Combination of inhibition of thrombin and blockade of thromboxane A2 synthetase and receptors enhances thrombolysis and delays reocclusion in canine coronary arteries
Animal model study published in Circulation (1992)
Abstract
BACKGROUND: The efficacy of thrombolytic therapy in treating patients with acute myocardial infarction is limited by failure to achieve reperfusion in some patients, by the prolonged time required to achieve reperfusion, and by reocclusion of some coronary arteries. We designed this study to examine the effect of combined inhibition of thrombin and thromboxane synthesis and blockade of thromboxane A2 receptors in addition to tissue-type plasminogen activator (t-PA) on thrombolysis and reocclusion in an experimental canine model with coronary thrombosis. METHODS AND RESULTS: Blood flow velocity in the left anterior descending coronary artery (LAD) of 32 anesthetized mongrel dogs was monitored by a pulsed Doppler flow probe. Coronary thrombosis was induced by applying electrical stimulation to the LAD at the site where an external constrictor was used to narrow the artery. Three hours after the formation of occlusive thrombus, animals were randomly assigned to receive one of the following: 1) t-PA (80 micrograms/kg + 8 micrograms.kg-1.min-1 i.v.) and saline; 2) t-PA and hirulog, a hirudin-based synthetic peptide and specific thrombin inhibitor (2 mg/kg + 2 mg.kg-1.hr-1 i.v.); 3) t-PA and ridogrel, a combined thromboxane A2 synthetase inhibitor and receptor antagonist (5 mg/kg + 2.5 mg.kg-1.hr-1 i.v.); or 4) t-PA, hirulog, and ridogrel. Reperfusion developed in 14% (one of seven) of dogs treated with t-PA alone at an average of 86 +/- 4 minutes after treatment, in 78% (seven of nine) of dogs treated with t-PA plus hirulog at 53 +/- 11 minutes, in 13% (one of eight) of dogs treated with t-PA plus ridogrel at 85 +/- 5 minutes, and in 88% (seven of eight) of dogs treated with t-PA, hirulog, and ridogrel at 37 +/- 10 minutes (comparison of the frequency of and the time to reperfusion, both p < 0.01). Among the dogs with reestablished coronary blood flow, reocclusion developed in the one treated with t-PA alone at 36 minutes after reperfusion, in seven of the seven treated with t-PA plus hirulog at 66 +/- 15 minutes, and in two of the seven treated with t-PA, hirulog, and ridogrel at 151 +/- 21 minutes (comparison of the frequency of and time to reocclusion, both p < 0.05). Reocclusion was not detected in the one dog treated with t-PA and ridogrel or in the other five dogs treated with t-PA, hirulog, and ridogrel within 180 minutes after reperfusion. Hirulog prolonged and maintained activated clotting times at a level twice that of baseline values. Hirulog inhibited ex vivo platelet aggregation induced by thrombin, and ridogrel inhibited platelet aggregation induced by U46619, a thromboxane mimetic. CONCLUSIONS: Inhibition of thrombin in addition to treatment with t-PA enhances thrombolysis. A combination of inhibition of thrombin and thromboxane synthetase and blockade of thromboxane A2 receptor enhances thrombolysis and delays or may prevent reocclusion of the recanalized coronary arteries.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Canine coronary thrombosis model: hirulog (hirudin-derived synthetic peptide thrombin inhibitor) plus t-PA gave reperfusion in 78% (vs 14% with t-PA alone); adding ridogrel (TxA2 synthetase/receptor antagonist) prevented reocclusion in 5/7 dogs for 180 min.
Por qué esto importa para la hirudoterapia
This canine study (32 dogs with electrically induced coronary thrombosis) tested whether combining the hirudin-based thrombin inhibitor hirulog with the thromboxane A2 synthetase inhibitor/receptor antagonist ridogrel plus t-PA would enhance thrombolysis compared to each agent alone. t-PA plus hirulog achieved reperfusion in 78% of dogs (vs 14% with t-PA alone), and the triple combination achieved 88% reperfusion at 37 min with delayed or prevented reocclusion (2 of 7 reoccluded at 151 min vs 7 of 7 at 66 min for hirulog alone, both P<0.05). These findings highlight the potential of hirudin-derived thrombin inhibitors as thrombolysis adjuncts, particularly combined with anti-thromboxane therapy. Limitations include the canine model and small group sizes (7–9 dogs per arm); hirulog is a synthetic hirudin-based peptide rather than native hirudin.
Citación
Combination of inhibition of thrombin and blockade of thromboxane A2 synthetase and receptors enhances thrombolysis and delays reocclusion in canine coronary arteries.
Yao SK et al. · Circulation, 1992
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Añadido a la biblioteca ASH: May 27, 2026 · Última actualización del sitio: June 18, 2026