Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the possible role of persistent thrombocytosis after splenectomy as being a predisposing factor causing thromboembolism. Blood coagulation profiles were studied in 35 patients (20 M and 15 F, mean age 42 +/- 17.5) suffering from thrombocytosis (> 500,000/dl) who underwent splenectomy for non-malignant and non-traumatic diseases. Seventy healthy subjects acted as a control group. Tests were performed 6 months after the operation and for both groups (patients and controls) blood samples were collected for: platelets, fibrinogen, PT, APTT, AT III, plasminogen, F1 + 2, t-PA and DNA analysis for F V, F II and MTHFR. After one year all subjects were controlled for thrombocytosis, genomic abnormalities and venous thrombosis. All the analyses were performed according to the Statistical Package for Social Science. The significance of the differences in means was evaluated by non-parametric tests, differences with a P value < 0.05 being considered significant. Increased plasma levels of fibrinogen, D-dimer, F1 + 2 and PAI-1 were found in the patients compared with the control group. TPA was significantly lower in the patients than in the controls. At the one year follow-up, two patients with genetic polymorphism had suffered deep venous thrombosis. Our findings indicate that splenectomy contributes to abnormal platelet aggregation and endothelial cell activation with hypercoagulability.
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PMID:[Blood coagulation changes in patients with post-splenectomy persistent thrombocytosis]. 1158 73

Deep venous thrombosis is a possible complication of indwelling central venous catheters (CVC), with an incidence as high as 61%. We report a case of successful thrombolysis of a CVC-related right atrial thrombus in a pediatric cancer patient with recombinant human tissue plasminogen activator (0.1 mg/kg per h for 12 h) and heparin (10 IU/kg per h for 24 h) administered for 6 days. Daily echocardiographic examination showed progressive lysis of the thrombus. The thrombolytic treatment was associated with mild oozing from the venipuncture sites, but no major bleeding was noted; moreover, thrombin, thromboplastin time and fibrinogen were normal or only minimally altered. Anticoagulant therapy, with or without CVC removal, is the treatment of choice for uncomplicated CVC-related thrombosis. Fibrinolytic therapy may be indicated in some cases at risk of pulmonary embolism or to avoid open heart surgery. Recombinant human tissue plasminogen activator is increasingly used for thrombolytic treatment of organ and limb thrombosis, but experience with it in the pediatric hematology-oncology setting is still limited. This report showed that administering recombinant human tissue plasminogen activator in a pediatric cancer patient prior to hematopoietic stem cell transplantation was effective and safe under strict biochemical and instrumental monitoring. Further studies are needed to determine the best antithrombotic treatment for CVC-related thrombosis, and also the dosage of the medication selected and the duration of treatment.
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PMID:Successful treatment of a catheter-related right atrial thrombosis with recombinant tissue plasminogen activator and heparin. 1190 91

Plasminogen activators (PA) are unique agents that are currently applied as thrombolytic therapy to achieve rapid vascular reperfusion. Regimens of PA plus anticoagulants and antiplatelet drugs have attained a high degree of sophistication and predictable rates of positive clinical outcomes for acute myocardial infarction (MI), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and thrombosed catheters. Included in the repertoire are newly approved mutants of tissue plasminogen activator (TPA), which have biochemical advantages that allow for bolus administration. Yet, despite tremendous effort devoted to enormous trials to establish the clinical efficacy of these agents in acute MI, mortality results are not superior to those with native TPA or streptokinase (SK). Furthermore, all PAs have the potential for hemorrhagic complication, most critically intracranial hemorrhage (ICH), occurring in 0.9% of patients treated with native or mutant TPA. It is possible that a limit of clinical effectiveness has been reached, beyond which more potent PAs do not achieve greater benefit without a serious increase in risk of bleeding. A breakthrough is possible, however, if the risk of ICH could be avoided. One solution is the application of the direct-acting thrombolytic enzyme, plasmin. While intravenous plasmin is not effective when administered systemically, regional infusion to a thrombus induces local thrombolysis. Unlike the PAs, plasmin treatment should not cause hemorrhage from vascular trauma sites, as it is neutralized by antiplasmin in the blood. Animal studies are fully consistent with this approach, which offers potential for achieving a truly regional thrombolytic treatment.
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PMID:Towards safer thrombolytic therapy. 1212 83

