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)

In the absence of accessory components, plasminogen activator inhibitor 1 (PAI-1) rapidly forms equimolar, inactive complexes both with tissue-type (t-PA) and with urokinase-type (u-PA) plamsinogen activator. In the presence of either the glycoprotein vitronectin or the glycosaminoglycan heparin, PAI-1 is endowed with additional, efficient thrombin-inhibitory properties (Ehrlich et al., 1990, 1991a). Here, we have investigated the interaction between PAI-1, thrombin, and glycosaminoglycans in more detail. Inhibition of thrombin by PAI-1 was quantitatively analyzed in the presence of a wide range of concentrations of heparin, heparan sulfate, dermatan sulfate, chondroitin 4-sulfate, chondroitin 6-sulfate, keratan sulfate, and hyaluronic acid by measuring residual amidolytic activity. In addition, a qualitative analysis was performed by determining the formation of SDS-stable, equimolar complexes between thrombin and PAI-1 in the presence of various glycosaminoglycans. Heparin, at concentrations between 0.1 and 1 microgram/mL, significantly promoted thrombin inhibition by PAI-1 as well as SDS-stable complex formation. Suboptimal inhibition was observed with dermatan sulfate, chondroitin 4-sulfate, and heparan sulfate at concentrations that are at least 1 order of magnitude higher than that required for optimal inhibition in the presence of heparin. Virtually no inhibition of thrombin and SDS-stable complex formation was detected with any of the other glycosaminoglycans at concentrations between 0.1 and 1 microgram/mL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific glycosaminoglycans support the inhibition of thrombin by plasminogen activator inhibitor 1. 843 48

Heparin is often used as an adjunct to thrombolytic therapy in order to prevent reocclusion of the patent vessels in patients with thrombotic disease. Controversy exists as to whether heparin is required for effective clot lysis with tissue-type plasminogen activator, while in vitro data and small scale clinical trials have suggested an enhancement of pro-urokinase efficacy by heparin. The present study was conducted to determine whether heparin pre-treatment is required to produce optimal clot lysis and blood flow restoration in response to recombinant pro-urokinase (r-proUK). In four groups of dogs, blood clots labelled with 125Iodine were formed in the femoral artery and were monitored continuously for loss of counts as an indicator of clot lysis. Femoral artery blood flow was measured simultaneously. Group 1 received vehicle (n = 5), while group 2 was given vehicle + heparin (n = 6; 500 U bolus + 350 U/h). This dose of heparin increased the activated partial thromboplastin time (APTT) by at least 1.5 times the control level for the 4 h observation period. Group 3 received r-proUK alone at a dose of 100,000 U/kg (50% given as a 1-min bolus injection, 50% as a 30 min infusion) (n = 8), while group 4 was treated with the same dose of r-proUK in the presence of heparin as described (n = 8).2
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PMID:Recombinant pro-urokinase requires heparin for optimal clot lysis and restoration of blood flow in a canine femoral artery thrombosis model. 849 50

In a previous report, we described the molecular cloning, expression, and partial characterization of a second human tissue factor pathway inhibitor (TFPI), which we designated as TFPI-2 [Sprecher, C. A., et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 3353-3357]. Recombinant TFPI-2 inhibited the amidolytic activity of trypsin as well as that of factor VIIa in complex with tissue factor. TFPI-2 recently has been shown to be identical to placental protein 5 (PP5), a glycoprotein originally isolated from placenta that exhibits serine protease inhibitory activity. In the present study, we have examined TFPI-2/PP5 for its ability to inhibit a number of serine proteases involved in blood coagulation and fibrinolysis, inasmuch as TFPI-2/PP5 prolonged the coagulation time of human plasma induced by either tissue factor or contact activation in a dose-dependent manner. In addition to its ability to inhibit the amidolytic and proteolytic activities of the factor VIIa-tissue factor complex, TFPI-2/PP5 strongly inhibited the amidolytic activities of human factor XIa, human plasma kallikrein, and human plasmin with Ki values of 15, 25, and 3 nM, respectively. TFPI-2/PP5 was also a weak inhibitor of the activation of factor X by a complex of human factor IXa and poly(lysine) with an apparent Ki of 410 nM. Heparin markedly enhanced the ability of TFPI-2/PP5 to inhibit factor VIIa-tissue factor both in the solution phase and on cell surfaces. In addition, heparin augmented the inhibition of human factor Xa amidolytic activity at relatively high levels (10-100 nM) of TFPI-2/PP5. No significant inhibition of glandular kallikrein, urinary plasminogen activator, tissue plasminogen activator, human activated protein C, human factor Xa, human thrombin, or leukocyte elastase was observed when these proteases were incubated with TFPI-2 in the absence of heparin.
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PMID:Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. 855 84

