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)

A numerical model of thrombosis/thromboembolism (T/TE) is presented that predicts the progression of thrombus growth and thromboembolization in low-shear devices (hemodialyzers, oxygenators, etc.). Coupled convection-diffusion-reaction equations were solved to predict velocities, platelet agonist (ADP, thromboxane A2, and thrombin) concentrations, agonist-induced and shear-induced platelet activation, and platelet transport and adhesion to biomaterial surfaces and adherent platelets (hence, thrombus growth). Single-platelet and thrombus embolization were predicted from shear forces and surface adhesion strengths. Values for the platelet-biomaterial reaction constant and the platelet adhesion strength were measured in specific experiments, but all other parameter values were obtained from published sources. The model generated solutions for sequential time steps, while adjusting velocity patterns to accommodate growing surface thrombi. Heparinized human blood was perfused (0.75 ml/min) through 580 microm-ID polyethylene flow cells with flow contractions (280 microm-ID). Thrombus initiation, growth, and embolization were observed with videomicroscopy, while embolization was confirmed by light scattering, and platelet adhesion was determined by scanning electron microscopy. Numerical predictions and experimental observations were similar in indicating: 1) the same three thrombotic locations in the flow cell and the relative order of thrombus development in those locations, 2) equal thrombus growth rates on polyethylene and silicon rubber (in spite of differing overall T/TE), and 3) similar effects of flow rate (1.5 ml/min versus 0.75 ml/min) on platelet adhesion and thrombosis patterns.
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PMID:Computational model of device-induced thrombosis and thromboembolism. 1607 18

We studied whether there was a relationship between the anticoagulant effects of recombinant human soluble thrombomodulin (rhsTM) and activation of protein C in a primate model of acute vascular graft thrombosis in 11 baboons (Papio species). Baboons were pretreated with 0.1, 1 and 5 mg/kg of rhsTM, with or without co-injection of a neutralising monoclonal antibody to protein C (HPC4) in the 1 mg/kg rhsTM group. Subsequently, thrombogenic polyester grafts were deployed for 3 h into chronic exteriorised arteriovenous shunts. Thrombus growth in the graft, plasma-activated protein C (APC) levels, coagulation and thrombosis markers were determined. In untreated baboons, baseline circulating APC levels more than doubled and graft thrombi propagated until reaching equilibrium in about 1 h. Treatment with rhsTM reduced thrombus propagation rates, prolonged the clotting and bleeding times, decreased thrombin-antithrombin complex, beta-thromboglobulin and fibrinopeptide A levels, and, surprisingly, also decreased systemic APC levels, in a dose-dependent manner. In the presence of HPC4 antibody to inhibit APC generation, the acute antithrombotic activity of rhsTM on graft thromboses was not attenuated for up to 80 min, but sustained thrombus accumulation was observed over a 180-min period. These findings suggest that, in contrast to the prevailing hypotheses, the primary antithrombotic activity of rhsTM is independent of protein C, at least in this primate model. Direct inhibition of thrombin's prothrombotic activity upon complex formation with rhsTM might explain the molecular mechanism of the observed antithrombotic effect.
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PMID:Soluble thrombomodulin is antithrombotic in the presence of neutralising antibodies to protein C and reduces circulating activated protein C levels in primates. 1639 53

The role of the collagen receptor glycoprotein VI (GPVI) in arteriolar thrombus formation was studied in FcRgamma-null mice (FcRgamma(-/-)) lacking platelet surface GPVI. Thrombi were induced with severe or mild FeCl(3) injury. Collagen exposure was significantly delayed and diminished in mild compared with severe FeCl(3) injury. Times to initial thrombus formation and vessel occlusion were delayed in FcRgamma(-/-) compared with wild-type mice after severe injury. Platelet accumulation in wild-type mice was decreased after mild compared with severe injury. However, there was little difference between platelet accumulation after severe or mild injury in FcRgamma(-/-). These data indicate a significant role for GPVI in FeCl(3)-induced thrombus formation. Pretreatment of wild-type mice with lepirudin further impaired mild FeCl(3)-induced thrombus formation, demonstrating a role for thrombin. Laser-induced thrombus formation in wild-type and FcRgamma(-/-) was comparable. Collagen exposure to circulating blood was undetectable after laser injury. Normalized for thrombus size, thrombus-associated tissue factor was 5-fold higher in laser-induced thrombi than in severe FeCl(3)-induced thrombi. Thus, platelet activation by thrombin appears to be more important after laser injury than platelet activation by GPVI-collagen. It may thus be important when considering targets for antithrombotic therapy to use multiple animal models with diverse pathways to thrombus formation.
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PMID:Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo. 1645 53

