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

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 antiocoagulation. Blood flow was restored in 25 of 27 dogs. Thrombotic occlusion of the everted segment graft with primarily platelet-rich thrombus or thrombus containing platelet-rich and erythrocyte-rich zones, persisting for at least 30 min, occurred within 4.5 +/- 3.5 min (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 reocclusion 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 less than 0.05 versus rt-PA alone and p less than 0.01 versus control). This study confirms that 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/IIIa receptor antibody 7E3. The results indicate that platelet-rich thrombus resistant to thrombolytic 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.

Guidelines for the Early Management of Adults With Ischemic Stroke

“…530 Neither fosphenytoin nor sipatrigine has demonstrated effectiveness in treatment of acute stroke. 531,532 Repinotan, a serotonin agonist, has shown some promise in preliminary studies. 533 Lubeluzole was tested in several clinical trials, including one that evaluated the combination of the medication and rtPA.…”

Significance of Susceptibility Vessel Sign on T2*-Weighted Gradient Echo Imaging for Identification of Stroke Subtypes

“…13,14 In acute coronary syndrome, obstructive arterial thrombi that are platelet rich are resistant to thrombolysis and have an increased tendency to reocclude after initial reperfusion. 16 In these circumstances, an antiplatelet agent used in combination with a thrombolytic agent not only offers the potential for enhancing thrombolysis and reducing the risk of reocclusion but also permits this to be accomplished with reduced doses of thrombolytics and heparin. 17 Therapeutic decisions with regard to clot composition may facilitate thrombolysis and reperfusion.…”

Toward a New Frontier in Myocardial Reperfusion Therapy

“…[57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] Cumulatively, these studies have shown that the dose of fibrinolytic therapy can be substantially reduced to Ϸ50% or even 25% of the dose required in control experiments 57,58 and that fibrinolysis occurs much more rapidly and more completely and is much more stable, as reflected by the absence of cyclic flow variations or reocclusion once flow is restored. Nicolini and associates 65 showed that a low dose of a GP IIb/IIIa inhibitor combined with a low dose of a direct thrombin inhibitor (hirudin) also markedly facilitated coronary fibrinolysis in the canine electrolytic model.…”