External pneumatic compression (EPC) devices prevent lower extremity deep venous thrombosis (DVT) by reducing stasis. There is a widely held belief that they also enhance endogenous fibrinolysis; however, recent studies of tissue plasminogen activator (the primary activator of fibrinolysis) and plasminogen activator inhibitor-1 (the primary inhibitor of fibrinolysis) failed to confirm this. The hypothesis of this study was that EPC devices increase the level of urokinase plasminogen activator (uPA), a second activator of fibrinolysis. This was a prospective trial in which 44 subjects who underwent major abdominal surgery were randomized to receive unfractionated heparin injections, thigh-length sequential EPC devices, or both for DVT prophylaxis. Prophylaxis was begun immediately before surgical incision and continued until postoperative day 5 or discharge. Venous blood samples were collected from an antecubital vein for measurement of systemic uPA levels and from the common femoral vein for measurement of regional uPA levels. Samples were collected the day before surgery, after induction of anesthesia but before surgical incision, and on postoperative days 1, 3, and 5. uPA levels (ng/mL) were measured with an enzyme-linked immunoassay. Baseline uPA levels (0.41 to 0.56 ng/mL; P >.05, analysis of variance with repeated measures) were similar among the three groups. uPA levels did not change after surgery in systemic or regional blood samples in any group. There were no significant differences in systemic or regional uPA levels in the groups treated with EPC devices relative to those treated with heparin at any time point (P >.05, analysis of variance with repeated measures). Enhancement of fibrinolysis with EPC devices remains unproven; the findings reported here suggest that effective DVT prophylaxis can only be assured when the devices are used in a manner that reduces venous stasis.
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PMID:External pneumatic compression does not increase urokinase plasminogen activator after abdominal surgery. 1242 1

Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described inhibitor of fibrinolysis. The aim of this study was to estimate the risk of deep venous thrombosis (DVT) caused by the polymorphisms in the TAFI gene in relation to polymorphisms of the other fibrinolytic variables such as PAI-844A>G and t-PA-7,351C>T. This study includes 130 patients with DVT and 130 age- and sex-matched healthy controls. Our results showed no association of the investigated "TAFI-increasing" alleles TAFI 505A (Thr147) and TAFI+1542C with the risk of venous thrombosis. However the adjustment for age, sex, factor V Leiden, PAI-844A allele and t-PA-7,351T allele indicates a tendency to a moderately increased thrombotic risk of TAFI+1542GG carriers (low TAFI level).
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PMID:Polymorphisms in the TAFI gene and the risk of venous thrombosis. 1465 35

Over the past two decades tissue-type plasminogen activator (t-PA), the main physiological plasminogen activator, has been developed as a fibrin-specific thrombolytic agent for the treatment of various thromboembolic diseases. Milestones in this development include: first purification of human t-PA from uterine tissue, elucidation of the interactions regulating physiological fibrinolysis, thus providing a molecular basis for the concept of fibrin-specific plasminogen activation, first animal models of thrombosis and pilot studies in patients supporting the therapeutic potential of t-PA, cloning and expression of recombinant t-PA providing sufficient amounts for large scale clinical use, and demonstration of its therapeutic benefit in large multicenter clinical trials, mainly in patients with acute myocardial infarction (AMI), but also in patients with massive pulmonary embolism, ischemic stroke, deep vein thrombosis and peripheral arterial occlusion. Genetically modified variants of t-PA have been developed for bolus administration in patients with AMI.
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PMID:Tissue-type plasminogen activator: a historical perspective and personal account. 1510 5