Alterations in hemostasis have frequently been observed in children with acute lymphoblastic leukemia. Thrombotic events are well documented in patients receiving L-asparaginase as a single agent or in combination with other chemotherapeutic drugs. The present prospective, randomized study evaluated the effect of two different L-asparaginase preparations, native Escherichia coli L-asparaginase (Crasnitin; Bayer AG, Leverkusen, Germany; n = 10) and L-asparaginase derived from Erwinia chrysanthemi (Erwinase; Porton Pruducts, London, UK; n = 10) on the changes in parameters concerning hypercoagulability. Patients were randomized to receive a total of eight doses of 10,000 IU/m2 L-asparaginase intravenously with intervals of 3 days during induction therapy. Before starting L-asparaginase treatment all patients had already demonstrated an increased thrombin generation shown by the elevated levels of prothrombin fragment 1+2 and thrombin antithrombin III, presumably due to therapy with prednisone, daunorubicin and vincristine. A significant decrease in alpha2-antiplasmin and plasminogen levels was measured in the E. coli L-asparaginase but not in Erwinase-treated patients. Increased thrombin generation combined with a decrease in alpha2-antiplasmin and plasminogen levels may lead to a state of increased risk for thrombosis due to a delay in fibrin elimination in E. coli L-asparaginase-treated patients only.
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PMID:Changes in hypercoagulability by asparaginase: a randomized study between two asparaginases. 1647 96

Thrombus on the atherosclerotic plaque is mainly responsible for acute coronary syndromes. Antithrombin therapy continues to be the mainstay of the therapy defeating thrombus. Up-to-date antithrombin therapy consists of vitamin K antagonists, unfractionated and low molecular heparins, direct thrombin inhibitors and selective inhibitors of factor Xa. Today, none of these drugs is effective enough in every aspect. The need for new antithrombin drugs, as well as the need for new antiplatelet drugs which can be safely and effectively used together with other antithrombin drugs, persists.
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PMID:[Antithrombotics (Antithrombin therapy)]. 1661 71

Synergism between low-molecular-weight heparin and low doses of unfractionated heparin (UH) enhancing anti-factor Xa activity and the release of tissue factor pathway inhibitor was observed. The aim of this study was to verify whether this association is effective in preventing experimental venous thrombosis. Seventy rats were allocated into 7 groups: the control group treated with distilled water, the H(350) group treated with UH 350 IU/kg, the E(2) group treated with enoxaparin 2 mg/kg, the H(175) group treated with UH 175 IU/kg, the E(1) group treated with enoxaparin 1 mg/kg, the H(175) + E(1) group treated with UH 175 IU/kg plus enoxaparin 1 mg/kg, and the H(100) + E(0.5) group treated with UH 100 IU/kg plus enoxaparin 0.5 mg/kg. Forty minutes after subcutaneous injection, thrombosis was induced in vena cava. Three hours later, if present, thrombi were withdrawn and weighed. Bleeding time, activated partial thromboplastin time, thrombin time (TT), and anti-factor Xa were measured at the beginning and end of the experiment. Forty-eight other animals were treated, but without inducing thrombus, and tests were performed 40 min after injection. Thrombus developed in 90.9% of control animals, 20% of the H(350) group, 22.2% of the E(2) group, 10% of the H(175) + E(1) group, and 30% of the H(100) + E(0.5) group; there was a difference between group C and the other groups. Only in the H(350) and H(175) + E(1) groups were TT and activated partial thromboplastin time prolonged in relation to control at the end of the experiment. Forty minutes after injection, TT was prolonged in the H(350) and H(175) + E(1) groups. In conclusion, combinations of low doses of low-molecular-weight heparin and low doses of UH were as effective as high doses of each one used alone in preventing thrombus development in rat vena cava.
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PMID:Combinations of low doses of unfractionated heparin and of low-molecular-weight heparin prevent experimental venous thrombosis. 1677 37

Cardiovascular disease is the leading cause for mortality and morbidity in the western world. Arterial thrombosis has multiple origins and may present with different clinical presentations such as acute coronary syndromes, stroke, and peripheral embolization. Furthermore, thrombotic complications may occur during percutaneous interventions. The underlying causes range from atherosclerosis with plaque rupture or erosion, embolization, stasis and hypercoagulable states. Thrombotic complications lead to activation of the intrinsic coagulation system and to platelet aggregation. Despite the development of effective platelet inhibitors, there is still the need for an optimal anticoagulation regimen. While unfractionated heparin is the most commonly used antithrombotic agent, which has major inherent limitations. Direct thrombin inhibitors and anti factor Xa agents are agents which may overcome the limitation of unfractionated heparin. The potential advantages of these new compounds are discussed on the basis of available clinical data in patients with coronary artery disease.
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PMID:Thrombin inhibitors and anti-factor Xa agents in the treatment of arterial occlusion. 1707 89

