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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombus formation and intimal hyperplasia on the surface of implantable biomaterials such as poly(ethylene terepthalate) (Dacron) vascular grafts are major concerns when utilizing these materials in the clinical setting. Thrombin, a pivotal enzyme in the blood coagulation cascade primarily responsible for thrombus formation and smooth muscle cell activation, has been the target of numerous strategies to prevent this phenomenon from occurring. The purpose of this study was to covalently immobilize the potent, specific antithrombin agent recombinant hirudin (rHir) to a modified Dacron surface and characterize the in vitro efficacy of thrombin inhibition by this novel biomaterial surface. Bovine serum albumin (BSA), which was selected as the "basecoat' protein, was reacted with various molar ratios of the cross-linker sulphosuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (sulpho-SMCC; 1:5-1:50). These BSA-SMCC complexes were then covalently linked to sodium hydroxide-hydrolysed Dacron (HD) segments via the cross-linker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Covalent linkage of these complexes to HD (HD-BSA-SMCC) was not affected by any of the sulpho-SMCC cross-linker ratios assayed. rHir, which was initially reacted with 2-iminothiolane hydrochloride (Traut's reagent) in order to create sulphydryl groups, was then covalently bound to these HD-BSA-SMCC surfaces (HD-BSA-SMCC-S-rHir). The 1:50 (BSA: sulpho-SMCC) HD-BSA-SMCC-S-rHir segments bound 22-fold more rHir (111 ng per mg Dacron) compared to control segments and also possessed the greatest thrombin inhibition of the segments evaluated using a chromogenic substrate assay for thrombin. Further characterization of the HD-BSA-SMCC-S-rHir segments demonstrated that maximum thrombin inhibition was 20.43 NIHU, 14.6-fold greater inhibition than control segments (1.4 NIHU). Thrombin inhibition results were confirmed by 125I-thrombin binding experiments, which demonstrated that the 1:50 HD-BSA-SMCC-S-rHir segments had significantly greater specific thrombin adhesion compared to control segments. Non-specific 125I-thrombin binding to and release from the 1:50 HD-BSA-SMCC-S-rHir segments was also significantly less than the control segments. Thus, these results demonstrate that rHir can be covalently bound to a clinically utilized biomaterial (Dacron) while still maintaining its ability to bind and inhibit thrombin.
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PMID:Covalent linkage of recombinant hirudin to poly(ethylene terephthalate) (Dacron): creation of a novel antithrombin surface. 915 59

Effective, therapeutic thrombolysis should not only promote dissolution of fibrin but should also regulate continued thrombin-induced fibrin formation and the accumulation of platelets on the thrombotic lesion. The aim of the present study was to assess the use of a synthetic, low molecular weight thrombin inhibitor, argatroban in association with a well defined thrombolytic agent in a reproducible animal model of thrombolysis in vivo. Thrombi were formed in rat mesenteric venules with a helium neon (He-Ne) laser in the presence of Evans blue and were stabilised for 10 minutes. Thrombi formed in this manner were shown by transmission electron microscopy to be composed mainly of platelets. Thrombolysis was induced with recombinant staphylokinase in the presence and absence of argatroban and the process was monitored using computerised image analysis. Co-infusion of argatroban at a dose of 2.0 mg/kg/h with staphylokinase significantly enhanced the rate of thrombolysis. The results suggested that administration of the thrombin inhibitor together with the fibrinolytic agent moderated platelet-dependent mechanisms and led to a more rapid restoration of blood vessel patency.
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PMID:Adjuvant effect of argatroban on staphylokinase induced thrombolysis of platelet rich thrombi in rat mesenteric venules in vivo. 917 33