We successfully implanted coronary stents into refractory reoccluded lesions after failed coronary angioplasty in three patients with acute myocardial infarction (AMI). Lesion location was the proximal left anterior descending coronary artery in two patients and the dominant right coronary artery in one patient. The reference diameters of the lesions were 3.64, 3.33, and 3.50 mm, respectively. A stent with a luminal diameter of 3.0 mm was implanted in all patients. Poststenting dilation of the stent was performed at high pressure (18 atm), and urokinase was administered immediately thereafter. Heparin was administered for 24 h with maintenance of activated coagulation time within 180-200 s. Warfarin was then administered to keep the international normalized ratio within 2.5-3.5. Luminal diameters immediately after stenting were 3.14, 2.89, and 3.26 mm, and those at 1 month after stenting were 3.09, 2.81, and 3.12 mm, respectively, indicating good patency. Our experience in these cases suggests that coronary stenting can be applied after unsuccessful coronary angioplasty in selected patients with AMI. The present report includes informative reference data on diameter, postdilation, adjunctive thrombolytic agent administration, and adequate anticoagulation therapy in coronary stenting in this acute application.
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PMID:Coronary artery stenting with high-pressure post-dilation followed by adjunctive thrombolysis after failed coronary angioplasty for acute myocardial infarction: report of three cases. 909 2

A 48-year-old woman underwent total gastrectomy, splenectomy, and distal pancreatectomy with en bloc regional lymph node dissection for gastric carcinoma. Dull pain in the right upper quadrant and the back developed postoperatively. Contrast-enhanced computed tomography and ultrasonography disclosed portal vein thrombosis (PVT). Heparin and urokinase were given in conjunction with antibiotics. This treatment resulted in clinical improvement, but failed to achieve complete thrombolysis. Cavernous transformation of the portal system was confirmed. Although PVT after splenectomy has been reported mainly in patients with hematological disorders, our case suggests that splenectomy for en bloc node dissection in gastric carcinoma is a possible cause of PVT.
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PMID:Splenectomy for en bloc node dissection in gastric cancer: a possible cause of portal vein thrombosis. 912 48

Thrombolysis of arterial occlusions has limitations, e.g. it requires extensive time for thrombolysis, occlusions may be resistant to lysis, and the rate of reocclusions may be high. c7E3 Fab inhibits platelet aggregation by binding to the GPIIb/IIIa receptor on platelets. Experimentally, this monoclonal antibody has been shown to decrease, the time required for lysis, and to prevent reocclusion. This is the first report on the adjunctive use of c7E3 Fab in peripheral arterial occlusions in humans. Three patients with occlusion of the iliac or femoropopliteal artery were treated with c7E3 Fab (bolus injection of 0.25 mg/kg KG + i.v.-application 12 micrograms/min for 12 h). In addition, the patients received urokinase (100,000 IU bolus + 100,000 IU/h). Heparin (5,000 IU bolus + 1,000 IU/h) and acetylsalicylate (100 mg/day/p.o.). Occlusion length ranged between 6-40 cm. Therapy was successful in all patients. During the follow-up period (4-6 months) no reocclusion occurred. There were no serious side effects like major bleeding or thrombocytopenia. We conclude that the applied doses appear safe. Even the time required for thrombolysis was short, a conclusion in respect of a significant reduction of the time required for lysis can be drawn only after further controlled studies.
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PMID:[The adjuvant use of the monoclonal antibody c7E3 Fab in peripheral arterial thrombolysis]. 915 99

Previous works suggest the interesting possibility of an effect of heparin on vascular smooth muscle cell (SMC) replication and migration via a selective inhibition of the expression of t-PA and u-PA both of which may play major roles during intimal hyperplasia following endothelial injury. The present study was undertaken to evaluate in vitro the effect of heparin on the growth and migration of aortic SMC isolated from transgenic mice showing single inactivations of the t-PA and u-PA genes comparatively to SMC isolated from control mice. With regard to serum-induced proliferation and migration, all cell types showed similar responses. On control cells, heparin inhibited in a dose-dependent manner the expression of both t-PA and u-PA protein and mRNA. Heparin however, similarly affected the mitogenic and chemotactic activity of FCS for SMC isolated from control, t-PA or u-PA-deficient mice therefore showing that heparin inhibits FCS-induced SMC proliferation via mechanism(s) other than single inhibition of t-PA or u-PA expression by smooth muscle cells.
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PMID:The inhibitory effect of heparin for vascular smooth muscle cell proliferation or migration is not mediated by u-PA and t-PA. 918 19