This study's objective was to investigate the potential thrombogenic effects of thrombin-containing fibrin sealant dressings (FSD) in a vascular repair model. Oval-shaped pieces of the rabbit abdominal aorta and vena cava were excised, the injuries were repaired with FSD, and animals were allowed to recover. Thrombus formation was examined by (1) an infusion of indium-labeled platelets into the rabbits following FSD application and estimation of total number of platelets attached to the wounds at 2, 4, and 6 h later (short-term effect, n = 12); and by (2) morphological and histological examinations of the vessels and dressings on days 1, 3, and 7 after repair operation in another group of rabbits (long-term effect, n = 12). Application of FSD sealed the vascular injures and produced immediate hemostasis that was stable up to 1 week. The highest numbers of platelets (both native and labeled) adhered to the arterial and venous repair sites were 6.5 x 106 and 4.4 x 107, respectively, 6 h after operation. The adhered platelets, however, did not form a visible and clinically significant thrombus. In long-term experiments, no evidence of thrombus was found in the lumens of the repaired vessels or on the dressings, and no microthrombi were detected histologically in other tissues at any time point. Although vena caval injuries showed signs of healing at day 7 postoperatively, the aortic wounds expanded progressively (pseudoaneurysm) and were prone to rupture at later times. Thus, direct exposure of FSD does not cause intravascular thrombosis or thrombotic events in rabbits. The dressing appears to be safe and effective for short-term repair of vascular injuries. It may also allow healing of minor venous defects, but cannot replace conventional surgical techniques (suturing) for permanent repair of arterial damages.
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PMID:Assessment of the thrombogenic effect of fibrin sealant dressing in a vascular surgery model in rabbits. 1710 8

Heparin-induced thrombocytopenia (HIT) is one of the most life-threatening adverse effects of heparin administration. It is characterized by thrombocytopenia and may also be associated with venous or arterial thrombosis. HIT type 2 is caused by the binding of antibodies, most likely IgG, to a complex of heparin and platelet factor-4, these complexes IgG/PF4/heparin activate platelets causing the release of pro-thrombotic particles that promote thrombin generation. HIT and HIT-thrombosis are associated with high morbidity and mortality. Thrombotic events are most frequently venous and may manifest as pulmonary embolism or cerebral venous thrombosis. Arterial thrombosis leading to limb damage and amputation and to myocardial infarction or stroke may also occur. HIT is a clinical syndrome that requires clinical and laboratory findings to confirm the diagnosis. All forms of heparin treatment should be stopped once HIT is suspected and patients should be treated with an alternative anticoagulant to treat and prevent thrombotic complications. Available alternative anticoagulants include argatroban and lepirudin, a recombinant form of hirudin.
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PMID:[Heparin-induced thrombocytopenia: implictions for cardiologist]. 1717 89

The vascular endothelium is a thromboresistant surface, allowing the free flowing of blood cell elements. Platelets are predominantly involved in the rapid response to a vascular lesion, exposing the underlying thrombogenic subendothelium and leading to initiation of thrombus formation. Thrombus growth requires on the one hand, the recruitment of circulating platelets to the luminal side of the thrombus and on the other hand, the assembly of the proteins of the blood coagulation cascade on the platelet catalytic surface leading to thrombin formation. High shear forces are necessary for the dual role of von Willebrand factor (VWF) in the initiation of platelet thrombus formation and in its growth and stabilization. In hemodynamic conditions, platelet adhesion depends on the interaction between VWF and the platelet receptor glycoprotein Ib (GPIb). This interaction is the only one able to resist to the high shear rates that prevail in arterioles, the microcirculation or stenosed arteries. Thereafter, the interaction between VWF and the alphaIIbbeta3 integrin allows the definitive arrest of platelets and induces thrombus formation. Thus, high shear forces by themselves are able to induce platelet activation/aggregation, without added exogenous agonist. VWF is synthesised by endothelial cells as a series of multimers of different sizes. The multimers with the highest molecular weight, the so-called ultra-large multimers, are strongly thrombogenic by their increased ability to bind platelet GPIb and to induce the formation of circulating aggregates. These ultra-large multimers are normally cleaved by the ADAMTS13 metalloprotease into smaller multimers which are also less thrombogenic. The in vivo proteolysis of VWF by ADAMTS13 depends on the high shear rates, which increase the opening of multimers anchored to the endothelial cell layer and the exposure of the cleavage site of VWF by ADAMTS13. An ADAMTS13 deficiency thus likely would result in the accumulation of ultra-large multimers on the endothelial surface, which retains platelets on the activated endothelium and results in micro-thrombi formation, as seen in thrombotic thrombocytopenic purpura. Platelet-VWF interactions are also involved in inflammation. Activation of endothelial cells induces the release of VWF from the Weibel-Palade bodies as well as the surface expression of VWF and P-selectin. These molecules allow leukocyte and platelet rolling on endothelial cells, and expression of E-selectin, VCAM-1 and other adhesion molecules. Recently, it has been shown that activated platelets allow transient activation of intact, non stimulated endothelial cells, thus increasing the inflammation process. VWF and platelet P-selectin have been shown to be essential to this process. Thus, platelet--vessel wall interactions are involved in thrombosis and inflammation essentially via VWF.
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PMID:[Platelet--vessel wall interactions]. 1724 65


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