Vipera lebetina fibrinogenase (VlF) was shown to render fibrinogen incoagulable and to solubilize fibrin. The fibrinogenolytic activity of this enzyme was found to be 33 mg fibrinogen/min/mg protein. The study of the specificity of this enzyme revealed that it has no effect on purified factor X, prothrombin and protein C and on the specific chromogenic substrates of their active form. Plasminogen was not activated by VlF but slightly degraded. We have also compared the effect of VlF and plasmin on fibrinogen and shown that these two enzymes have a different sites of cleavage. This enzyme inhibited human platelet aggregation on PRP initiated by ADP and collagen but was without effect on the aggregation of washed rabbit platelets using thrombin as agonist. Administration of VlF in rat did not show any necrosis or hemorrhage in treated rats organ's. We therefore, examined the thrombolytic activity of VlF in a rat model of venous thrombosis. Thrombus was produced in the posterior vena cava by injection of human fibrinogen and thrombin. Injection of 5 mg/Kg body weight showed an evident flow restoration after one hour and measurement of the fibrinogen level a decrease of about 30% after 3 hrs. VlF's action is not dependent on plasminogen activators and may act synergistically with them, thereby providing an intriguing potential clinical application for dissolution of blood clots.
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PMID:Further characterization and thrombolytic activity in a rat model of a fibrinogenase from Vipera lebetina venom. 917 44

Thrombotic occlusion is responsible for most acute manifestations of coronary artery disease, including unstable angina and non-Q-wave myocardial infarction. Antiplatelet therapy plays a major role in reducing the risk of ischemic events in such patients. Since thrombin generation is vital to the pathogenesis of thrombosis, recent studies have focused on thrombin inhibition in the management of acute ischemia. Heparin is the most widely used anticoagulant for acute management of thrombosis and is the treatment of choice in preventing and treating venous thromboembolism. Given in therapeutic doses intravenously, it is more effective than aspirin in reducing the risk of death or myocardial infarction in patients with unstable angina. Low-molecular-weight (LMW) heparins have improved pharmacologic and pharmacokinetic properties over standard heparin that may result in greater efficacy and safety. LMW heparins may be given in a fixed dose subcutaneously without monitoring, resulting in greater clinical utility and cost-effectiveness compared with standard heparin. Given subcutaneously in fixed, weight-adjusted doses they are more effective and safer than intravenous heparin in treating deep-vein thrombosis. Several studies have evaluated LMW heparins in unstable angina. In a small open trial, LMW heparin (nadroparin) reduced the risk of acute myocardial infarction compared with aspirin alone or a combination of aspirin and standard heparin. In 2 large clinical trials, LMW heparin (dalteparin) has been shown to be effective in the management of unstable angina with a 63% reduction in risk of death or acute myocardial infarction over patients treated with aspirin alone (Fragmin during Instability in Coronary Artery Disease; FRISC) and to be as effective as intravenous heparin (Fragmin in Unstable Coronary Artery Disease; FRIC).
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PMID:New frontiers in the management of unstable coronary artery disease. 929 65

Tissue factor is a membrane-bound glycoprotein that functions in the extrinsic pathway of blood coagulation by acting as a cofactor for factor VII, and the resulting complex leads to thrombin production in vivo. The purpose of the present study is to determine whether macrophages express tissue factor in human coronary atherosclerotic plaques. We examined directional coronary atherectomy specimens from 24 patients with unstable angina and 23 with stable exertional angina. In these specimens, macrophages were detected in 22 (92%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P = .003). The percentage of macrophage infiltration area was significantly larger in patients with unstable angina than in those with stable exertional angina (17 +/- 3% versus 6 +/- 2%, P = .008). The immunohistochemical double staining revealed the expression of tissue factor on macrophages in 18 (75%) of 24 patients with unstable angina versus 3 (13%) of 23 with stable exertional angina (P < .0001). Thrombus was identified in 20 (83%) of 24 patients with unstable angina versus 12 (52%) of 23 with stable exertional angina (P = .02). Fibrin deposition was mainly observed around macrophages expressing tissue factor in the patients with unstable angina. We have shown that tissue factor expression on macrophages was more frequent in coronary atherosclerotic plaques in patients with unstable angina. Tissue factor expressed on macrophages may play an important role in the thrombogenicity in coronary atherosclerotic plaques of these patients.
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PMID:Tissue factor expression on macrophages in coronary plaques in patients with unstable angina. 935 94

