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)

The diagnostic efficiency of autologous 111In-labelled platelets (ILP) as a scanning agent in deep vein thrombosis (DVT) was investigated in 24 South African baboons (Papio ursinus). Thrombi were surgically induced by stasis, intimal injury and the injection of thrombin in the common femoral veins of adult baboons. The thrombi were allowed to age for 1, 2, 4, 8, 24, 48 and 72 h before injecting the ILP. Scanning was done with a large field gamma camera at 10 min post injection and again at 2, 4, 6, 8, 10, 14, 24, 48 and 72 h. Time-activity curves were thus obtained and it was possible to establish an optimal time after injection of the ILP to scan for each group of thrombi. The results indicate that only the younger thrombi (1-8 h after thrombus formation) were detected. Twenty-four hour and older thrombi were not visualised. A favourable time to scan in the case of the younger thrombi appeared to be approximately 20 h after the injection of ILP. However, the thrombus age limitation still impairs the diagnostic efficiency of the procedure.
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PMID:Evaluation of the diagnostic efficacy of autologous 111In-labelled platelets as a scanning agent for deep vein thrombosis in the chacma baboon. 400 84

The antithrombotic effects of the synthetic thrombin inhibitor 4-amidinophenylpyruvic acid and the naturally occurring thrombin inhibitor heparin were studied in a stasis-induced venous thrombosis model and an extracorporeal shunt model in rats. The incidence of venous thrombosis was reduced in a dose-dependent manner by both inhibitors. Thrombus size was reduced in the animals in which thrombi continued to form under treatment. The antithrombotic effect of the synthetic inhibitor was accompanied by considerable prolongation of the plasma thrombin time, whereas the effect of heparin on the thrombin time was less pronounced. The time until thrombotic occlusion of the extracorporeal arterio-venous shunt occurred was prolonged by both inhibitors in dependence upon the dose. The amount of thrombotic occluding material in the shunt was reduced and altered in composition. Synthetic thrombin inhibitors are potential antithrombotic agents whose effectivity corresponds to that of heparin.
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PMID:Comparative study on the antithrombotic effects of a synthetic thrombin inhibitor and of heparin in animal models. 665 12

A simple venous thrombosis model in rabbits was used for the quantitative evaluation of the thrombolytic effect of human extrinsic (tissue-type) plasminogen activator as compared with urokinase.A thrombus was formed in an isolated segment of the jugular vein from a mixture of (125)I-labeled fibrinogen, whole rabbit blood, and thrombin. In order to immobilize the thrombus during lysis, it was formed around a woolen thread introduced longitudinally in the lumen of the vein. Thrombotic extension of the clot was prevented by subcutaneous injection of heparin. The extent of thrombolysis was measured as the difference between the radioactivity introduced in the clot and that recovered in the vein segment at the end of the experiment. In control animals the extent of thrombolysis was 5.6+/-1.4% (n = 5) after 6 h, 14.5+/-1.7% (n = 10) after 30 h, 16.0+/-1.5% (n = 11) after 78 h, and 48.1+/-2.7% (n = 10) after 174 h (mean+/-SEM). Extrinsic (tissue-type) plasminogen activator, highly purified from the culture fluid of a human melanoma cell line, was administered systemically or locally over a time period of 4 h and the percent thrombolysis measured 2 h after the end of the infusion. One- and two-chain extrinsic plasminogen activator had very similar thrombolytic potency. Systemic infusion resulted in a dose-dependent degree of thrombolysis. The activator-induced thrombolysis, after infusion of 100,000 IU ( congruent with1 mg protein), was approximately 75% for fresh clots, 35% for 1-d-old clots, 30% for 3-d-old clots, and 50% for 7-d-old clots. The thrombolytic activity of urokinase was more than five times lower than that of extrinsic plasminogen activator: Infusion of 500,000 IU resulted in approximately 40% lysis of fresh clots and 25% of 1-3-d-old clots, while 7-d-old clots appeared to have become resistent to urokinase. Local infusion resulted in a 5-10 times higher thrombolytic effect of both extrinsic plasminogen activator and urokinase. Thrombolysis with extrinsic plasminogen activator was not associated with systemic activation of the fibrinolytic system as evidenced by unaltered plasma levels of fibrinogen, plasminogen, and alpha(2)-antiplasmin. Systemic infusion of urokinase resulted in significant thrombolysis only at doses that were associated with disseminated plasminogen activation. Local infusion of urokinase required a 5-10-fold higher dose than extrinsic plasminogen activator to obtain a similar degree of thrombolysis, which also occurred in the absence of systemic activation of the fibrinolytic system. It is concluded that the extent of thrombolysis by extrinsic plasminogen activator is mainly determined by the dose of activator and its delivery in the vicinity of the thrombus and much less by the age of the thrombus or the molecular form of the activator. Extrinsic plasminogen activator appears to be superior to urokinase because of its higher (5-10-fold) specific thrombolytic activity and the absence of systemic activation of the fibrinolytic system, which results in defibrinogenation and a bleeding tendency.
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PMID:Thrombolysis with human extrinsic (tissue-type) plasminogen activator in rabbits with experimental jugular vein thrombosis. Effect of molecular form and dose of activator, age of the thrombus, and route of administration. 668 15

