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)

Basic fibroblast growth factor (bFGF) and its specific receptors have diverse roles on a variety of cell types, such as the induction of vascular smooth-muscle cell proliferation which contributes to restenosis after coronary balloon angioplasty. bFGF is also known to interact with heparan sulphate proteoglycans present on the cell surface or in the extracellular matrix. In this study, the binding of 125I-bFGF to human aortic smooth-muscle cells was investigated. 125I-bFGF binding to these cells was reversible and saturable. Scatchard analysis revealed the presence of two distinct binding sites: a high-affinity receptor (Kd=38+/-7 pM; 1480+/-220 sites/cell) and a low-affinity non-saturable binding site (Kd=8. 0+/-2.0 nM). Pretreatment of the cells with heparinase resulted in a large reduction of 125I-bFGF binding to its low-affinity receptors, suggesting that they are heparin-like molecules. The specificity of the low- and high-affinity binding sites for bFGF was determined with acidic FGF, platelet-derived growth factor-BB and epidermal growth factor, which did not compete for 125I-bFGF binding. Expression of FGF receptor isoforms analysed by reverse transcriptase-PCR revealed the presence of only the type-1 receptor. Binding to low-affinity binding sites was antagonized by heparin, suramin, protamine sulphate and platelet factor 4. Unexpectedly, these molecules also reduced the binding of 125I-bFGF to its high-affinity sites. Consistent with these results, heparin, suramin, protamine sulphate and platelet factor 4 inhibited bFGF-induced proliferation of human aortic smooth-muscle cells. Heparin abrogated bFGF-induced release of tissue-type plasminogen activator by these cells. These observations suggest that the interaction of bFGF with human aortic smooth-muscle cells is different from that described for other cells such as endothelial cells, in which heparin acts as a potentiating factor of the mitogenic activity of bFGF.
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PMID:Heparin inhibits the binding of basic fibroblast growth factor to cultured human aortic smooth-muscle cells. 930 14

A canine model of electrolytic injury-induced coronary artery thrombosis and rtPA-induced thrombolysis was used to evaluate the relative antithrombotic efficacy of enoxaparin (a low molecular weight heparin), conventional therapy (heparin or heparin plus aspirin), and hirulog (a direct thrombin inhibitor), when used as adjunctive therapy during thrombolysis. After 60 min of clot aging, adjunctive therapy was begun at doses which elevated APTT approximately 2-fold over baseline. Fifteen minutes after the start of adjunctive therapy, recombinant tissue plasminogen activator (rtPA) was administered (100 microg/kg i.v. bolus + 20 microg/kg/min for 60 min). Adjunctive therapy continued for 1 h after termination of rtPA and blood flow was monitored for two additional hours. Enoxaparin (1 mg/kg i.v. bolus + 30 microg/kg/min, n = 10 for each treatment group) was the only adjunctive treatment that significantly increased the total minutes of flow (143 +/- 25 min out of a possible 240 min, vs 54 +/- 25 min for vehicle, p <0.05) and decreased thrombus mass (6.0 +/- 1.3 mg vs 11.8 +/- 3.2 mg for vehicle). Although hirulog (2 mg/kg i.v. bolus + 40 microg/kg/min) did not significantly increase the minutes of flow (120 +/- 27 min, p <0.06) or decrease thrombus mass (8.7 +/- 1.7 mg) compared to vehicle, these values were not significantly different than those measured in the enoxaparin group. However, the results with hirulog were achieved at the expense of a significantly greater increase in template bleeding time than that measured during enoxaparin treatment. Minutes of flow for heparin (50 U/kg i.v. bolus + 0.6 U/kg/min) and heparin plus aspirin (5 mg/kg i.v. bolus) were 69 +/- 20 and 60 +/- 23 min, respectively; thrombus masses were 8.2 +/- 1.3 and 7.3 +/- 1.0 mg, respectively. In summary, enoxaparin was more effective than conventional therapy in this model in terms of vessel patency and thrombus mass, and was as effective as hirulog, at least at a dose of hirulog that only modestly impaired hemostasis. Therefore, enoxaparin may prove to be a safe and effective alternative agent for adjunctive therapy during thrombolysis with rtPA.
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PMID:Comparison of enoxaparin, hirulog, and heparin as adjunctive antithrombotic therapy during thrombolysis with rtPA in the stenosed canine coronary artery. 936 98