Neutralase (heparinase I; E.C. 4.2.2.7) is a heparin-degrading enzyme undergoing clinical evaluation as an alternative to protamine for reversing the anticoagulant effects of heparin in coronary bypass surgery. The objective of this study was to assess the relative effects of Neutralase and protamine on reversal of heparin-dependent elevations in coagulation parameters and inhibition of clot formation in a rabbit vena caval stasis model. Rabbits were treated with saline or heparin (300 U/kg) for 10 minutes, followed by saline, protamine (2.6 mg/kg), or Neutralase (10 or 30 microg/kg, representing 1.23 IU/kg and 3.69 IU/kg, respectively). Twenty minutes later, venous stasis was induced, and vena caval clots were excised, weighed, and characterized. Coagulation parameters [activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT)] and antiFactor IIa and Xa levels were measured throughout the protocol. Both protamine and Neutralase reversed heparin-mediated increases in aPTT (>300 seconds to 26-35 seconds) and TCT (>300 seconds to 29-56 seconds) to values that were not different from saline-treated, nonheparinized animals. Thrombus weight in the nonheparinized saline group was 62+/-7 mg; heparin-treated animals had no detectable clots. Protamine reversal of heparin was associated with clot formation (89+/-20 mg) while Neutralase reversal was not (no clots). Heparin-induced increases in antiFactor IIa activity were reversed similarly by protamine and Neutralase (from 4.3-8.8 U/ml to 0.2-0.3 U/ml) while antiFactor Xa activity was differentially reversed (from 3.9-5.9 U/ml to 0.7-1.3 U/ml Neutralase; 5.5 U/ml to 0.02 U/ml protamine). These results are consistent with a hypothesis that Neutralase cleaves heparin into fragments, which are devoid of antiFactor IIa activity that retain modest antiFactor Xa activity, resulting in reversal of anticoagulant, but not antithrombotic, heparin activity. This property of Neutralase may be beneficial in reducing post-surgical thrombotic events after reversal of heparin.
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PMID:Neutralase reverses the anti-coagulant but not the anti-thrombotic activity of heparin in a rabbit model of venous thrombosis. 973 58

Thrombotic complications are a common sequel to percutaneous transluminal coronary angioplasty (PTCA), and may present either acutely as abrupt vessel closure, or as late restenosis. Pre-treatment with heparin, in conjunction with aspirin, reduces the incidence of thrombosis although the optimal dose and duration of treatment has still not been established. Continued heparin treatment after PTCA does not reduce the event rate in patients with no angiographic evidence of thrombosis. Low-molecular-weight heparins are more convenient to use than standard heparin and offer theoretical advantages, but these have not yet been demonstrated to affect outcomes. Similarly, there is no evidence that direct thrombin inhibitors improve long-term outcomes, despite their theoretical advantages over heparin. Mixed results have been seen with thrombolytic agents in abrupt vessel closure, but in unstable angina there is conclusive evidence that they are associated with a worse prognosis. Good results have been seen with the glycoprotein IIb/IIIa inhibitors, used in conjunction with aspirin and heparin. Trials of abciximab have shown significantly improved outcomes at 30 days, and encouraging trends have been seen with eptifibatide and tirofiban. Abciximab is the only agent in this class which has been demonstrated to reduce the incidence of late restenosis.
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PMID:Anticoagulation in interventional cardiology: optimizing patient outcome. 979 Feb 84

