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)

Considering the important surface in pulmonary circulation where blood can interact with the endothelium, the maintenance of blood fluidity through the lung, by antithrombotic pathways and products of the endothelium, is essential. This function appears to be ineffective in primary pulmonary hypertension and in severe secondary pulmonary hypertension. Thrombotic lesions are frequently found in pulmonary arteries in these diseases. Thrombin activity appears to be increased in severe pulmonary hypertension. Antithrombotic pathway disorders may account for this abnormality, particularly in chronic thromboembolic pulmonary hypertension and primary pulmonary hypertension. Injured endothelium, a constant feature in severe pulmonary hypertension, either primary or secondary, enhances thrombus formation in pulmonary vessels. This is probably related to thrombomodulin and tissue factor imbalance, impairment of prostacyclin and nitric oxide release, as well as inefficiency of fibrinolysis. Moreover, platelets appear to be activated in the pulmonary circulation of these patients. They release several mediators acting on vascular tone and as mitogenic agents, and may also contribute to thrombin and clot generation. Long-term oral anticoagulant and continuous infusion of prostacyclin, treatments which impede thrombosis, are known to improve the survival rate in patients with primary pulmonary hypertension. These are the strongest arguments, so far, in favour of the role of thrombosis in severe pulmonary hypertension. However, we do not know whether these abnormalities result from a previous vascular injury or represent the primary disturbance.
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PMID:The role of thrombosis in severe pulmonary hypertension. 877 77

One of the main areas of interest in interventional cardiology is the understanding, and ultimate prevention of restenosis after an initially successful percutaneous transluminal coronary angioplasty. Restenosis is the recurrence of luminal narrowing following angioplasty, and still frustrates the late results in the treatment of angina pectoris. Experimental, pathological and clinical studies suggest that restenosis may occur via activation of the coagulation cascade, platelet activation and thrombus formation. Thrombin itself is identified as the most potent platelet activator, and has a pivotal role in the coagulation system. Furthermore, thrombin directly mediates smooth muscle cell proliferation by stimulating thrombin receptors at the smooth muscle cell surface. Thrombus indirectly induces excessive intimal smooth muscle cell proliferation by means of released mitogens (growth factors), which may contribute to late restenosis. Therefore direct and irreversible thrombin blockade by hirudin is deemed to be effective in the prevention of restenosis following angioplasty. The HELVETICA trial is a multicentre, randomized, double-blind heparin-controlled study, designed to compare the effects of two dose regimens of recombinant-hirudin (CGP 39,393/TMRevasc) with those of heparin on event-free survival, safety, tolerability and luminal renarrowing using quantitative coronary angiography no later than 26 weeks after the coronary angioplasty procedure.
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PMID:Evaluation of recombinant hirudin (CGP 39,393/TMREVASC) in the prevention of restenosis after percutaneous transluminal coronary angioplasty. Rationale and design of the HELVETICA trial, a multicentre randomized double blind heparin controlled study. 886 20

We describe a new method for quantification of fibrin in thrombi formed in native human blood at venous and arterial shear conditions in a parallel-plate perfusion chamber device. Thrombi consisting of various proportions of fibrin and platelets were digested by plasmin. Fibrin deposition (micrograms/cm2) was calculated from the measured D-dimer levels. Fibrin deposition in thrombi formed on a tissue factor (TF)-rich surface increased with increasing shear rate from 37 micrograms/cm2 at 100/s to 77 micrograms/cm2 at 2600/s (significant at 95%, ANOVA). The plasma levels of thrombin-antithrombin III complexes (TAT) increased in concert. In contrast, fibrin deposition in thrombi formed on collagen fibrils and the corresponding TAT plasma levels were independent of the shear rate and much lower than those elicited by the TF-rich surface (significant at 95%, ANOVA). The intra-individual variation in fibrin deposition was on average 10%, whereas the inter-individual differences were > 500%. Such a large inter-individual difference has not been detected by morphometry which usually is employed in similar studies. The present method is more accurate and less time-consuming than the morphometric approach. The novel method measures fibrin on the surface and in and around the thrombi, thus total deposited fibrin. In contrast, the morphometry approach quantifies surface coverage with fibrin only, thus being semiquantitative at best.
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PMID:Immunologic quantification of fibrin deposition in thrombi formed in flowing native human blood. 890 99