Fibrinolytic therapy substantially reduces mortality from acute myocardial infarction. Patient selection is, however, important. The patient must present within 12 hours of the onset of ischaemic symptoms, have definite ECG changes of ST elevation or left bundle branch block and no contraindications. The major contraindications are those for risk of an intracerebral bleed, recent stroke, intracranial tumour or risk of a major systemic bleed. Age and hypertension are not contraindications but may modify the regimen used. Heparin is required with recombinant tissue plasminogen activator but is optional with streptokinase. The recent COBALT trial suggests that the accelerated weight related t-PA regimen given over 90 minutes is more satisfactory than double bolus t-PA. However, in patients under 75 years of age, the two regimens were equivalent. For patients suffering acute myocardial infarction, practitioners should now individualise choice of therapy, rather than give the same cocktail to all patients. The choice of regimen will depend on the cardiac risk, the stroke risk, the bleeding risk and the cost.
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PMID:The current status of thrombolytic therapy. 944 5

Stroke is a very common medical emergency that, until recently, had no specific treatment. Following the results of several major trials (including 2 'mega-trials'), aspirin (acetylsalicylic acid) can be recommended for the majority of patients with acute ischaemic stroke. While the benefit of aspirin is only modest, i.e. an increase of 11 per 1000 long term independent survivors, the public health benefit in the world will be substantial as this treatment could be given to millions of patients with acute ischaemic stroke each year. Heparin is associated with a reduction in early recurrent ischaemic stroke, but there is no net benefit because of a similar sized excess of recurrent haemorrhagic stroke (even for those in atrial fibrillation). Thrombolytic therapy has not been so widely tested and the results of the small trials to date have yielded conflicting results. The only positive publication to date (comprised of 2 related trials) evaluated the recombinant tissue plasminogen activator alteplase, but such treatment is probably only indicated for highly selected patients. Further trials are almost certainly required and it would be unwise to change clinical practice based on the current evidence. No other stroke treatments have been shown to be beneficial, and much larger trials will be required to confirm or refute possible moderate benefits of treatment. A well organised stroke service and participation in clinical trials will improve the future care of patients with acute ischaemic stroke.
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PMID:Drug therapy for acute ischaemic stroke: risks versus benefits. 982 50

The safety and tolerability of clopidogrel coadministration to patients with recent acute myocardial infarction (AMI) treated with recombinant tissue plasminogen activator (rt-PA) and heparin were assessed. Patients of either sex who had a recent uncomplicated AMI with ischemic pain lasting at least 20 minutes and ST-segment elevation, and with indication for thrombolysis were included. Treatment was started within 12 hours after the onset of pain. Clopidogrel 75 mg was administered within 3 hours of starting the rt-PA infusion, and was continued at 75 mg once daily over the next 6 days. Heparin was administered as a 5000 IU intravenous bolus followed by a 1000 IU/h infusion for at least 48 hours to maintain an activated partial thromboplastin time at 1.8 to 2.2 times the control value. rt-PA was administered as a 15 mg bolus injection, followed by a 0.75 mg/kg (up to 50 mg) infusion over 30 minutes and a subsequent 0.50 mg/kg (up to 35 mg) infusion over 60 minutes. The patients were hospitalized at least during the 7-day study period, after which they were followed for 10 days. The primary end point of the study was the occurrence of bleeding complications validated by a data monitoring and safety committee as severe (intracerebral or with substantial hemodynamic alteration requiring treatment), moderate (need for transfusion), or minor (other bleeding). Based on the statistical assumption, at alpha = 0.05 of a true probability of severe bleeding < or =0.06, the required minimum number of patients was calculated as 45, 65, or 94 if no, one, or two moderate-to-severe bleeding events occurred, respectively. Efficacy was assessed based on mortality, reinfarction, or need for emergency revascularization procedures. One intracranial hemorrhage occurred among the first 49 patients included, and one after the inclusion of 16 additional patients (total of 65). After further increase in the number of patients to 94, then to 116 in order to secure a number of 94 evaluable patients for safety, there were no additional cases of severe bleeding. Hence, the observed rate of moderate-to-severe bleeding was estimated at 1.7%, with a 95% probability that the underlying rate was below 7.5%. Deaths occurred in 3.6% compared to 6.3% in the GUSTO trial. Recurrent myocardial infarctions occurred in 4.5% and emergency revascularization procedures in 14.5% of the 110 patients deemed evaluable for efficacy, rates which are similar in this study and the GUSTO trial. The results of the study compare favorably with historical data showing a moderate-to-severe bleeding rate of 6% with aspirin given concomitantly with rt-PA and suggest that clopidogrel could be safely given as platelet aggrega
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PMID:Clopidogrel-rt-PA-heparin combination in the treatment of acute myocardial infarction. 1044 Apr 28