Thrombotic events have been reported in acute lymphoblastic leukaemia patients, especially during or after L-asparaginase administration. A so-called L-asparaginase associated coagulopathy has been well recognized, being characterized by a hypercoagulable state (decrease of antithrombin III, plasminogen, protein C, protein S and increase of prothrombin fragment F1 + 2, thrombin-antithrombin complexes and fibrinopeptide A). The aim of this study was to determine whether the supplementation of antithrombin III (AT-III) concentrates could improve the L-asparaginase associated coagulopathy, thereby blocking the activation of the haemostatic system. In 25 adult patients with acute lymphoblastic leukaemia (M 19, F6, mean age 34 years) antithrombin III (AT-III) concentrates were administered at daily doses of 50 U/kg for 10 consecutive days from the beginning of L-asparaginase therapy (6,000 U/m2/day s.c. for 7 days), given according to the GIMEMA ALL 0288 trial. A marked increase of antithrombin III was recorded on days IV-VIII-XI (P < 0.001). No changes in protein C, protein S, plasminogen, alpha 2-antiplasmin, factor VII and platelet count were observed and there was no increase in markers of hypercoagulability. There was no evidence of disseminated intravascular coagulation. In conclusion, AT-III concentrate supplementation during L-asparaginase therapy, by the achievement of high levels of antithrombin III, is associated with a lack of activation of the haemostatic system and appears to overcome the complex coagulopathy associated with L-asparaginase.
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PMID:Antithrombin III infusion suppresses the hypercoagulable state in adult acute lymphoblastic leukaemia patients treated with a low dose of Escherichia coli L-asparaginase. A GIMEMA study. 751 43

Thrombus generation is central to thrombosis at vascular lesion sites, including post-PCTA acute reocclusion and chronic restenosis. Thrombin stimulates platelet activation, monocyte and neutrophil chemotaxis, and endothelial production of prothrombotic factors. The varied physiologic effects of thrombin are due to the widespread presence of thrombin receptors in many cell types. The receptor is uniquely activated: thrombin binds to the receptor at the thrombin anion-binding exosite, the receptor ligand ("tethered ligand") apparently being a sequence of 6 amino acids (SFLLRN). Thus, peptides corresponding to the sequence of the tethered ligand can stimulate almost all functions of native thrombin itself. Several intracellular signaling pathways have been identified as important in the restenosis process: the G protein-related pathway, cyclic adenosine monophosphate (cAMP) mediator pathway, and tyrosine kinase activation pathway. In situ hybridization has demonstrated an increase in thrombin receptor mRNA throughout the period of neointimal and vascular lesion development. The mechanism of this increase is unknown, but may be mediated by multiple inflammatory modulators. Several strategies have been tested in animal models for inhibiting thrombin: (1) Hirudin not only prevents thrombin from cleaving fibrinogen, but also prevents thrombin receptor activation. (2) Thrombin receptor antagonist peptides block platelet aggregation effects of thrombin. (3) Mono- and polyclonal antibodies inhibit thrombin receptor activation. (4) Antisense oligonucleotides block thrombin receptor expression.
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PMID:Role of the thrombin receptor in restenosis and atherosclerosis. 786 77

