on the one hand oxidants in high (local) concentrations might be considered as direct pro-fibrinolytic agents due to their powerful protein modulating efficacy. On the other hand, oxidants at low concentrations may act as indirect pro-fibrinolytic compounds, i.e. as chemoattractants to concentrate phagocytes to the site of a thrombus. In this case the oxidants would play the role of signal elements faraway from the thrombus, a self amplifying mechanism possibly mediated by oxidation of blood arachidonat/lipid metabolites.
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PMID:Nonradical excited oxygen species induce selective thrombolysis in vivo. 171 80

We studied the quantitative changes of hemostatic molecular markers with time during the course of disseminated intravascular coagulation (DIC) induced by endoscopic embolization using thrombin for esophageal varices in nine patients with liver cirrhosis. The plasma levels of D-dimer, a product of plasmin degradation of cross-linked fibrin, and thrombin-antithrombin-III complex (TAT) were significantly higher in patients before treatment when compared with 60 healthy individuals. The plasma levels of TAT, D-dimer, and plasmin alpha 2-plasmin inhibitor complex (PIC) increased significantly 5-15 min after thrombin injection into the varices, earlier than the changes of conventional coagulofibrinolytic factors, reached a maximum level after 180 min, and started to decline after 1 day. Although the plasma PIC level returned to normal after 7 days, both TAT and D-dimer were still above the pretreatment level. Although there was no change in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) increased significantly after 5 min. The plasma level of plasminogen activator inhibitor type 1 (PAI-1) showed only a slight elevation after treatment. We propose that the hemostatic molecular markers TAT, D-dimer, and PIC are suitable for the early diagnosis of DIC after endoscopic embolization using thrombin in patients with liver cirrhosis and that the increase of PAI-1 is too small for the regulation of fibrinolysis due to t-PA in DIC occurring in liver cirrhosis.
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PMID:Significance of hemostatic molecular markers during disseminated intravascular coagulation in patients with liver cirrhosis treated by endoscopic embolization for esophageal varices. 171 8

The effect of simultaneous infusions of low-dose recombinant tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, pro-urokinase) on coronary arterial thrombolysis was investigated in 23 patients treated within 6 hours (mean 2.6 +/- 1.1, range 1.2 to 5.9) of symptoms of an acute myocardial infarction. Infarct artery patency at 90 minutes was achieved in 16 (70%, 95% confidence limits of 0.47 to 0.87) of 23 patients after a 1-hour intravenous infusion of 20 and 16.3 mg of t-PA and scu-PA, respectively. At 90 minutes, the fibrinogen concentration decreased from 369 +/- 207 to 316 +/- 192 mg/dl (p = not significant), while plasminogen decreased to 69 +/- 24% (p = 0.001) and alpha-2-antiplasmin to 77 +/- 24% (p = 0.001) of pretreatment values. Although no bleeding requiring termination of drug infusion or transfusion occurred, 1 patient with cerebrovascular amyloidosis had a fatal intracerebral hemorrhage. These findings suggest that combination therapy may allow substantial reductions in total thrombolytic doses while still achieving effective fibrin-specific coronary thrombolysis.
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PMID:Clot-selective coronary thrombolysis with low-dose synergistic combinations of single-chain urokinase-type plasminogen activator and recombinant tissue-type plasminogen activator. The Pro-Urokinase for Myocardial Infarction Study Group. 174 55

In order to evaluate precisely the fibrinolytic states in clinical disorders, plasma levels of D dimer (cross-linked fibrin degradation products) were measured by a newly developed, rapid quantitative method based on the latex photometric immunoassay in patients with hematological malignancies, diabetes mellitus, collagen disease, liver disease, thrombotic disease and disseminated intravascular coagulation (DIC). Plasma levels of D dimer were elevated in a variety of diseases, especially in DIC. Patients with hematological malignancies, liver disease and thrombotic disease also had relatively high levels of D dimer. On the whole, D dimer values were positively correlated with plasmin-alpha 2-plasmin inhibitor complex and thrombin-antithrombin III complex. In addition, plasma D dimer was measured during fibrinolytic therapy with urokinase or tissue-type plasminogen activator; its elevation was detected in some patients. These findings indicate that accelerated fibrinolysis is frequently observed in a variety of diseases, and that a rapid quantitative measurement of D dimer would be valuable for the precise assessment of fibrinolysis in these disease states.
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PMID:[Evaluation of clinical usefulness of a rapid quantitative measurement of D dimer (cross-linked fibrin degradation products)]. 177 52

Single chain- urokinase (scu-PA) is the proenzyme of the plasminogen activator urokinase (tcu-PA). In human blood scu-PA is of great stability. Activated phagocytes generate large amounts of single chain- urokinase and of reactive oxidants (chloramines and HOCl). Since these cells participate in physiologic fibrinolysis, we were interested in the interaction between plasmatic scu-PA and chloramines. The oxidants dose dependently induce the activation of plasmatic scu-PA. Optimal activation of scu-PA occurs at about 3-5 mmol/l of chloramine-T. The findings suggest a control mechanism of scu-PA stability/activity by oxidatively modifiable plasma proteins, such as alpha-2-antiplasmin. The oxidation mechanism seems to be mediated by singlet molecular oxygen, an excited oxygen species. Basing on this scu-PA/oxidant synergism a sensitive and fast functional assay of scu-PA in human plasma is presented. Plasmatic inhibitors normally interfering with functional scu-PA measurements are inactivated by addition of chloramine-T, imitating the physiological oxidants generated by activated phagocytes. The scu-PA concentration in plasma of n = 36 healthy individuals has been determined to be 5.8 +/- 1.6 ng/ml. The lower detection limit of plasma scu-PA by the procedure described is about 1.5 ng/ml of plasma. By means of this technique scu-PA concentration during thrombolytic therapy can be measured within minutes in undiluted (direct) plasma samples, allowing adjustments of the scu-PA dosage. The present study gives further credence for a role of singlet molecular oxygen, possibly a new type of locally acting hormones (autacoid), in the regulation of the fibrinolytic pathway.
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PMID:Nonradical oxidants of the phagocyte type induce the activation of plasmatic single chain- urokinase. 180 64


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