Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis.

Sitko, Gary R.; Ramjit, Denise; Stabilito, Inez I.; Lehman, Dale; Lynch, Joseph J.; Vlasuk, George P.

doi:10.1161/01.cir.85.2.805

Cited by 131 publications

(58 citation statements)

References 52 publications

(7 reference statements)

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“…These results are consistent with observations that platelet-dependent thrombosis, like venous thrombus formation, is thrombin dependent (33). Importantly, APC did not significantly affect measurements of hemostasis (e.g., template bleeding tests) or produce an increased bleeding tendency; these results are in contrast to those obtained with direct inhibitors of thrombin (33,34), but are similar to observations with an-other inhibitor of prothrombinase, tick anticoagulant peptide (35,36). However, because infused APC is inhibited in the circulation and exhibits a half-life of 10-15 min (12,25,27,32), maintenance of elevated plasma levels (> 100 ng/ml) requires continuous intravenous administration of the enzyme (25,31,32).…”

Section: Introductionsupporting

confidence: 89%

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.

et al. 1993

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The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrinrich venous-type thrombus. Thrombosis was quantified by "'In-platelet imaging and '25I-fibrinogen accumulation. Intravenous infusion of a-thrombin, 1-2 U/kg-min for 1 h, increased baseline activated PC levels (-5 ng/ml) to 250-500 ng/ml (P < 0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P < 0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P < 0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin-antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P < 0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P < 0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy. (J. Clin. Invest.

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Section: Introductionsupporting

confidence: 89%

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.

et al. 1993

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“…This higher concen tration may contribute to the better patency status with YM866 than t-PA after successful thrombolysis. Further improvement of vascular patency may be expected with adjunctive use of antiplatelet agents such as anti GPIIb/IIIa monoclonal antibody (18) and GPIIb/IIIa receptor antagonist (19), or anticoagulants such as throm bin inhibitors (20) and Xa inhibitors (21). A slight but significant decrease (14%) in plasma fibrinogen occurred only with YM866 at 1 mg/kg.…”

Section: Discussionmentioning

confidence: 98%

Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

Kawasaki¹,

Kawamura²,

Katoh³

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-We compared the thrombolytic activity of a novel modified t-PA, YM866, with that of t-PA in a rat model of electrically-induced thrombosis. Histological examination revealed the thrombus to be composed mainly of platelet clumps. Measurement of the decrease in carotid blood flow showed that com plete occlusion occurred within 14 min. At 10 min after the induction of thrombus, a test drug (YM866, t PA, or saline) was administered by i.v. bolus injection under heparinization (300 IU/kg, i.v.). Both YM866 and t-PA exhibited dose-dependent thrombolytic activity; the reperfusion rate of YM866 was twice that of t-PA. There was no significant difference in time to reperfusion between the agents, but YM866 showed a greater improvement in patency status after successful thrombolysis than t-PA. Plasma fibrinogen fell slight ly but significantly (14% of baseline value) in animals given 1 mg/kg of YM866. All groups of rats showed a significant decrease in carotid artery blood flow at 1 hr after successful reperfusion or injection of the drug, but this decrease showed significant recovery in animals given 1 mg/kg of YM866. These results suggest that YM866 by single bolus injection is a superior thrombolytic agent to t-PA, and that YM866 can improve the patency status after successful thrombolysis. Furthermore, this platelet-rich thrombosis model permits con tinuous observation of the process of thrombus formation and subsequent thrombolysis and provides a useful tool for the screening and evaluation of efficacy of new antithrombotic agents.

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“…It is, however, not easy to directly compare the results from different studies with experimental coronary thrombosis. The techniques for inducing the thrombus have varied from study to study, and the experimental protocol concerning the mode of drug administration, dose levels, and imaging the thrombus and its lysis has also varied between studies [166][167][168][169][170][171].…”

Section: Thrombolysis and Carboxypeptidase U Inhibition -Paper IVmentioning

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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Conjunctive enhancement of enzymatic thrombolysis and prevention of thrombotic reocclusion with the selective factor Xa inhibitor, tick anticoagulant peptide. Comparison to hirudin and heparin in a canine model of acute coronary artery thrombosis.

Cited by 131 publications

References 52 publications

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.

Experimental Model of Carotid Artery Thrombosis in Rats and the Thrombolytic Activity of YM866, a Novel Modified Tissue-Type Plasminogen Activator

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

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