Arterial and venous thromboembolic events, including myocardial infarction, ischemic stroke, peripheral arterial thrombosis, deep venous thrombosis, and pulmonary embolism are common potentially life-, organ-, and limb-threatening vascular diseases. Anticoagulant therapy is recommended in these settings to prevent further thrombosis pending gradual clearance of the thrombotic occlusion by the endogenous fibrinolytic system. Recognition of the importance of the fibrinolytic system in thrombus resolution has resulted in the development of pharmacologic fibrinolytic (thrombolytic) agents to facilitate rapid restoration of vascular patency. Several plasminogen activator (PA) thrombolytic agents with different pharmacokinetic and pharmacodynamic properties have been developed to treat thrombotic disease. Newer PAs have been developed as "fibrin-specific", bolus-administration drugs to primarily treat acute coronary syndromes. Continuous infusions of these fibrin-specific PAs have become popular for the lysis relatively larger peripheral vascular thromboses. Loss infusion of newer tissue-type plasminogen activator-based PAs may result in an increased risk of bleeding, including intracranial hemorrhage. Currently available data fail to provide compelling evidence that newer PAs offer significantly greater efficacy and safety than well-established agents like urokinase when used to treat peripheral vascular thrombosis.
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PMID:Pharmacologic and clinical characteristics of thrombolytic agents. 1511 13

The role of the fibrinolytic system in the development of deep vein thrombosis (DVT) is unclear. We determined the plasma fibrinolytic potential of patients enrolled in the Leiden Thrombophilia Study (LETS), a population-based case-control study on risk factors for DVT. Plasma fibrinolytic potential was determined in 421 patients and 469 control subjects by means of a tissue factor-induced and tissue-type plasminogen activator (tPA)-induced clot lysis assay. Using clot lysis times above the 70th, 80th, 90th, 95th, and 99th percentiles of the values found in control subjects as cut-off levels, we found a dose-dependent increase in risk for DVT in patients with hypofibrinolysis (odds ratios of 1.4, 1.6, 1.9, 2.1, and 2.2, respectively). This indicates a 2-fold increased risk of DVT in subjects with clot lysis times above the 90th percentile. The risk increase was not affected by age or sex (adjusted odds ratio for 90th percentile, 2.0), and after correction for all possible confounders (age, sex, and levels of procoagulant proteins shown to associate with clot lysis times in the control population), the risk estimate was marginally reduced (odds ratio, 1.6 for 90th percentile). Taken together, these results indicate that plasma hypofibrinolysis constitutes a risk factor for venous thrombosis, with a doubling of the risk at clot lysis times that are present in 10% of the population.
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PMID:Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. 1546 29

