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)

Heparin is commonly included in the irrigation solution used during microvascular surgery. Evidence has accumulated to indicate a beneficial effect of heparin on anastomotic patency, implying that its topical use is critical to success even in routine microvascular repairs. This investigation compared heparin and urokinase as additives to the irrigation solution (Ringer's lactate) used during rat groin free flap replantation. A newly trained microsurgeon performed all surgical procedures to lower the possible success rate through microsurgical inexperience and, thus, to create a stronger challenge for the topical irrigant. Solutions were administered on a blinded, randomized basis. Vessel patency and flap survival were followed for 7 days. No statistically significant differences were found between any of the treatment groups: patency and survival rates of 67% for heparin, 57% for urokinase, and 73% for controls (vehicle only). The flap failures that occurred may have been attributable to undetected technical errors due to the microsurgical inexperience of the surgeon. In a separate series, an experienced microsurgeon achieved 93% success using vehicle without additives for irrigation. These results suggest that topical heparin or urokinase is not essential for achieving high levels of success during microvascular surgery.
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PMID:Comparison of the influence of intralumenal irrigation solutions on free flap survival. 158 9

Plasminogen activator inhibitor 1 (PAI-1) is the fast-acting inhibitor of both tissue-type and urokinase-type plasminogen activators (t-PA, u-PA) and is an essential regulatory protein of the fibrinolytic system. In the presence of either the protein vitronectin or the glycosaminoglycan heparin, PAI-1 is also an efficient inhibitor of thrombin. To assess whether these cofactors turn PAI-1 into a general protease inhibitor or whether their influence is restricted to thrombin, the second-order association rate constants between PAI-1 and the human plasma proteases t-PA, u-PA, plasmin, thrombin, Factor Xa (FXa), and Factor XIIa (FXIIa) in the absence and in the presence of either vitronectin or heparin are determined. In addition, the role of the PAI-1 reactive site P3 to P3' residues for the specificity of inhibition was studied by using PAI-1 reactive site mutants. Our results show that: (1) Heparin exclusively increases the rate of inhibition of thrombin by PAI-1, whereas in the presence of heparin the rate of inhibition of the other proteases is not altered; (2) Vitronectin is an obligatory cofactor for the inhibition of thrombin by PAI-1. In addition, vitronectin moderately increases the rate of inhibition by PAI-1 of u-PA and of plasmin, but does not alter the rate of inhibition of t-PA, FXa, or FXIIa; (3) Apart from the important role of the P1 residue, no consensus can be presented on the nature of other residues within the P3 to P3' region with regard to target protease specificity.
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PMID:On the target specificity of plasminogen activator inhibitor 1: the role of heparin, vitronectin, and the reactive site. 171 20

Thrombolytic therapy for evolving acute myocardial infarction (AMI) reduces infarct size, preserves ventricular function, and reduces mortality. Intravenous streptokinase is commonly followed by approximately 50% patency of coronary arteries within 90 minutes and by reduction of mortality by 25%. Recombinant tissue plasminogen activator (rt-PA) is more potent for coronary arterial thrombolysis, producing both more rapid and more frequent recanalization (approximately 75% patency at 90 minutes) with a dose of 100 mg given over 3 hours. Side effects (mainly bleeding) associated with the use of streptokinase and rt-PA are not markedly different. That the higher efficacy of rt-PA would translate into a larger reduction of mortality is suggested by the results of several small trials but remains to be confirmed in well-designed comparative clinical trials. This question has not been adequately answered by the recent International rt-PA/streptokinase mortality trial and the International Study on Infarct Survival (ISIS-3) study, because of concerns with respect to the role of conjunctive intravenous heparin administration and the dose of rt-PA used in ISIS-3. All available thrombolytic agents still have significant shortcomings, including the need for large doses to be maximally efficient, a limited fibrin specificity, and a significant associated bleeding tendency. New developments toward improved efficacy and fibrin-specificity of thrombolytic agents include the use of mutants of rt-PA, chimeric rt-PA or single chain urokinase plasminogen activator molecules, and antibody-targeted thrombolytic agents. Some of these artificial plasminogen activators have a 5- to 10-fold increased potency (thrombolytic activity per unit dose), but whether they are safe enough to be clinically useful remains to be established. The conjunctive use of anticoagulants and antiplatelet agents with thrombolytic agents increases their efficacy to an extent that monotherapy with a plasminogen activator alone is no longer tenable. Heparin and aspirin are only moderately efficient for acceleration of lysis and prevention of reocclusion, but are relatively safe. More selective thrombin inhibitors and antiplatelet agents are more potent, but their safety remains to be confirmed. Continued investigation in this area will provide new insights and promote progress toward the development of the ideal thrombolytic therapy, characterized by maximized stable coronary arterial thrombolysis with minimal bleeding.
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PMID:Designing thrombolytic agents: focus on safety and efficacy. 172 81