Accelerated thrombin generation is central to the development of hemostatic abnormalities during cardiopulmonary bypass (CPB) that are associated with both thromboembolic complications and serious, abnormal bleeding. Thrombin not only converts fibrinogen to fibrin, but also activates platelets and coagulation factors V, VIII, and XI and causes release of von Willebrand factor from vascular endothelium. Thrombin can also downregulate the hemostatic system by inducing formation of platelet inhibitory agents, such as nitric oxide and prostacyclin, and release of tissue plasminogen activator, facilitating activation of protein C, and releasing tissue factor pathway inhibitor. Excessive thrombin activity may also result in substantial consumption of platelets, fibrinogen, and labile coagulation factors and abnormal bleeding. Elevated tissue plasminogen activator levels secondary to activation of the contact system and surgery catalyze the formation of plasmin, which also consumes or internalizes platelet glycoprotein receptors and coagulation factors V, VIII, and fibrinogen. Heparin can reduce the generation of and mediate neutralization of excessive and CPB-associated thrombin activity. Heparin anticoagulation is commonly monitored with the activated clotting time (ACT). However, the ACT may be prolonged by factors other than heparin during CPB, such as hemodilution and hypothermia, and therefore may not accurately reflect the extent of anticoagulation by heparin. Aprotinin, a nonspecific serine protease inhibitor used with CPB, can also prolong celite-based ACT values, rendering it less reliable for monitoring heparin anticoagulation. Therefore, several alternative anticoagulation strategies have been recommended when aprotinin is used, such as a higher celite ACT trigger (>750 seconds), monitoring of whole blood heparin concentrations (eg, >2.7 U/mL), or administration of heparin based on a CPB duration-dependent, fixed-dose regimen. Administration of heparin doses higher than those generally recommended, as guided by predetermined, patient-specific whole blood heparin concentration measurements during bypass, can reduce excessive thrombin-mediated consumption of platelets and coagulation factors as well as post-CPB blood loss and blood component transfusions. New modalities of improving suppression of excess thrombin generation during CPB include use of heparin-bonded CPB circuits, heparin cofactor II or related analogs, supplemental antithrombin III, direct thrombin inhibitors (eg, hirudin, argatroban), and inhibitors of the contact and tissue factor pathways. The safety and efficacy of these approaches remains to be established by additional, appropriately powered, prospective studies.
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PMID:Anticoagulation and anticoagulation reversal with cardiac surgery involving cardiopulmonary bypass: an update. 1046 45

Plasma carboxypeptidase B (PCB) is an exopeptidase that exerts an antifibrinolytic effect by releasing C-terminal Lys and Arg residues from partially degraded fibrin. PCB is produced in plasma via limited proteolysis of the zymogen, pro-PCB. In this report, we show that the K(m) (55 nM) for plasmin-catalyzed activation of pro-PCB is similar to the plasma concentration of pro-PCB (50-70 nM), whereas the K(m) for the thrombin- or thrombin:thrombomodulin-catalyzed reaction is 10-40-fold higher than the pro-PCB level in plasma. Additionally, tissue-type plasminogen activator triggers activation of pro-PCB in blood plasma in a reaction that is stimulated by a neutralizing antibody versus alpha(2)-antiplasmin. Together, these results show that plasmin-mediated activation of pro-PCB can occur in blood plasma. Heparin (UH) and other anionic glycosaminoglycans stimulate pro-PCB activation by plasmin but not by thrombin or thrombin:thrombomodulin. Pro-PCB is a more favorable substrate for plasmin in the presence of UH (16-fold increase in k(cat)/K(m)). UH also stabilizes PCB against spontaneous inactivation. The presence of UH in clots prepared with prothrombin-deficient plasma delays tissue-type plasminogen activator-triggered lysis; this effect of UH on clot lysis is blocked by a PCB inhibitor from potato tubers. These results show that UH accelerates plasmin-catalyzed activation of pro-PCB in plasma and PCB, in turn, stabilizes fibrin against fibrinolysis. We propose that glycosaminoglycans in the subendothelial extracellular matrix serve to augment the levels of PCB activity thereby stabilizing blood clots at sites where there is a breach in the integrity of the vasculature.
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PMID:Characterization of plasmin-mediated activation of plasma procarboxypeptidase B. Modulation by glycosaminoglycans. 1057 83

