The Reliability of Thrombotic Tendency Measured by Intravascular Wires in the Rat

Lavelle, S. M.; Iomhair, Maura Mhic

doi:10.1016/s0049-3848(97)00138-2

Cited by 11 publications

(5 citation statements)

References 12 publications

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“…Edoxaban (0.3 and 1 mg/kg/h) or vehicle (2 ml/kg/h) was intravenously administered through the right jugular vein (n = 8). Venous thrombus was induced by the insertion of a platinumwire (0.5 mm diameter, 2 cm long) into the inferior vena cava of rats just caudal to the left renal vein 1.5 hours (h) after drug administration according to the method of Lavelle and Iomhair (16). The resulting thrombus was fixed 1 h later with 1% glutaraldehyde-PBS.…”

Section: Venous Thrombosis Model In Ratsmentioning

confidence: 99%

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Fukuda¹,

Honda²,

Kamisato³

et al. 2012

Thromb Haemost

125

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Edoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

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Section: Venous Thrombosis Model In Ratsmentioning

confidence: 99%

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Fukuda¹,

Honda²,

Kamisato³

et al. 2012

Thromb Haemost

125

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“…The preparation is then left for ten minutes, after which the isolated segment is extirpated and the thrombotic mass dried beneath moistened filter papers before the weight is recorded. However, batch to batch variations in the activity of TF, the active ingredient in thromboplastin, is a large source of error in this model, and other thrombogenic stimuli, such as ferric chloride [124], platinum wire [125], intravascular foreign surface e.g. silk thread combined with partial stasis [126], or surgical trauma in combination with partial stasis [127], are now more frequently used.…”

Section: Fibrin-rich Thrombus Modelsmentioning

confidence: 99%

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

Björkman

Abrahamsson

Nerme

et al. 2005

Thrombosis Research

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The physiologically most important activator of intravascular fibrinolysis is tissue-type plasminogen activator (t-PA) released from endothelial cells. In man, sympathomimetic drugs increase the systemic concentration of t-PA. It is therefore of interest to investigate whether cardiac sympathetic activation can induce a local t-PA release, which could counteract intra-coronary clot formation.Thrombolytic therapy with recombinant t-PA (rt-PA) is effective in acute myocardial infarction, but the treatment is limited by a fairly slow reperfusion rate and frequent early reocclusions. A potential mechanism behind early reocclusions might be that active thrombin is released from the thrombus during thrombolytic therapy. Thrombin has recently been shown to activate procarboxypeptidase U, which in its active form (CPU) down-regulates endogenous fibrinolysis. Therefore, one way of improving thrombolytic efficacy may be to combine rt-PA with a lowmolecular weight direct thrombin inhibitor, which theoretically could have a pro-fibrinolytic effect, either by inhibition of fibrin-bound thrombin and/or by inhibition of CPU activation. An alternative way may be direct inhibition of CPU.In a porcine model, experimental activation of cardiac sympathetic nerves by electrical stimulation at 1 and 8 Hz induced 5-and 20-fold increase in the release of both total and active t-PA together with frequency-dependent increases in heart rate, blood pressure, and coronary blood flow. The t-PA release was independent of the heart rate and coronary flow response, but local infusion of isoprenaline suggested that part of the t-PA response was mediated by stimulation of β-adrenergic receptors. Next, we studied the combined effect of rt-PA and thrombin inhibitors (melagatran, hirudin and heparin) in a canine model of copper coil-induced coronary thrombosis. The profibrinolytic effect of rt-PA, either measured as patency rate or time-to-patency, was significantly enhanced with the low-molecular weight direct thrombin inhibitor melagatran, but to a lesser degree by hirudin and heparin. In the same model it was shown that active CPU is produced locally in the coronary vascular bed during both thrombus formation and clot lysis. Inhibition of thrombin attenuated CPU formation and improved patency. A similar effect was obtained with a direct inhibitor of CPU.In conclusion, the coronary t-PA response to sympathetic stimulation may constitute a thromboprotective defence mechanism to counteract its prothrombotic effects on the systemic level. Furthermore, direct thrombin and/or CPU inhibition may be potential targets for prevention of thrombus formation via facilitation of the endogenous fibrinolytic system.

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“…Platinum wire‐induced venous thrombosis model in rats Thrombus was induced by the insertion of a platinum wire (2 cm long) into the inferior vena cava of rats ( n = 8 per dose group) just caudal to the left renal vein 30 min after oral administration of DU‐176b (0.1–2.5 mg kg −1 ) or 0.5% methylcellulose according to the method of Lavelle and Iomhair [18]. The resulting thrombus was fixed 1 h later with 1% glutaraldehyde.…”

mentioning

confidence: 99%

DU‐176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles

Furugohri¹,

Isobe²,

Honda³

et al. 2008

Journal of Thrombosis and Haemostasis

283

207

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Summary. Background: Factor Xa (FXa), a key serine protease that converts prothrombin to thrombin in the coagulation cascade, is a promising target enzyme for the prophylaxis and treatment of thromboembolic diseases. DU-176b is a novel antithrombotic agent that directly inhibits FXa activity. Objective: To evaluate the in vitro pharmacological profiles and in vivo effects of DU-176b in animal models of thrombosis and bleeding. Methods: In vitro, FXa inhibition, specificity and anticoagulant activities were examined. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail bleeding. Results: DU-176b inhibited FXa with Ki values of 0.561 nM for free FXa, 2.98 nM for prothrombinase, and exhibited >10 000-fold selectivity for FXa. In human plasma, DU-176b doubled prothrombin time and activated partial thromboplastin time at concentrations of 0.256 and 0.508 lM, respectively. DU-176b did not impair platelet aggregation by ADP, collagen or U46619. DU-176b was highly absorbed in rats and monkeys, as demonstrated by more potent anti-Xa activity and higher drug concentration in plasma following oral administration than a prototype FXa inhibitor, DX-9065a. In vivo, DU-176b dose-dependently inhibited thrombus formation in rat and rabbit thrombosis models, although bleeding time in rats was not significantly prolonged at an antithrombotic dose. Conclusions: DU-176b is a more potent and selective FXa inhibitor with high oral bioavailability compared with its prototype, DX-9065a. DU-176b represents a promising new anticoagulant for the prophylaxis and treatment of thromboembolic diseases.

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The Reliability of Thrombotic Tendency Measured by Intravascular Wires in the Rat

Cited by 11 publications

References 12 publications

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

DU‐176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles

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