Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

125I-labeled heparin cofactor II (HCII) was mixed with plasma and coagulation was initiated by addition of CaCl2, phospholipids, and kaolin or tissue factor. In the presence of 67 micrograms/ml of dermatan sulfate, radioactivity was detected in a band which corresponded to the thrombin-HCII complex (Mr = 96,000) upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No other complexes were observed. The thrombin-HCII complex was undetectable when 5 units/ml of heparin was present or when prothrombin-deficient plasma was used. In experiments with purified proteases, HCII did not significantly inhibit coagulation factors VIIa, IXa, Xa, XIa, XIIa, kallikrein, activated protein C, plasmin, urokinase, tissue plasminogen activator, leukocyte elastase, the gamma-subunit of nerve growth factor, and the epidermal growth factor-binding protein. HCII inhibited leukocyte cathepsin G slowly, with a rate constant of 8 X 10(4) M-1 min-1 in the presence of dermatan sulfate. These results indicate that the protease specificity of HCII is more restricted than that of other plasma protease inhibitors and suggest that the anticoagulant effect of dermatan sulfate is due solely to inhibition of thrombin by HCII.
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PMID:The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation. 383 15

The pathophysiology of deep-vein thrombosis (DVT) and pulmonary embolism (PE) is briefly discussed, and the efficacy, dosage and administration, laboratory monitoring, and adverse effects of thrombolytic agents, heparin, and warfarin are reviewed. Acute therapy of DVT and PE is usually initiated with intravenous heparin; however, thrombolytic agents such as streptokinase and urokinase may be preferred in patients with massive PE or severe DVT when clot lysis rather than clot stabilization is deemed necessary. For DVT or PE, an intravenous loading dose of streptokinase or urokinase is given, followed by a continuous infusion of the drug. Therapy with streptokinase is continued for 24 hours in patients with PE and for 72 hours in those with DVT; urokinase is continued for 12 hours in patients with PE. Monitoring of blood coagulation tests during thrombolytic therapy is recommended primarily for ensuring that a lytic state is achieved. Intravenous heparin is preferred for acute treatment of DVT or PE; controversy exists regarding whether administration by continuous infusion or intermittent bolus injection is superior. Heparin dosage is usually adjusted to maintain the activated partial-thromboplastin time (APTT) ratio between 1.5 and 2.5; however, the ideal therapeutic range has never been firmly established. After acute treatment with heparin, most patients should continue to receive either warfarin or subcutaneous heparin for several months to prevent recurrent thromboembolism. Bleeding is the major adverse effect of thrombolytic agents and anticoagulants. The risk of bleeding with heparin and warfarin therapy increases with excessive prolongation of the APTT and prothrombin time (PT), respectively. Future clinical trials should further define the role of thrombolytic agents in the treatment of DVT and PE and the efficacy of less-intense warfarin therapy for pulmonary embolism or arterial thromboembolic events.
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PMID:Pathophysiology and treatment of deep-vein thrombosis and pulmonary embolism. 389 Dec

Twelve amino acid sequences of kringle-forming polypeptides were compiled from the known sequences of urokinase A-chain (human), a tissue-type plasminogen activator (human), prothrombin (human and bovine), and plasminogen (human). Their sequence homologies with maximum match were examined by a computer program. A homology alignment and graphic matrix analyses did show that they had a great degree of homology. All the cysteine residues responsible for the kringle structures of urokinase and the tissue-type plasminogen activator were confidently preserved as well as other proteins. A phylogenetic tree was then reconstructed, and the A- and S-chain of bovine and human prothrombins were accounted for the measurement of the evolutionary time span. It was found that urokinase had a larger time span, as much as 60 million years (MY), than the tissue-type plasminogen activator. A common ancestral element of the kringle-related serine proteases was placed at around 500 MY ago, as old as the diversion of the alpha- and beta-chains of hemoglobin. Thus, the kringle-families have undergone a substantial evolutionary divergence. Moreover, they can be subgrouped into three subfamilies: plasminogen activators, plasminogen, and prothrombin A-chains, the last being the most distantly diverged prothrombin S-chains.
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PMID:Homology of kringle structures in urokinase and tissue-type plasminogen activator: the phylogeny with the related serine proteases. 393 78

Twenty-nine patients received intracoronary thrombolytic therapy for acute myocardial infarction 3.5 +/- 1.4 hours (mean +/- standard deviation) after the onset of pain. Ten patients received urokinase (UK) and 19 patients received streptokinase (SK). Laboratory variables of the coagulation system were measured before and immediately after therapy. When comparing patients in whom coronary artery recanalization occurred vs those in whom the artery remained occluded, those in whom recanalization was achieved had greater alterations in fibrinogen, prothrombin time, activated partial thromboplastin time, fibrin/fibrinogen degradation products and plasminogen by thrombolytic therapy than did those in whom recanalization was not achieved (p less than 0.05 for all variables). Euglobulin lysis time showed a similar but nonsignificant trend (p = 0.114). Patients who received SK showed markedly greater alterations in coagulation parameters than did patients treated with UK (p less than 0.05 for 5 of 6 variables measured) and had a much higher incidence of successful thrombolysis (74% for SK, 20% for UK). These data indicate that the development of a systemic fibrinolytic state contributes to success when using intracoronary thrombolytic agents in acute myocardial infarction. Rather than being considered an adverse effect of therapy, a systemic lytic state may serve as a reasonable clinical goal in attempting to produce thrombolysis.
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PMID:Relation of effectiveness of intracoronary thrombolysis in acute myocardial infarction to systemic thrombolytic state. 403 24

