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, including platelet adhesion, activation, secretion and aggregation as well as tissue factor-initiated thrombin generation and fibrin formation, has been studied in the past using in vitro systems, often with isolated components. Given the complexity of hemostasis and thrombosis, many of the concepts that have been developed to explain these processes are being revisited by studying thrombus formation in live animals using intravital microscopy and genetically altered mice. Although much of the dogma that has evolved has been confirmed by in vivo studies of thrombus formation, there have also been conflicts between old concepts and new direct observations. In vivo studies of the initiation of thrombus formation, platelet accumulation and thrombin generation have provided evidence for the participation of novel proteins and identified new pathways and mechanisms.
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PMID:In vivo thrombus formation. 1763 3

A fundamental property of platelets is their ability to transmit cytoskeletal contractile forces to extracellular matrices. While the importance of the platelet contractile mechanism in regulating fibrin clot retraction is well established, its role in regulating the primary hemostatic response, independent of blood coagulation, remains ill defined. Real-time analysis of platelet adhesion and aggregation on a collagen substrate revealed a prominent contractile phase during thrombus development, associated with a 30% to 40% reduction in thrombus volume. Thrombus contraction developed independent of thrombin and fibrin and resulted in the tight packing of aggregated platelets. Inhibition of the platelet contractile mechanism, with the myosin IIA inhibitor blebbistatin or through Rho kinase antagonism, markedly inhibited thrombus contraction, preventing the tight packing of aggregated platelets and undermining thrombus stability in vitro. Using a new intravital hemostatic model, we demonstrate that the platelet contractile mechanism is critical for maintaining the integrity of the primary hemostatic plug, independent of thrombin and fibrin generation. These studies demonstrate an important role for the platelet contractile mechanism in regulating primary hemostasis and thrombus growth. Furthermore, they provide new insight into the underlying bleeding diathesis associated with platelet contractility defects.
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PMID:Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth. 1857 34

Recent evidence implicating tissue factor and the protein C pathway in the hypercoagulable state associated with intestinal inflammation suggests that thrombin is likely to contribute to this response. The objective of this study was to assess the role of thrombin in the extraintestinal thrombosis associated with experimental colitis. Thrombus formation was quantified in microvessels of the cremaster muscle in mice with dextran sodium sulfate (DSS)-induced colonic inflammation. The light/dye endothelial injury model was used to elicit thrombus formation in DSS colitic mice treated with either hirudin, heparin, or antithrombin III. The initiation and propagation/stabilization phases of thrombus formation were quantified using the time of onset of the thrombus and time to blood flow cessation, respectively. Thrombus formation was accelerated in arterioles of DSS colitic mice, as exhibited by significant reductions in the time of thrombus initiation and propagation/stabilization. Colitic mice treated with hirudin, heparin, or antithrombin III did not exhibit a significant change in the time of onset of the thrombus compared with untreated colitic mice. However, all three antithrombin agents largely prevented the DSS-induced reduction in the time to flow cessation following light/dye injury, with hirudin offering complete protection. These findings indicate that thrombin plays a major role in the extraintestinal thrombus formation associated with experimental colitis. Thrombin appears to contribute to the propagation/stabilization, rather than initiation, phase of the colitis-associated thrombogenesis at the distant vascular site. The results support the therapeutic use of antithrombin agents for reducing the risk of thromboembolism in patients with inflammatory bowel disease.
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PMID:Thrombin mediates the extraintestinal thrombosis associated with experimental colitis. 1877 59

Bivalirudin, a direct thrombin inhibitor binds specifically and reversibly to both fibrin-bound and unbound thrombin. Bivalirudin is approved for use as an anticoagulant in patients undergoing percutaneous coronary intervention. The OASIS-5 trial presented a significant increase in cardiac catheter thrombosis for the pentasaccharid fondaparinux compared to enoxaparin. Catheter thrombosis has never been reported in any trial using bivalirudin. Our study compared the development of catheter thrombosis for bivalirudin, enoxaparin, and unfractionated heparin in a controlled in-vitro environment. Ten healthy male volunteers were pretreated with aspirin 500 mg 2 hours before venesection of 50 ml of blood. The seven groups of anticoagulant combinations tested were: UFH, UFH + eptifibatide, enoxaparin, enoxaparin + eptifibatide, bivalirudin bolus, bivalirudin + eptifibatide, bivalirudin bolus + continuous infusion. The blood/anticoagulant mix continuously circulated through a cardiac guiding catheter for 60 minutes or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy was used to quantify the degree of erythrocyte, platelet and fibrin deposition. Following anticoagulation with bolus dose bivalirudin, the catheter was invariably occluded with thrombus after 33 minutes of circulation. However, a continuous infusion of Bivalirudin prevented the development of occlusive catheter thrombosis. In the bolus bivalirudin group the mean thrombus weight was significantly greater than in all other groups (p-value < 0.01 in all analyses). Bivalirudin given as a bolus was not sufficient to prevent cardiac catheter thrombosis in our in-vitro study. However, a continuous infusion of bivalirudin had similar anti-thrombotic efficacy compared to other treatment strategies.
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PMID:Comparison of bivalirudin, enoxaparin, and unfractionated heparin in preventing cardiac catheter thrombosis. Results of an in-vitro study. 1884 Dec 94