Thrombolytic treatment with urokinase (5000 U/ml) or streptokinase can restore patency in central venous catheters occluded by thrombosis. In pediatric patients preferable urokinase should be used. The therapy in case of catheter-induced central venous thrombosis is a continuous urokinase infusion (125,000 U/1.73(2)/h) for about 3 to 8 days, followed by a long-term heparinization. The treatment in persistent withdrawal occlusion is significantly shorter, a few hours of systemic lysis are sufficient. The treatment of choice in case of chemical obstructions in patients with long-term parenteral nutrition is the injection of 0.1 N HCl in combination with Heparin. By these procedures most of obstructed central venous catheters can be reopened and maintained in place. This preserves the count of possible catheter implantation sites.
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PMID:[Treatment of obstruction and thrombosis due to central venous catheterization]. 175 44

The functional operation of the cell surface pro-u-PA and plasminogen activating system has previously been shown to depend on the assembly of u-PA receptors, plasminogen binding sites, and their respective ligands at the focal adhesions of cell extensions. We now show that additional factors operate that affect the persistence of functional activity and that evidently involve charge interactions mediated by polyanions, such as those found in the cell surface proteoglycans. Heparin-like compounds and protamine were identified as fast-acting stimulators of cell surface plasminogen activation. Heparin stabilized surface u-PA activity during plasminogen activation, and we propose that a heparin binding site exists in the kringle structure of u-PA. Heparin at 40 micrograms/ml could reduce u-PA loss to only 20% compared with 60% on control cells activating plasminogen. Protamine (25 micrograms/ml) exerted a strong stimulatory effect on the level of generated bound plasmin and notably prolonged the persistence of this activity, so that 100 minutes after addition of plasminogen the level of plasmin on protamine-treated cells was five times higher than on control-treated cells. The effect of protamine on plasmin clearance suggests that an unknown plasmin inhibitor may be produced by rhabdomyosarcoma cells, whose action is accelerated by endogenous polyanions, in an analogous manner to thrombin inactivation by antithrombin III and protease nexin on endothelial cells and fibroblasts, respectively. The stimulatory effects of heparin and protamine do not affect the inactivation of cell surface u-PA by recombinant PAI-2.
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PMID:Stimulation of cell surface plasminogen activation by heparin and related polyionic substances. 183 80