Thrombotic occlusion of coronary arteries is the reason of most acute coronary syndromes. A significant role in their prevention and therapy is taken by antiplatelet therapy. Acute coronary syndrome justifies also the use of anticoagulation therapy, name by heparin. The adjuvant therapy by means of heparin in thrombolysis seems to be necessary especially when alteplase (t-PA) is used. Peroral anticoagulants represent a further therapeutical procedure in patients with coronary ischaemia. Regarding the increased risk of bleeding, the cost and difficulties coinciding with therapy by cumarine derivates, the antiplatelet therapy is currently preferred. Cumarine derivates, however, should be used in patients with simultaneous atrial fibrillation, venous thromboembolism and it should be considered in patients with heart failure and pre-thrombotic states. Studies aimed at the assessment of the role of low-molecular heparin in acute coronary ischaemia currently take place. Encouraging results are gained from experience with high effective direct inhibitors of thrombin (e.g. hirudin) and antagonists of glycoprotein IIb/IIIa. It seems that they soon will find justification in the therapy of arterial thrombosis. Interesting field of the research is represented by the studies which compare low doses of acetylosalicylic acid with low doses of cumarine derivates. (Ref. 43.)
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PMID:[Antithrombotic therapy in acute myocardial infarct]. 896

Reversibility in vivo of acute platelet thrombosis in response to specific anticoagulants is analyzed with thrombi that develop in segments (1 cm) of porcine carotid arteries externally crushed with a hemostat. Most thrombi fill the lumens of the injured segments (ca. 1 cm x 3 mm, 1 x w) within 30 min and comprise masses of platelets interpenetrated with neutrophil-lined seepage channels of blood. Continuous quantitative assay of thrombus mass is provided by a gamma detector placed over the injured segments to collect counts from 111In-labeled platelets. Thrombi established 30 min after injury, otherwise stable for 6 h, clear during 30-60 min of continuous infusion of either hirudin, tick anticoagulant or activated porcine protein C, or intermittent activation of endogenous protein C with a latent thrombin reagent. Anticoagulant dose-dependence of thrombus clearance is established for hirudin between 0.01 and 1.0 mg/kg/min. Thrombi become progressively refractory to hirudin between 0.5 and 6 h after injury. Neither heparin no low-molecular-weight heparin in full (clinical) anticoagulant doses yield significant dethrombosis. It is concluded that, within time limits, controlled thrombin generation in platelet thrombi maintains platelet cohesion without catalyzing irreversible platelet aggregation or clotting of fibrinogen.
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PMID:Reversibility of platelet thrombosis in vivo. Quantitative analysis in porcine carotid arteries. 897 39

Conversion by alpha-thrombin of the zymogen human protein C (HPC) to activated protein C (aPC) is an important physiologic feedback control mechanism for the coagulation cascade. Although activation of HPC by thrombomodulin-bound thrombin is relatively rapid, activation by free thrombin occurs at a significantly slower rate. Previously, we generated a "hyper-activatable" derivative of HPC (FLIN-Q3) with an increased activation rate by free alpha-thrombin in vitro. In this study, the antithrombotic efficacy of FLIN-Q3 was compared with both native zymogen and aPC in an arteriovenous shunt model of thrombosis in the guinea pig. Recombinant proteins were infused 15 minutes before and throughout a 15-minute period while blood was circulated from carotid to jugular through tubing that enclosed a thread on which fibrin was deposited. Parallel dose-dependent antithrombotic responses were observed. Under these non-steady-state conditions, the calculated infusion doses associated with a 50% reduction of thrombus mass were 2.7, 24, and 250 mg/kg/h for aPC, FLIN-Q3, and HPC, respectively. Thrombus weight correlated inversely with plasma concentration of aPC, measured amidolytically, from either direct infusion of aPC or that generated from the zymogens in the animal, and similarly correlated inversely with anticoagulant activity measured by whole blood aPTT. Neither zymogen form showed significant aPC activity before shunt circulation, suggesting a requirement for exposure to thrombin. After the infusion was discontinued for 15 minutes, a second period of thrombus formation in the shunt demonstrated the ability of zymogen forms of PC, unlike aPC, to provide "on-demand" anticoagulant responses to repeated thrombotic stimuli. Thus, a "hyper-activatable" PC molecule such as FLIN-Q3 may represent a superior form of anticoagulant therapy than either the native zymogen or aPC.
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PMID:Antithrombotic efficacy in the guinea pig of a derivative of human protein C with enhanced activation by thrombin. 900 56