Platelets are central players in atherothrombosis development in coronary artery disease. The PKC family provides important intracellular mechanisms for regulating platelet activity, and platelets express several members of this family, including the classical isoforms PKCalpha and PKCbeta and novel isoforms PKCdelta and PKCtheta. Here, we used a genetic approach to definitively demonstrate the role played by PKCalpha in regulating thrombus formation and platelet function. Thrombus formation in vivo was attenuated in Prkca-/- mice, and PKCalpha was required for thrombus formation in vitro, although this PKC isoform did not regulate platelet adhesion to collagen. The ablation of in vitro thrombus formation in Prkca-/- platelets was rescued by the addition of ADP, consistent with the key mechanistic finding that dense-granule biogenesis and secretion depend upon PKCalpha expression. Furthermore, defective platelet aggregation in response to either collagen-related peptide or thrombin could be overcome by an increase in agonist concentration. Evidence of overt bleeding, including gastrointestinal and tail bleeding, was not seen in Prkca-/- mice. In summary, the effects of PKCalpha ablation on thrombus formation and granule secretion may implicate PKCalpha as a drug target for antithrombotic therapy.
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PMID:PKCalpha regulates platelet granule secretion and thrombus formation in mice. 1914 82

This study investigated the relationship between right atrial SEC (RA-SEC) and silent pulmonary embolism (PE) in patients with nonvalvular atrial fibrillation (NVAF). Spontaneous echo contrast (SEC) within the cardiac chambers is associated with an increased risk of thromboembolism. However, most studies have examined the relationship between left atrial SEC and systemic thromboembolic disease. Transesophageal echocardiography (TEE) was performed in 210 patients with NVAF to assess a risk of thromboembolism. Right atrial SEC was detected in 37 patients, and 35 of these patients with RA-SEC and 29 patients without RA-SEC were enrolled in this study. However, patients with a history of symptomatic PE or deep vein thrombosis were excluded. Spontaneous echo contrast was diagnosed by TEE as the presence of smoke-like echoes that swirled in a circular pattern. PE was diagnosed by pulmonary scintigraphy. Thrombotic and thrombolytic parameters, including serum concentrations of plasmin-alpha-plasmin inhibitor complex (PIC), thrombin-antithrombin complex (TAT), D-dimer, and fibrinogen were measured in all patients. Left ventricular dimension, cardiac function, and hematologic parameters were similar in the two groups. Nevertheless, the incidence of perfusion defects in pulmonary scintigraphy was significantly higher in the group with RA-SEC (40%) than in the group without RA-SEC (7%; chi-square, P=0.006). The increased incidence of perfusion defects in pulmonary scintigraphy in patients with RA-SEC indicates that right atrial SEC may be a predictable factor at a high risk of PE.
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PMID:Right atrial spontaneous echo contrast indicates a high incidence of perfusion defects in pulmonary scintigraphy in patients with atrial fibrillation. 1916 66

Thrombotic complications of long-term blood-contacting devices can be avoided by formation of an endothelial cell layer on the blood-contacting surface. The endothelial cells form a bioactive boundary between the synthetic surface and blood, regulating haemostasis and inflammation. Biofunctionalization of synthetic blood-contacting surfaces is necessary to accommodate growth of endothelial cells. Vascular endothelial growth factor E (VEGF-E) or collagen I may stimulate endothelialization of a polymeric surface coating of a prototype small diameter vascular prosthesis. VEGF-E was produced in Escherichia coli and could be easily purified in large quantities. Recombinant VEGF-E or purified collagen I was allowed to adsorb onto the polymeric surfaces and enhanced formation of an endothelial cell layer. Adsorption of VEGF-E was increased by the inclusion of the anti-coagulant drug heparin in the polymeric coating. Collagen I adsorption induced rapid thrombin generation and increased platelet adhesion on surfaces with or without heparin. VEGF-E inhibited thrombus formation, and did not interfere with the anti-thrombogenic effect of heparin. Additionally, VEGF-E did not affect platelet adhesion. Adsorption of VEGF-E, especially on heparin containing surfaces, provides an economical strategy to improve endothelialization of cardiovascular implants without disturbing blood-compatibility.
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PMID:VEGF-E enhances endothelialization and inhibits thrombus formation on polymeric surfaces. 1948 71