Procoagulant and fibrinolytic disturbances are described in patients with acute coronary syndromes (ACS), but whether defective maximal tissue plasminogen activator (t-PA) release from the endothelium is also present is still controversial. Previous studies did not take into consideration the contribution of heparin, which strongly affects fibrinolysis. Accordingly, in this study, we measured maximal t-PA release in patients with ACS before, during, and after heparin treatment. Maximal t-PA release was measured by the venous occlusion test in 38 hospitalized patients with confirmed ACS (18 acute myocardial infarctions and 20 unstable anginas) before starting heparin, during heparin treatment, and 4 and 12 h after discontinuation. Plasma plasminogen activator inhibitor type 1 (PAI-1), D-dimer and prothrombin fragment F1 + 2 were also measured. Eighteen age-matched subjects with no evidence of coronary disease were used as controls. At admission, patients showed significantly higher plasma levels of t-PA, PAI-1, and F1 + 2 than controls. Before heparin, maximal t-PA release was similar in patients and controls. Heparin treatment was associated with a significant increase of plasma t-PA, while it did not affect maximal t-PA release. Coagulative and fibrinolytic disturbances are present in patients with ACS, but these do not include maximal t-PA release. Among our patients, maximal t-PA release appears stable over time and is not affected by heparin treatment.
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PMID:Maximal endothelial tissue plasminogen activator release is not impaired in patients with acute coronary syndromes before heparin treatment. 1146 9

Heparin has been proposed to enhance thrombolysis by inhibiting thrombin-dependent generation of activated TAFI (thrombin activatable fibrinolysis inhibitor), a carboxypeptidase that inhibits fibrinolysis. We evaluated the effect of heparin in an in vitro thrombolysis model consisting of a radiolabelled blood clot submerged in defibrinated plasma. Fibrinolysis was induced by adding t-PA (250 ng/ml) and calcium to the plasma bath. Control experiments indicated that thrombin generation induced by recalcification caused significant TAFI activation and inhibited clot lysis. Heparin (up to 1 U/ml), added to the plasma bath, failed to enhance clot lysis. Thrombin generation in the fluid phase was totally inhibited by heparin at concentrations > 0.5 U/ml. In contrast, thrombin generation on the clot surface was not inhibited by heparin (1 U/ml). TAFIa generation did occur in heparin-containing samples (1 U/ml) and amounted to about 10% of TAFIa formed in control samples. This low amount of TAFIa did exert antifibrinolytic activity as indicated by the observation that the addition of a specific TAFIa inhibitor (PTI) along with heparin enhanced clot lysis. Hirudin (10 micrograms/ml), at variance with heparin, inhibited clot-bound thrombin and enhanced clot lysis. These data show that heparin is unable to stimulate fibrinolysis through a TAFI-dependent mechanism, most likely because of its inefficiency in inhibiting thrombin generation on the clot surface. Moreover, they suggest that clot-bound thrombin plays a major role in TAFI-mediated inhibition of fibrinolysis through "localized" TAFIa generation.
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PMID:Effect of heparin on TAFI-dependent inhibition of fibrinolysis: relative importance of TAFIa generated by clot-bound and fluid phase thrombin. 1287 66

Patients with acute stroke caused by atherosclerotic carotid artery occlusion (ACAO) should receive intravenous tissue plasminogen activator if they meet eligibility criteria. Patients with acute stroke caused by ACAO who are not eligible for intravenous tissue plasminogen activator should receive aspirin. Heparin or heparin-like drugs do not improve outcome and should not be used. Therapy for prevention of recurrent stroke in patients with ACAO should consist of lifestyle modifications, risk factor intervention, and aspirin. Other antiplatelet drugs should be considered in patients with contraindication to aspirin. Warfarin is not indicated. Extracranial-intracranial bypass surgery provides no benefit over medical therapy in preventing recurrent stroke in a general population of patients with ACAO or in any subgroups selected by clinical or arteriographic criteria. Extracranial-intracranial bypass surgery in patients selected by hemodynamic criteria should only be performed as part of a randomized controlled clinical trial. Other surgical or endovascular procedures have no proven value in treating or preventing stroke caused by ACAO. Asymptomatic carotid occlusion has a benign prognosis, and requires no specific treatment other than lifestyle modification and risk factor intervention.
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PMID:Atherosclerotic Carotid Artery Occlusion. 1289 1


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