Left atrial thrombus after mitral valve surgery is believed to be relatively rare. However, we previously reported on cases of left atrial thrombus (LAT) with spontaneous regression in the early postoperative period. Forty two patients who underwent mitral valve replacement were studied using computerized tomography (CT). Early postoperative LAT was found in 11 patients out of 42 (26.2%); all of whom had an uneventful postoperative course. The mean preoperative atrial diameter in the LAT group (81.4 mm) was greater than that in the non-LAT group (57.0 mm). This was the most decisive factor significant enough for discriminating between the two groups. Other factors, including age, sex, length of symptoms, preoperative NYHA classification, cardiac rhythms, preoperative cardiac index, duration of cardiopulmonary bypass, type of artificial valve used, duration of intubation and period prior to anticoagulant therapy were not significant. From March 1988, 10,000 U/day of heparin was administered to 20 of the 42 patients. LAT developed in 2 cases (10%). Of the 22 patients who did not accept heparin therapy, 9 (41%) developed LAT. Of the 11 patients having postoperative LAT, 6 were treated by fibrinolytic therapy (urokinase plus heparin). A decrease in thrombus size was observed in 3 cases, and no change in the other 3. Postoperative anticoagulant therapy with warfarin and dipyridamole was administered to all 11 LAT patients, in 8 cases, LAT disappeared for 3 to 42 months period. We therefore conclude as follows: 1) The incidence of early postoperative LAT was 26.2% (11/42). 2) Postoperative thrombus was more likely to occur in the left atrium with a large diameter. 3) Heparin dose of 10,000 U/day seemed to be an effective prophylactic therapy for LAT. 4) Fibrinolytic therapy with urokinase and heparin was not always favorable in LAT cases. 5) In 8 cases out of 11, LAT was resolved under standard anticoagulant therapy with warfarin and dipyridamole in long-term period.
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PMID:[Left atrial thrombus in the early postoperative period after mitral valve replacement]. 189 86

The authors report on the influence of plasminogen activators (PA) on implantation of TA3Ha mammary tumor cells in the healing hepatic wounds of syngeneic strain A mice. Intravenously injected TA3Ha cells, although they rarely metastasize to the liver, formed tumors in the hepatic wounds of a significant percent (42%, P less than 0.0001) of mice. The frequency of tumor formation declined as the interval between surgery and tumor cell inoculation was increased. Furthermore, preexposure of cells to fibrinogen, fibronectin, laminin, or peptides containing the arginine-glycine-aspartic acid-serine residues dramatically reduced the frequency of tumor formation in the hepatic wounds. These results indicate that TA3Ha cells interact with fibrinogen-related proteins in the wound to aid their attachment and growth. Because these proteins are susceptible to digestion by plasmin, PA were used in this study to examine whether administration of these drugs to the mice would modulate tumor formation in the liver wounds. Among the PA tested, human plasmin B-chain-streptokinase complex (B-SK) and recombinant tissue plasminogen activator (t-PA) inhibited tumor implantation in a dose-related manner. Administration of 900 units (U) of B-SK or 3300 U of t-PA per mouse reduced the frequency of tumor formation from 42% to 0% (P = 0.02) and 11% (P = 0.02), respectively. The B-SK was complexed with p-nitrophenyl-p-guanidinobenzoate; it did not activate the plasminogen or inhibit tumor formation in the hepatic wounds. Although urokinase activated the plasminogen, it did not inhibit tumor implantation in the hepatic wound. Heparin, an anticoagulant that prevents conversion of fibrinogen to fibrin without being fibrinolytic, had no influence on tumor formation in the hepatic wounds. The PA can generate plasmin that digests the cell attachment proteins in wounds and consequently inhibits tumor cell attachment.
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PMID:Inhibition of tumor implantation at sites of trauma by plasminogen activators. 191 15

Thrombotic events are a serious and potentially fatal complication during the neonatal period. Despite clinically serious thromboses in up to one percent of neonates and less severe complications (e.g., catheter malfunction secondary to clots) in a much higher percentage, well-designed studies on prevention and treatment of thromboses are lacking. Treatment approaches are largely anecdotal and involve the use of heparin and, occasionally, thrombolytics. Proper monitoring of anticoagulant and thrombolytic effects is difficult because of the limited blood volumes available from neonates and the relatively large sample volumes needed for most coagulation studies. Activated clotting times (ACTs) are preferred because they use low blood volume and are a rapid bedside test. Heparin should be administered with an initial loading dose of 50-100 units/kg followed by a continuous infusion of 20 units/kg/h. Further doses should then be adjusted based on the ACT, targeting a value of 1.5-2.5 times the control. Thrombolytics also have been used in several case reports and are guided by both clinical response and serial D-dimer values. We prefer urokinase 100 units/kg/h for local infusion to the thrombus and urokinase 1000-10,000 units/kg/h for systemic therapy.
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PMID:Neonatal thrombosis: treatment with heparin and thrombolytics. 194 44