Owing to its beneficial pharmacological profile, the low-molecular-weight heparin (LMWH) enoxaparin is increasingly being taken as an alternative to UFH in the treatment of ACS with an early invasive strategy and in elective percutaneous coronary interventions (PCI). Insufficient anticoagulation increases the risk of catheter thrombus formation during PCI. The aim of the present study was to test in vitro the hypotheses that (i) inhibiting thrombin or thrombin generation by administering LMWH is a critical intervention in preventing catheter thrombus formation and (ii) other LMWH such as certoparin or dalteparin are as effective as enoxaparin. Blood pre-treated with the anticoagulants of interest was continuously circulated through a guiding catheter by using a roller pump for a maximum experimental period of 60 min or until the catheter became occluded. Overall thrombus weight, anti-Xa activity and electron microscopic features such as deposits of platelets, erythrocytes and fibrin on the catheter surface were quantified as endpoints. All LMWH tested significantly reduced catheter thrombus generation comparable to UFH treatment whereas there was no difference between the specific LMWH with respect to catheter thrombus formation or deposition of platelets, erythrocytes and fibrin. Thrombus generation was found to negatively correlate with anti-Xa activity. The additional use of eptifibatide did not affect thrombus formation. These data suggest that modulating plasmatic coagulation by employing LMWH is critical for preventing catheter thrombus formation and at the same time offer a potential for administering LMWH other than enoxaparin, such as certoparin or dalteparin, in the setting of PCI.
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PMID:Efficacy of enoxaparin, certoparin and dalteparin in preventing cardiac catheter thrombosis: an in vitro approach. 1951 16

Carbon monoxide, derived from carbon monoxide-releasing molecules, has been recently demonstrated to enhance the velocity of formation and strength of plasma thrombi. We tested the hypothesis that carbon monoxide-releasing molecule-2 would modulate fibrinolysis of plasma thrombi. Normal plasma was exposed to 0, 25, 50, 100 or 200 micromol/l carbon monoxide-releasing molecule-2, with coagulation activated with tissue factor and fibrinolysis initiated with tissue-type plasminogen activator. Additional experiments utilized factor XIII, plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor or alpha2-antiplasmin-deficient plasmas. Thrombus growth/disintegration kinetics was monitored with thrombelastography. Carbon monoxide-releasing molecule-2, in a concentration-dependent fashion, increased the velocity of thrombus formation and strength, and markedly attenuated fibrinolysis in normal plasma. In factor XIII-deficient plasma, carbon monoxide-releasing molecule-2 mediated effects on thrombus growth/disintegration kinetics were similar to that seen with normal plasma; however, carbon monoxide-releasing molecule-2 had a less marked effect on thrombus growth/disintegration in both plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor-deficient plasma, with even less carbon monoxide-releasing molecule-2-mediated effects noted in alpha2-antiplasmin-deficient plasma. Carbon monoxide-releasing molecule-2 attenuated fibrinolysis by enhancing the velocity of clot growth and strength while augmenting the effects of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor and alpha2-antiplasmin. These findings serve as the rationale for further investigations to determine if carbon monoxide-releasing molecules could be utilized as hemostatic agents.
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PMID:Carbon monoxide-releasing molecule-2 decreases fibrinolysis in human plasma. 1958

Thrombus formation on a disrupted atherosclerotic coronary artery plaque is the usual event that precipitates acute coronary syndromes (ACS). Anticoagulation therapy with unfractionated heparin, in addition to antiplatelet therapy with aspirin, decreases the risk of myocardial infarction and death with ACS. However, unfractionated heparin has pharmacological limitations that limit efficacy and safety. Low-molecular-weight heparins (enoxaparin), direct thrombin inhibitors (bivalirudin) and Factor Xa inhibitors (fondaparinux) are new anticoagulant therapy options with either superior efficacy or improved safety over unfractionated heparin. Compared with unfractionated heparin, enoxaparin and fondaparinux are easier to administer, do not require monitoring and facilitate longer treatment duration. Bivalirudin offers advantages for patients undergoing percutaneous revascularization. Careful attention to dosing and excellent vascular access site management are required to decrease the risk of bleeding and blood transfusion, which have been associated with increased mortality risk.
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PMID:Anticoagulant therapy in acute coronary syndromes. 1980 21


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