This report characterizes risk factors in patients who suffer pulmonary embolus (PE) after insertion of vena caval filter (VCF) and formulates an organized diagnostic and therapeutic plan of management. Three hundred eighteen patients were included in a review of patients undergoing insertion of VCF from 1989 to 1995. Ten patients (six men and four women, ages 25-72 years) from this group (3.1%) experienced PE after VCF insertion. Risk factors for deep venous thrombosis were documented in these ten patients. Venacavography was performed after diagnosis of PE. Thrombus length measured from the apex of the filter was used to determine further therapy. Thrombus 5 cm or greater in length was treated with a second VCF (VCF-2). Smaller clots were treated with anticoagulation (AC). All patients treated with AC underwent repeat vena caval study (CT scan or venacavagram) 10 days to 18 months after treatment. PE occurred from 8 days to 5.5 years after original VCF insertion. Five patients suffered PE longer than 6 months (range, 21-66 months; mean, 39 months) after VCF insertion. Venacavagrams demonstrated thrombus in all ten patients with PE. Six patients were treated with VCF-2 and four patients with AC. Dissolution of thrombus was seen on follow-up in all patients given AC. All 10 patients harbored at least two risk factors for deep venous thrombosis. Malignancy was found in only two patients. Five patients were found to have procoagulant states characterized by decreased levels of anti-thrombin III or protein C or S. No postoperative deaths or early recurrent PE occurred. One patient experienced another PE 5 years after treatment with AC when she discontinued warfarin. Contraindications to AC appeared to be self-limited, and all patients were discharged on warfarin. No significant bleeding occurred during early follow-up. Our findings confirm the reliability and low complication rate for VCF. Patients experiencing PE after insertion of VCF mandate an aggressive diagnostic approach that should include venacavography and a search for identifiable risk factors including procoagulant state. Treatment with AC and insertion of a second VCF both give favorable results. All patients appear to benefit from short- or long-term warfarin therapy, and contraindications to AC frequently are self-limited. Therapy based on clot size warrants further study.
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PMID:Pulmonary embolus after vena cava filter placement. 1019 Mar 60

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

Thrombotic risk in hyperlipidemic women and its response to lipid therapy is unknown. We prospectively studied 28 men and 29 women with high low-density lipoprotein (LDL) cholesterol during 6 months of therapy with pravastatin. Women had significantly higher high-density lipoprotein (HDL) cholesterol (54.2 +/- 1.7 vs 39.5 +/- 2.2 mg/dl, p <0.01), lower prevalence of coronary artery disease (41% vs 67%, p = 0.04), and otherwise similar baseline characteristics compared with men. Both genders achieved a 33% reduction in LDL at 6 weeks (188 +/- 6 to 133 +/- 5 mg/dl) and maintained similar LDL levels throughout the study. Systemic hemostatic markers and thrombus formation under dynamic flow conditions were evaluated at baseline, and at 3 and 6 months of follow-up. Prothrombin fragment F1.2, a marker of thrombin generation, was higher in women versus men at baseline (2.4 +/- 0.2 vs 1.4 +/- 0.3 nmol/L, p = 0.02). The levels decreased in women to 2.0 +/- 0.3 nmol/L at 3 months and to 1.6 +/- 0.2 nmol/L at 6 months (p <0.045, analysis of variance), whereas it remained unchanged in men. Plasminogen activator inhibitor-I significantly decreased at 3 and 6 months of follow-up: by 12.6% and 18.7%, respectively, in women, and by 18.8% and 23.5%, respectively, in men. Similarly, tissue plasminogen activator decreased significantly by 7.4% in women and 11.8% in men at 6 months compared with baseline. Fibrinogen showed an increase in both genders at follow-up. Thrombus formation was similar at baseline between the 2 genders, and decreased at 3 and 6 months compared with baseline by 12.5% and 29.5% in women, and by 18.6% and 19.4% in men (p <0.04 at 6 months vs baseline in both men and women). Other markers, including C-reactive protein, fibrinopeptide A, D-dimer, and factor VIIa, did not differ between genders and did not change with therapy. Thus, despite higher HDL, and lower incidence of coronary disease, women with high LDL had a comparable thrombotic and/or fibrinolytic profile to men and even evidence of increased thrombin generation at baseline. Blood thrombogenicity was reduced with pravastatin in both genders; in addition, thrombin generation was gradually reduced in women to a level similar to that of men by 6 months of follow-up.
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PMID:Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin. 1049 31


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