Kringle 4, an 88-residue plasminogen fragment carrying a lysine-binding site, loses its affinity for lysine-Sepharose upon reductive cleavage of its disulfide bridges. Aerobic incubation of the reduced, denatured fragment results in the rapid restoration of the disulfide bonds with concomitant recovery of lysine-Sepharose affinity. The ability of the unfolded fragment to regain its native conformation suggests that the kringle structure is an autonomous folding domain. During refolding of kringle 4 the native disulfide bonds, (formula; see text) and (formula; see text), appears first. The folding intermediate possessing these two disulfide bridges already binds to lysine-Sepharose, indicating that the third native bridge, which in native kringle 4 connects residues Cys1 and Cys79, is not essential for the maintenance of the biologically active conformation of kringle 4. Comparison of the sequences of human prothrombin, urokinase, and plasminogen kringles revealed that the residues surrounding the (formula; see text) and (formula; see text) bridges constitute the most conservative segments of kringles, whereas the residues neighboring the (formula; see text) bridge are not highly conserved. We propose that conservation of various residues in the different kringles reflects their importance for the folding autonomy of kringles.
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PMID:Folding autonomy of the kringle 4 fragment of human plasminogen. 630 85

Since the introduction of synthetic chromogenic and fluorogenic peptide substrates from serine proteases, the testing of coagulation has undergone a dramatic conceptual and methodological change. The concept of coagulation profiling has emerged and automated methodologies are being introduced. Synthetic substrate methods for the evaluation of antithrombin-III; progressive antithrombin; plasminogen; antiplasmin; prekallikrein; antikallikrein ; alpha 1-antitrypsin; prothrombin; heparin; platelet factor IV; urokinase; tissue activator of plasminogen; factor assays; amidolytic equivalents of prothrombin time; and partial thromboplastin time have been developed. Studies on antithrombin-III indicate that immunological methods evaluate the total immunoreactive-antithrombin-III (antigenic) level and do not discriminate between functionally active forms and the AT-III serine protease complex. The clinical significance of AT-III measured by immunological methods is highly questionable. The coagulant assays for the measurement of AT-III require purified alpha-thrombin preparations. The noncoagulant forms of thrombin (beta- and gamma-) result in falsely low antithrombin-III quantitation. The molecular heterogeneity in a given thrombin preparation if standardized in terms of its amidolytic activity does not produce any errors in the quantitation of AT-III levels with synthetic peptide methods. None of the immunological methods provide clinically relevant information except in normal plasma where the immunological and functional activities are identical. Analysis of pathologic plasma samples using laser nephelometry, radial immunodiffusion and radioimmunoassay methods revealed that the functional activity of various serine protease inhibitors is greatly reduced but the reduction in the immunological quantities is minimal. Since coagulation proteins are functional, a ratio between their functional activity and absolute protein levels may be a useful parameter. Employing human and bovine thrombin; bovine and human Xa with their respective substrates, the absolute quantitation of heparin is satisfactorily carried out, however, these assays only measure heparin concentrations and do not reflect the overall anticoagulant effect of heparin. Using the synthetic substrates, the value of measuring absolute concentrations of heparin in a patient on heparin therapy is questionable. With the introduction of fluorogenic substrates, the presence of activated coagulation factors may be demonstrated in patients with thrombotic disorders.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Synthetic peptide substrates in hemostatic testing. 637 39

Inhibitory effects of FUT-175 (nafamstat mesilate) on coagulation, platelets and fibrinolysis were examined. FUT-175 prolonged activated partial thromboplastin time, thrombin time and prothrombin time in rabbit plasma. FUT-175 prolonged these coagulation times in human plasma at lower concentration than in rabbit plasma. FUT-175 inhibited platelet aggregation induced by a variety of aggregation agents in rabbit platelet-rich plasma (PRP). In human PRP, FUT-175 inhibited platelet aggregation induced by a variety of aggregation agents at lower concentration than in rabbit PRP. Lipopolysaccharide induced a dose-dependent platelet aggregation in dog PRP. FUT-175 showed an inhibitory effect on this aggregation. FUT-175 inhibited clot retraction in rabbit plasma. The fibrinolysis activity was measured on fibrinolysis of rabbit plasma activated by urokinase. FUT-175 prolonged this fibrinolysis time. Inhibitory effects on coagulation and fibrinolysis were also found ex vivo. FUT-175 prolonged bleeding time in mice. These results indicate that FUT-175 has potent inhibitory effects on coagulation, platelets and fibrinolysis.
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PMID:[Pharmacological studies of FUT-175, nafamstat mesilate. IV. Effects on coagulation, platelets and fibrinolysis]. 651 80