Thrombotic complications are frequent with indwelling central venous catheters and result in catheter dysfunction, vascular obstruction and may also contribute to catheter-associated infections. The pathogenesis of catheter thrombosis is not well characterized but may involve vessel damage, local stasis and catheter-associated thrombin formation. We have, therefore, measured the thrombin activity associated with central venous catheters removed from patients and have also determined the ability of hirudin to inactivate catheter-associated thrombin. We obtained 48 catheters from 46 patients and removed 1 cm portions for study. These were taken from the distal end, 5 cm proximal, and 15 cm proximal from the end. Following washing, thrombin activity was measured with a chromogenic assay. Thrombin was associated with 40 of 48 catheters and with 100 of 144 segments with a mean activity of 132 +/- 27 microU/cm with a range of 0 to 2,160 microU/cm. Incubation in hirudin reduced the activity from a mean of 122 +/- 33 microU/cm to 18 +/- 6 microU/cm (p < .001). Scanning electron microscopy of selected catheters showed that some had areas of fibrin deposition which was not apparent visually. The findings indicate that indwelling central venous catheters frequently have associated thrombin activity which can be inhibited by a direct-acting thrombin inhibitor such as birudin.
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PMID:Thrombin activity associated with indwelling central venous catheters. 903 48

Two thrombosis models in rats are described in which mixed type thrombi are formed at arterial and venous flow rates. The models, containing a silk thread in the aorta and vena cava, respectively, were characterised for the activity of three platelet inhibitors, three thrombin active site inhibitors and five glycosaminoglycans (GAGs). In the two models a similar highly platelet-dependent thrombus developed both in size and composition during the first 10 min after insertion of the silk thread. The thrombotic processes were self-limiting, thus maintaining blood flow, but persisted twice as long in the vena cava model. In both models the thrombus consisted for more than 65% of platelets. Thrombus development under arterial as well as under venous flow conditions was inhibited dose dependently by all tested compounds including aspirin and the synthetic alpha-methyl glycoside copy of the ATIII binding pentasaccharide within heparin, Org31540/SR90107A. Simultaneous fibrin deposition and platelet activation, which represents an essential element of arterial thrombosis, initially dominated-in both models. The gradual thrombus outgrowth, in the cava model, was more sensitive to factor Xa selective anti-coagulants, as is venous thrombosis.
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PMID:Two new closely related rat models with relevance to arterial thrombosis--efficacies of different antithrombotic drugs. 903 71

We developed a fibrin-rich thrombotic focal cerebral ischemic model with reproducible and predictable infarct volume in rats. In male Wistar rats (n = 77), a thrombus was induced at the origin of the middle cerebral artery (MCA) by injection of thrombin via an intraluminal catheter placed in the intracranial segment of the internal carotid artery (ICA). Thrombus induction and consequent ischemic cell damage were examined by histopathological analysis and neurological deficit scoring, and by measuring changes in cerebral blood flow (CBF) using laser-Doppler flowmetery (LDF), perfusion-weighted imaging (PWI), and by diffusion weighted imaging (DWI). Histopathology revealed that a fibrin-rich thrombus localized to the origin of the right MCA. Regional cerebral blood flow (rCBF) in the right parietal cortex was reduced by 34-58% of preinjection levels after injection of thrombin in rats administered 30 U of thrombin (n = 10). Magnetic resonance imaging (MRI) showed a reduction in CBF and a hyperintensity DWI encompassing the territory supplied by the right MCA. The infarct volume in rats administered 80 U of thrombin was 31.29 +/- 12.9% of the contralateral hemisphere at 24 h (n = 13), and 34.7 +/- 16.4% of the contralateral hemisphere at 168 h (n = 6). Rats administered 30 U of thrombin exhibited a hemispheric infarct volume of 34.0 +/- 14.5% (n = 9) at 24 h and 29.7 +/- 13.9% (n = 8) at 168 h. In addition, thrombotic rats (n = 3) treated with recombinant tissue plasminogen activator (rt-PA) (10 mg/kg) 2 h after thrombosis showed that CBF rapidly returned towards preischemic values as measured by PWI. This model of thrombotic ischemia is relevant to thromboembolic stroke in humans and may be useful in documenting the safety and efficacy of thrombolytic intervention as well as for investigating therapies complementary to antithrombotic therapy.
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PMID:A new rat model of thrombotic focal cerebral ischemia. 904 Apr 91

Thrombus deposits on foreign surfaces in contact with blood. Substances adsorbed on the surface can influence thrombus formation. Platelet activator substances and coagulation components thrombin and fibrinogen, were adsorbed onto respective series of platinum wire. A treated wire and a control untreated wire inserted for one hour into the vena cava in groups of rats and the deposited thrombus was weighed. A control group of rats bore two untreated wires which attracted similar thrombus. Arachidonic acid and adenosine diphosphate negligibly affected thrombus. Collagen, fibrinogen, thrombin and egg albumin significantly reduced thrombus deposits by up to 85%.
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PMID:Antithrombotic effect in vivo of thrombotic substances adsorbed on a platinum surface. 904 89


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