Lysis of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GPIIb/IIIa antibody

Tsunehiro Yasuda, Herman K. Gold, Robert C. Leinbach, Tomiyoshi Saito, J. Luis Guerrero, Ik Kyung Jang, Robert Holt, John T. Fallon, Desire Collen

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Abstract

Resistance of coronary occlusive thrombus to thrombolytic therapy, found in some patients with acute myocardial infarction, may be due to the presence of platelet-rich coronary clot. Reperfusion therapy in such patients may require the development and evaluation of alternative strategies in animal models. Therefore, platelet-rich coronary artery thrombus was developed by excision, eversion (inside out) and reanastomosis of a 1 cm segment of the left circumflex coronary artery in anesthetized dogs maintained on heparin anticoagulation. Blood flow was restored in 25 of 27 dogs. Thrombotic occlusion of the everted segment graft with primarily plateletrich thrombus or thrombus containing platelet-rich and erythrocyle-rich zones, persisting for at least 30 min, occurred within 4.5 ± 3.5 nun (mean ± SD) in 20 of these 25 dogs. In 5 of these 20 dogs (group I, control), stable occlusion, as monitored with an ultrasound flow probe and coronary angiography, was maintained during a 2 h observation period. In group II (n = 5), intravenous bolus injections of recombinant tissue-type plasminogen activator (rt-PA) at a dose of 0.45 mg/kg body weight at four 15 min intervals did not cause reperfusion in four dogs and produced cyclic reperfusion and reocdusfcm in one dog. In group III (n = 5), a single intravenous bolus injection of 0.8 mg/kg of the F(ab')2 fragment of a murine monoclonal antibody (7E3) against the human platelet GPIIb/IIIa receptor [7E3-F(ab')2] produced stable reperfusion in two of the five dogs, whereas occlusion persisted in the other three. In group IV (n = 5), injection of 7E3-F(ab')2 (0.8 mg/kg) followed by rt-PA (0.45 mg/kg) caused stable reperfusion without reocclusion in all dogs (p < 0.05 versus rt-PA alone and p < 0.01 versus control). This study confirms ihat platelet-rich occlusive coronary thrombus is very resistant to lysis with intravenous rt-PA. However, this resistance may be overcome by the combined use of a reduced dose of rt-PA and the antiplatelet GPIIb/ IlIa receptor antibody 7E3. The results indicate that platelet-rich thrombus resistant to thrombolytlc agents may be dispersed pharmacologically without resort to mechanical recanalization. The present dog model may be useful in investigating specific strategies for the dispersion of resistant platelet-rich coronary thrombus.

Original languageEnglish
Pages (from-to)1728-1735
Number of pages8
JournalJournal of the American College of Cardiology
Volume16
Issue number7
DOIs
StatePublished - Dec 1990
Externally publishedYes

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