The relationship between thrombosis and atherosclerosis has been already suggested in the middle of the last century. More recently, in 1976 a hypothesis has been put forward which emphasize the leading role of chronic injury to endothelial cells followed by platelet attachment and the release of platelet derived growth factors in pathogenesis of atherosclerosis. There is also a growing body of evidence that cytokines, thrombin and the fibrinolytic system are involved in the initiation and progression of atherosclerotic lesions. Lipoprotein (a) is emerging as a link between atherogenic role of lipids and the haemostatic system. At the same time epidemiological data are pointing at the possible role of fibrinogen, factor VII and plasminogen activator inhibitor-1 as risk factors for ischemic heart disease. Thrombus formation is also responsible for the majority of acute coronary syndromes. On the other hand aspirin and other antiplatelet drugs seem to protect from vascular complications of atherosclerosis. Than the question which rather arises is: what is the best antithrombotic strategy in patients with cardiovascular diseases?
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PMID:[Should hemostatic factors be considered in the prevention of cardiovascular disease?]. 797 94

In vivo arterial thrombosis occurs preferentially at curvatures and branchings, i.e. regions of flow separation and recirculation where blood is retained orders of magnitude longer than within straight vessel sections. To examine the effect of such disturbed flow on endothelial thromboresistance glass T-branchings lined with endothelial cells from human umbilical cord veins (HUVEC) were perfused with buffered fibrinogen solution (3mg/ml). The flow was adjusted to form a large recirculation zone and flow conditions were determined beforehand by means of flow visualization via dye injection as well as by laser ultramicroscope anemometry. Thrombus formation, which was registered on-line by video and evaluated planimetrically, was induced by injection of thrombin at concentrations ranging from 0.3 to 2.0 units/ml. Fibrin thrombus growth always began within the flow niche at the point of flow separation and extended downstream along the wall and into the vessel lumen finally occluding up to 80% of the lumen. Light and electron microscopy revealed that overall thrombus form as well as the orientation of single fibrin fibers were correlated strictly to the prevailing streamlines. Despite the integrity of the endothelial lining fibrin thrombus formation occurred. The fibrin fibers closely contacted the endothelial surface. These results indicate that recirculation zones promote fibrin thrombus formation sufficient to obstruct the vessel lumen and that intact endothelium alone is insufficient in preventing adhesion of fibrin to its surface.
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PMID:Flow mediated fibrin thrombus formation in an endothelium-lined model of arterial branching. 809 5