We compared peritoneal dialysis effluents from 18 CAPD patients who had not suffered from peritonitis during the last 6 months (group 1) with the effluents from five patients with acute peritonitis (group 2), measuring activation markers of coagulation and fibrinolysis. These markers included prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complex (TAT), fibrin monomer (FM), and fibrin degradation products (FbDP). In the dialysate of group 1 we found remarkably high levels of F1 + 2, TAT and FM concomitant with a high concentration of FbDP, indicating a high rate of intraperitoneal fibrin turnover. The balance between peritoneal generation and degradation of fibrin was disturbed in untreated patients of group 2, who had significantly higher levels of coagulation markers and a higher ratio between FM and FbDP. Seven days after treatment with intraperitoneal administration of antibiotics and heparin, F1 + 2, TAT, FM and FbDP decreased significantly. To evaluate the role of mesothelial cells (MC) in the high peritoneal fibrin turnover we investigated the expression of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor type-1 (PAI-1), and tissue factor in cultured human peritoneal MC under basal conditions and after exposure to tumour necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), or bacterial lipopolysaccharide (LPS). The exposure of MC to TNF alpha or to a lesser extent IL-1 alpha or LPS reduced their fibrinolytic activity by decreasing t-PA production and increasing PAI-1 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Imbalance between intraperitoneal coagulation and fibrinolysis during peritonitis of CAPD patients: the role of mesothelial cells. 756 82

A novel plasminogen activator from Trimeresurus stejnegeri venom (TSV-PA) has been identified and purified to homogeneity. It is a single chain glycoprotein with an apparent molecular weight of 33,000 and an isoelectric point of pH 5.2. It specifically activates plasminogen through an enzymatic reaction. The activation of human native Glu-plasminogen by TSV-PA is due to a single cleavage of the molecule at the peptide bond Arg561-Val562. Purified TSV-PA, which catalyzes the hydrolysis of several tripeptide p-nitroanilide substrates, does not activate nor degrade prothrombin, factor X, or protein C and does not clot fibrinogen nor show fibrino(geno)lytic activity in the absence of plasminogen. The activity of TSV-PA was readily inhibited by phenylmethanesulfonyl fluoride and by p-nitrophenyl-p-guanidinobenzoate. Oligonucleotide primers designed on the basis of the N-terminal and the internal peptide sequences of TSV-PA were used for the amplification of cDNA fragments by polymerase chain reaction. This allowed the cloning of a full-length cDNA encoding TSV-PA from a cDNA library prepared from the venom glands. The deduced complete amino acid sequence of TSV-PA indicates that the mature TSV-PA protein is composed of 234 amino acids and contains a single potential N-glycosylation site at Asn161. The sequence of TSV-PA exhibits a high degree of sequence identity with other snake venom proteases: 66% with the protein C activator from Agkistrodon contortrix contortrix venom, 63% with batroxobin, and 60% with the factor V activator from Russell's viper venom. On the other hand, TSV-PA shows only 21-23% sequence similarity with the catalytic domains of u-PA and t-PA. Furthermore, TSV-PA lacks the sequence site that has been demonstrated to be responsible for the interaction of t-PA (KHRR) and u-PA (RRHR) with plasminogen activator inhibitor type 1.
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PMID:A novel plasminogen activator from snake venom. Purification, characterization, and molecular cloning. 773 Mar 29

After placement of a Gianturco-Roubin metallic, coiled coronary stent(s) following balloon angioplasty (PTCA), a pre-discharge (7 day) angiogram determined the patency of the old coronary bypass vein graft(s) (SVG) (> or = 5 years remote from their last surgery, mean age: 8.5 +/- 1.8 years). Metallic, coiled stents were successfully deployed in 95/96 (99%) patients within 100/101 (99%) SVGs. The indications for deployment were threatened [81 patients (84%)] or acute [15 patients (16%)] vein graft closure following PTCA. Intragraft urokinase infusion was performed in 17 patients (17%) [6 patients with baseline occlusions; 11 with abrupt closure post PTCA]. Complications encountered included three (3%) in-hospital deaths (two procedure related) two (2%) Q wave myocardial infarctions, six (6%) non-Q wave myocardial infarctions, and 22 (22%) bleeding problems. These included, not mutually exclusively, 21 (22%) requiring transfusions, six (6%) cases of gastrointestinal bleeding, six (6%) pseudoaneurysms, five (5%) retroperitoneal haemorrhages and two (2%) cerebrovascular accidents. All patients received dipyridamole, aspirin, dextran, and anticoagulation (heparin 10-20,000 U intra-procedurally); a heparin infusion was continued for 5 +/- 1 days, despite warfarin administration which attained a therapeutic prothrombin time (PT) (1.5-2 times control) by 3 +/- 1 days. Out of the 95 successfully treated patients, six with eight stented grafts were ineligible for pre-discharge angiography. Of the six, three died in hospital (four SVGs), one had an intracerebral haemorrhage (one SVG), and two were asymptomatic patients with chronic renal failure (three SVGs).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The use of Gianturco-Roubin flexible metallic coronary stents in old saphenous vein grafts: in-hospital outcome and 7 day angiographic patency. 783 59


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