Thrombin inhibitors are potentially useful in medicine for their anticoagulant and antithrombotic effects. We synthesized and evaluated diverse heterocycle-activated ketones based on the d-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors. The peptide-based alpha-ketoheterocycles were typically prepared by either an imidate or a Weinreb amide route (Schemes 1 and 2), the latter of which proved to be more general. Test compounds were generally assayed for inhibition of human alpha-thrombin and bovine trypsin. From a structure-based design standpoint, the heterocycle allows one to explore and adjust interactions within the S1' subsite of thrombin. The preferred alpha-ketoheterocycle is a pi-rich 2-substituted azole with at least two heteroatoms proximal to the carbon bearing the keto group, and a preferred thrombin inhibitor is 2-ketobenzothiazole 3, with a potent K(i) value of 0.2 nM and ca. 15-fold selectivity over trypsin. 2-Ketobenzothiazole 13 exhibited exceedingly potent thrombin inhibition (K(i) = 0.000 65 nM; slow tight binding). Several alpha-ketoheterocycles had thrombin K(i) values in the range 0.1-400 nM. The "Arg" unit in the alpha-ketoheterocycles can be sensitive to stereomutation under mildy basic conditions. For example, 2-ketothiazoles 4 and 59 readily epimerize at pH 7.4, although they are fairly stable stereochemically at pH 3-4; thus, suitable conditions had to be selected for the enzymatic assays. Lead d-Phe-Pro-Arg 2-benzothiazoles 3, 4, and 68 displayed good selectivity for thrombin over other key coagulation enzymes (e.g., factor Xa, plasmin, protein Ca, uPA, tPA, and streptokinase); however, their selectivity for thrombin over trypsin was modest (<25-fold). Compounds 3, 4, and 68 exhibited potent in vitro antithrombotic activity as measured by inhibition of gel-filtered platelet aggregation induced by alpha-thrombin (IC(50) = 30-40 nM). They also proved to be potent anticoagulant/antithrombotic agents in vivo on intravenous administration, as determined in the canine arteriovenous shunt (ED(50) = 0.45-0.65 mg/kg) and the rabbit deep vein thrombosis (ED(50) = 0.1-0.4 mg/kg) models. Intravenous administration of 3, and several analogues, to guinea pigs caused hypotension and electrocardiogram abnormalities. Such cardiovascular side effects were also observed with some nonguanidine inhibitors and inhibitors having recognition motifs other than d-Phe-Pro-Arg. 2-Benzothiazolecarboxylates 4 and 68 exhibited significantly diminished cardiovascular side effects, and benzothiazolecarboxylic acid 4 had the best profile with respect to therapeutic index. The X-ray crystal structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S(1)' region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate of 4 forms a salt bridge with the side chain of Lys-60F such that it adopts an extended anti conformation. Since 3 has a 10-fold greater affinity for thrombin than does 4, any increase in binding energy resulting from this salt bridge is apparently offset by perturbations across the enzyme (viz. Figure 4). The increased affinity and selectivity of 2-ketobenzothiazole inhibitors, such as 3, may be primarily due to the aromatic stacking interaction with Trp-60D. However, energy contour calculations with the computer program GRID also indicate a favorable interaction between the benzothiazole sulfur atom and a hydrophobic patch on the surface of thrombin.
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PMID:In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1' subsite and its implications to structure-based drug design. 1577 42

Pregnancy due to its physiological changes is a procoagulant state. The rate of cardiac valve prosthesis thrombosis, deep venous thrombosis and pulmonary embolism are all increased. Thrombolytic therapy with tissue plasminogen activator (rt-PA) is an approved therapy for ischemic stroke, myocardial infarction, pulmonary embolism and thrombosis of cardiac valve prosthesis. However, there are no data from controlled randomized trials in pregnant patients. Thrombolytic therapy has been rarely used in pregnancy with only 28 cases of rt-PA thrombolysis reported in the literature so far. Indications for rt-PA thrombolysis were stroke (n = 10), thrombosis of cardiac valve prosthesis (n = 7), pulmonary embolism (n = 7), deep venous thrombosis (n = 3), and myocardial infarction (n = 1). Remarkably, all thrombosis of cardiac valve prostheses occurred after switching from warfarin to heparin in order to prevent teratogenicity and fetal loss. Two patients died (7%) and three suffered from complications that were managed conservatively (11%). In another three patients thrombolysis was not successful. Thrombolysis complication rates were similar compared to non-pregnant patients for the above mentioned indications. Six out of the 26 fetus from surviving mothers died (23%), three of them after induced abortion for maternal reasons (12%). A likely causal relation to the prior thrombolysis could only be established in two fetal fatalities (8%). None of the live born children suffered a permanent deficit. Considering that rt-PA does not cross the placenta and taking into account that the complication rates do not exceed those of large randomised controlled trials thrombolytic therapy should not be withheld in pregnant patients in case of life-threatening or potentially debilitating thrombembolic disease.
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PMID:Thrombolytic therapy in pregnancy. 1668 20


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