Bay U3405 is a thromboxane A2 (TxA2)-receptor antagonist that inhibits the binding of TxA2 to its target cells. The aim of this study was to determine if Bay U3405 could be used to inhibit arterial thrombosis. A thrombogenic device, consisting of uncrimped Dacron vascular graft material (0.5 cm2) built into the wall of silicone rubber tubing with 4 mm inside diameter, was exposed to native flowing blood under arterial blood flow conditions (100-140 ml/min) by interposing the devices as extension segments into permanent femoral arteriovenous shunts implanted in baboons. Thrombus formation was quantified in vivo by measuring the deposition of 111In-labelled platelets onto the graft material with a scintillation camera. In six baboons, a bolus injection of Bay U3405, calculated to attain an initial plasma concentration of 300 ng/ml, reduced the maximum thrombus formation measured over a 2 h study period. Platelet deposition was reduced by 33 +/- 14% (SD) at 2 h as compared to control studies done in the same baboons. The accumulation of additional platelets onto a thrombus that was allowed to form for 1 h, was reduced by 58 +/- 28% at 2 h. Ex vivo platelet aggregation in response to ADP, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) were not affected by the treatment. Ex vivo platelet aggregation in response to collagen was markedly inhibited for 2 h after treatment. The results demonstrated that selective blocking of the TxA2-receptor on platelets reduced platelet-dependent thrombus formation and the accumulation of additional platelets in a freshly formed thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo inhibition of acute platelet-dependent thrombosis in a baboon model by Bay U3405, a thromboxane A2-receptor antagonist. 811 94

An in vitro model was designed to test the hypothesis that thrombi of varying composition have different echogenic patterns. Thrombi were prepared in specially designed tubes, mounted on a holder that allows introduction of an intravascular ultrasound catheter rotated inside a subselective sheath. The thrombi were made by the addition of thrombin to whole blood, platelet-rich plasma, and to mixtures of whole blood and platelet-rich plasma with increasing concentration of whole blood relative to the volume of the mixture in the following ratios: 1:5, 2:5, 3:5 and 4:5. Sixty-six thrombi prepared from 11 blood samples of healthy subjects were studied and compared with control tubes filled with saline solution. Platelet-rich thrombi showed low echogenicity similar to saline solution. Whole blood thrombi appeared uniformly "speckled." Mixtures of whole blood and platelet-rich plasma showed a gradual increase in echogenicity with an increasing amount of whole blood in the mixture. Quantitative videodensitometry compared the gray scale intensity of each image relative to background saline. The mean value of echogenicity of platelet-rich thrombi was 0.9 +/- 1.2, and the mean value of whole blood thrombi was 13 +/- 5.3. Platelet-rich thrombi are echo-lucent, and the main echogenic reflectance of thrombi originates from red blood cells. The ultrasound intensity is in linear relation to the amount of red blood cells in the thrombus.
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PMID:Intravascular ultrasound characterization of thrombi of different composition. 819 29

Nitroglycerin provides an external source of nitric oxide which stimulates guanylate cyclase and produces vasodilatation and inhibition of platelet function. The antithrombotic effects of intravenous nitroglycerin were recently documented in various experimental models and in patients with unstable angina. This protocol was designed to evaluate whether these effects could also be detected with transdermal nitroglycerin in patients with stable angina. In a randomized, double-blind, controlled parallel trial, 22 patients received transdermal nitroglycerin, 0.6 mg/hour (11 patients), or placebo (11 patients). Platelet aggregation to adenosine diphosphate (ADP) and to thrombin was measured in whole blood. Thrombus formation was assessed on porcine aortic media exposed to the patient's venous blood for 3 minutes at shear rates of 2,546 and 754 s-1. Platelet aggregation to ADP decreased from 7.7 +/- 0.8 to 5.3 +/- 0.8 ohms (p < 0.05) with nitroglycerin, and to thrombin from 15.6 +/- 1.2 to 12 +/- 1.2 ohms (p < 0.05). Thrombus size at the high-shear rate decreased from 2.8 +/- 0.7 to 1.0 +/- 0.3 microns 2 (p < 0.05), and at the low-shear rate from 2.5 +/- 0.5 to 1.0 +/- 0.2 microns 2 (p < 0.05). Placebo had no significant effect on platelet aggregation and platelet thrombus deposition. These parameters were all reduced by > or = 20% in 8 patients taking nitroglycerin but only in 3 patients taking placebo (p < 0.05). Transdermal nitroglycerin significantly inhibits platelet aggregation and mural thrombus formation in patients with angina pectoris.
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PMID:Antithrombotic properties of transdermal nitroglycerin in stable angina pectoris. 819 30


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