From March 1989 to March 1993, six athletic patients were treated in our institution by thrombolytic therapy for acute effort axillary-subclavian vein thrombosis in thoracic outlet syndrome. Mean age of these patients was 20 (range 14 to 27). An in situ infusion with urokinase (2,500 U/kg/h) and Heparin (100 U/kg/12 hours) was given during 64 hours (Range 14 to 72). Phlebography showed a complete reperfusion in three cases (the treatment began within an average period of 5.6 days), partial reperfusion in two cases (the treatment began within an average period of 8.5 days). In one case there was no reperfusion on phlebography: treatment began within an average period of 15 days. For this patient, a venous axillo-jugular bypass graft was performed. In all cases, there was no bleeding complication. A trans-axillary first rib resection was done three months later. Mean follow up was 31 months (range: two to 51 months). All patients recovered their previous physical status. Echo-Doppler exam showed normal subclavian vein flow in four cases, partial occlusion in one case and a total occlusion of the subclavian vein flow in one case. In this last case, the thrombolytic therapy failed to restore the permeability of the subclavian vein. Bypassgraft was patent. Axillary-subclavian vein thrombosis seen within a period of seven days should be treated by local thrombolytic therapy using urokinase and heparin.
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PMID:[In situ thrombolysis in the treatment of venous thrombosis of effort in the arm]. 930 35

The non-specific serine-protease inhibitor protein-C inhibitor (PCI) inactivates its target enzymes by forming stable 1:1 complexes. Heparin stimulates most PCI/protease reactions, but interferes with the inhibition of tissue kallikrein by PCI by a hitherto unknown mechanism. In this study we analyzed the inhibitory effect of heparin on the tissue-kallikrein-PCI interaction. Free PCI and tissue-kallikrein x PCI complexes but not free tissue kallikrein bound to heparin-Sepharose, implying that the inhibitory effect of heparin cannot be caused by a tissue-kallikrein-heparin interaction. Heparin did not dissociate tissue-kallikrein x PCI complexes, making it unlikely that in the presence of heparin PCI becomes a substrate for, rather than an inhibitor of, tissue kallikrein. However, heparin-bound PCI, which was able to form complexes with 125I-urokinase, did not form complexes with 125I-tissue-kallikrein. This suggests that the inhibitory effect of heparin is either based on the neutralization of positive charges in the PCI molecule, which might be required for the interaction of PCI with the acidic protease tissue kallikrein, or on a change in reactivity of PCI upon heparin binding, making heparin-bound PCI no longer a tissue-kallikrein inhibitor. Neutralization of basic amino acids in the PCI molecule by glutamic acid, which prevented in a dose-dependent way the inhibitory effect of heparin, did not have any effect on the tissue-kallikrein-PCI interaction. Therefore, direct involvement of basic amino acid residues present in the heparin-binding site of PCI in the tissue-kallikrein-PCI interaction can be excluded. Heparin binding might rather cause a change in reactivity of PCI (e.g. by inducing a conformational change or by steric interference), thereby preventing its interaction with tissue kallikrein.
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PMID:Heparin binding of protein-C inhibitor--analysis of the effect of heparin on the interaction of protein-C inhibitor with tissue kallikrein. 934 5

The data gained from clinical studies in the past years have indicated that the thrombolytic therapy (TL) has favourable effect on patients with acute myocardial infarction (AMI). It is aimed at reperfusion in the ischaemic area, a decrease in the extent of infarction site and a decrease in mortality. TL administered within the initial hours after the onset of AMI leads to better results than when administered after several hours. Currently, TL is not limited by age. The patients who were given streptokinase (SK) or anistreplase (APSAC) prior to more than 4 days, if necessary, urokinase or alteplase (rt-PA) should be given. There are differences in the opinions as to the optimal selection of thrombolytic drugs. However, all currently used drugs lead to a significant decrease in mortality due to AMI. The preferential use of accelerated administration of rt-PA in contrast to SK is justified in younger patients with extensive AMI of the anterior wall, in whom the therapy has begun within 4 hours since its onset. The occurence of severe bleeding indicates that TL should be halted and coagulation factors should be replaces by freshly frozen plasma or fibrinogen concentrate, if necessary, transfusion of full blood should take place. If the severe bleeding occurs shortly after the administration of SK, the persisting plasminaemia can be arranged by antifibrinolytic drugs. An improvement in TL results can be achieved by adjuvant antithrombotic therapy. At the same time, in addition to acetylsalicylic acid, the patient treated with rt-PA should be given heparin. Heparin administration is not necessary in patients treated with SK or APSAC. However, heparin is indicated in patients at risk due to systemic embolization in congestive heart disease, extensive infarction or atrial fibrillation. (Tab. 1, Ref. 28).
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PMID:[In Process Citation] 966 37


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