Acute and subacute deep venous thrombosis can be followed by two serious complications: pulmonary embolism feared in the early stadium and the postthrombotic syndrome (PTS) as a late complication. After a lapse of months and years there might appear a complete or incomplete recanalization, but the valves of the veins will be destroyed. Therefore it is understandable to strive first an active therapy as thrombectomy or thrombolysis to remove thrombosis. There will be released a physiological tissue plasminogen activator from the endothelium of the vein increasing a local fibrinolytic activity. But it is not strong enough to reopen the occlusion within a few days. This is only possible adding exogenous activators as streptokinase, urokinase and recently rt-PA. Heparin is well known at low-dose subcutaneously for thrombosis prophylaxis. The high doses of heparin infusion intravenously with 30-40,000 units daily are used "therapeutically" inhibiting growth-promotion of the thrombus and reducing the incidence of pulmonary embolism markedly. In respect of a postthrombotic syndrome (oedema, leg ulcers) it needs the evaluation of the early and follow up late results and the analysis of efficiency and risk of the two models of treatment. It was necessary comparing the success rate of reopening of the occluded veins after some days and follow up 5 or 6 years in clinical studies. The reopening rate in thrombolysis was about 3 times higher than in heparin therapy. But in contrast bleeding was 3 times lower in heparin therapy. For the long term follow up, physical examination, doppler-sonography phlebodynamometry and vein occlusion plethysmography were assessed. The acute intervention, regarding treatment, turned out to be the crucial prognostic parameter. Syndromes and clinical findings did indeed correlate quite well with the outcome of fibrinolytic treatment. Postthrombotic syndrome was rare in cases with complete patency. In cases where patency was only partially or not at all achieved, postthrombotic syndrome was present to a higher degree the more central and the more extensive the remaining thrombus was. In deep venous thrombosis of the lower extremity thrombolytic therapy is recommended mostly to younger patients with acute, the popliteal and the femoral vein including thrombosis, except of contraindications. More over in each of an individual case it has to be decided whether the aggressive or conservative therapy is to prefer.
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PMID:[The treatment of deep venous thrombosis. Thrombolysis vs heparin]. 209 22

We have examined the cellular mechanisms by which heparin potentiates the ability of 3T3-adipocytes to stimulate the formation of new blood vessels. Both anticoagulant and non-anticoagulant heparin species enhanced the angiogenic activity of adipocyte-secreted products in the chick chorioallantoic membrane assay, indicating that the angiotropic effect of this glycosaminoglycan is independent of its effect on the coagulation cascade. Heparin alone was unable to produce a neovascular response. The ability of heparin to modulate three endothelial functions in vitro thought to be related to angiogenesis were examined: protease activity, motility, and mitogenesis. Heparin caused a 100% increase in the adipocyte-induced stimulation of endothelial cell plasminogen activator activity and motility, but had no effect on proliferation. The enhancement of plasminogen activator and chemoattractant activities had a similar ED50 (1-2 micrograms/ml) and optimum dose (10-30 micrograms/ml). When we examined the direct effect of heparin on the activity of two distinct plasminogen activator enzymes--urokinase and tissue-type--a dual action of heparin was observed: tissue-type enzyme activity was stimulated 100% by heparin at 10 micrograms/ml, whereas urokinase activity was inhibited by 77% at this dose. These data suggest that heparin potentiates angiogenesis in vivo by stimulating endothelial cell plasminogen activator, motility, or both. Our results further suggest that for adipocyte-induced blood vessel formation, in contrast to other angiogenesis systems, heparin does not appear to affect the mitogenic activity.
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PMID:Heparin potentiation of 3T3-adipocyte stimulated angiogenesis: mechanisms of action on endothelial cells. 242 84


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