Electrical induction of coronary artery thrombosis in the ambulatory canine: A model for evaluation of anti-thrombotic agents

Romson, Joseph L.; Haack, David W.; Lucchesi, Benedict R.

doi:10.1016/0049-3848(80)90249-2

Cited by 162 publications

(84 citation statements)

References 5 publications

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“…We used an experimental model in which thrombosis was induced by electrical stimulation applied to the intimal surface of the left circumflex coronary artery (LCCA) at the point of an external stenosis. 13 We found that administration of the 7E3 F(ab')2 after rt-PA-induced thrombolysis not only prevented thrombotic coronary artery reocclusion but also stabilized coronary artery blood flow in the recanalized vessel and was associated with an overall reduction in infarct size. Despite inhibition of platelet-fibrinogen interactions and rethrombosis, restoration of coronary artery blood flow at a level similar to baseline was not maintained.…”

mentioning

confidence: 72%

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

et al. 1990

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Coronary artery rethrombosis can complicate initially effective thrombolytic therapy. Platelets interacting with injured vascular endothelium in a region along the coronary artery with reduced luminal cross-sectional area contribute to rethrombosis. The purpose of this study was to investigate the potential of the F(ab')2 fragment of the murine monoclonal antibody 7E3 [7E3 F(ab')2] to prevent rethrombosis after intracoronary clot lysis with recombinant tissue-type plasminogen activator (rt-PA) in an experimental model. The 7E3 F(ab')2 binds to the platelet glycoprotein lIb/llla complex (GPIIb/IIIa), thereby preventing platelet-fibrinogen interaction and intravascular thrombus formation. Experimental coronary artery thrombosis was produced in the anesthetized dog by application of direct anodal current to the intimal surface of the left circumflex coronary artery in the region of an external stenosis. Lysis of the established intracoronary thrombus was achieved with the intravenous administration of rt-PA (25 mg) after which the animals were randomized into two groups. Group 1 (n=10) served as the control, receiving the saline diluent, and group 2 (n =9) received 7E3 F(ab')2, given as a single intravenous injection (0.8 mg/kg). The times required for occlusive thrombus formation, rt-PA-induced thrombolysis, and rethrombosis (if it occurred) were similar in the animals treated with saline and those treated with 7E3 F(ab')2. The initial left circumflex coronary artery blood flow was similar in both groups but decreased to a negligible level in group 1. In group 2, left circumflex coronary artery blood flow declined modestly (24±+2 to 10±2 ml/min).Rethrombosis occurred in all animals in group 1 but in only two of nine animals in group 2 (p

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mentioning

confidence: 72%

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

et al. 1990

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“…Platelet aggregation to collagen and the endoperoxide/thromboxane A2 mimetic U46619, as well as to ADP, was also assessed in some experiments before and after administration of bitistatin. Platelet aggregation to collagen and U46619, as well as ADP, was blocked by bitistatin at a bolus dose of 30 ,u/kg i.v. followed by an infusion of 3 ,ug/kg/min ( Figure 5).…”

Section: Discussionmentioning

confidence: 93%

Acceleration of recombinant tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by the combination of heparin and the Arg-Gly-Asp-containing peptide bitistatin in a canine model of coronary thrombosis.

et al. 1990

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The effect of tissue-type plasminogen activator (t-PA) alone or in combination with heparin, the Arg-Gly-Asp-containing peptide bitistatin, or both heparin and bitistatin was evaluated on thrombolysis time and acute reocclusion in a canine model of coronary thrombosis. Thrombus formation was elicited by electrolytic injury with a needle electrode to the endothelial surface of the circumflex coronary artery in the open-chest, anesthetized dog in the presence of a flow-limiting critical stenosis. Thirty minutes after spontaneous coronary artery occlusion, t-PA (1 mg/kg i.v. over 90 minutes) was administered. Group 1 was given t-PA alone; reperfusion occurred at 78.2±5.6 minutes with a reperfusion incidence of 60o (6/10). Group 2 received t-PA plus heparin (100 units/kg plus 50 units/kg/hr); reperfusion occurred at 61.9±9.1 minutes with a reperfusion incidence of 90%o (9/10). Group 3 received t-PA plus heparin plus bitistatin (30 ,ug/kg plus 3 ,ug/kg/min); reperfusion occurred at 47.3+±7.6 minutes (p<0.05 versus group 1) with a reperfusion incidence of 90% (9/10). Group 4 received t-PA plus bitistatin, and reperfusion occurred at 51.8±8.5 minutes; however, the reperfusion incidence was only 60%o (6/10). In groups 1, 2, and 4, acute reocclusion occurred in more than 80% of the reperfused dogs, whereas in group 3 reocclusion occurred in 22% (2/9) of the reperfused dogs (p<0.05 versus group 1). The dose of heparin used in this study increased activated partial thromboplastin times 1.5-2.0-fold over control. Bitistatin elicited a fourfold increase in bleeding time with almost complete suppression of platelet aggregation to ADP, collagen, and U46619. Residual thrombus wet weights, which were determined at the end of each experiment, were significantly lower only for group 3 (2.0±0.4 mg) compared with control group 1 (5.0±0.8 mg). These data demonstrate, in this model of coronary thrombosis in the canine, that the Arg-Gly-Asp-containing peptide bitistatin accelerates t-PA-induced thrombolysis and in combination with heparin prevents acute thrombotic reocclusion. (Circulation 1990;82:169-177

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“…26 The experimental procedure results in the formation of a platelet-rich intravascular thrombus at the site of an electrolytically induced endothelial lesion in proximity to a distal arterial stenosis. Use of both carotid arteries made it possible to examine dose-response relations as well as the effects of time on efficacy of the interventions.…”

Section: Model Of Carotid Occlusionmentioning

confidence: 99%

Chimeric 7E3 prevents carotid artery thrombosis in cynomolgus monkeys.

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Nedelman

et al. 1994

Stroke

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We compared the current antithrombotic strategy of antiplatelet therapy with aspirin, and anticoagulant therapy with heparin, with a specific genetically engineered chimeric antibody (c7E3 Fab) directed against the human glycoprotein IIb/IIIa receptor in an animal model of arterial thrombosis. Anesthetized cynomolgus monkeys (Macaca fascicularis) were instrumented for monitoring of arterial blood pressure, heart rate, and carotid artery flow velocity. Animals were treated with saline (n = 6), aspirin (25 mg PO daily for 3 days; n = 6), heparin (100 U/kg i.v. plus infusion adjusted to maintain activated partial thromboplastin time at 2 to 3 times baseline; n = 6), aspirin plus heparin (as administered separately, n = 6), or c7E3 Fab (0.10 mg/kg i.v., n = 7; 0.15 mg/kg i.v., n = 6; 0.20 mg/kg i.v., n = 6; 0.25 mg/kg i.v., n = 6). Thrombus formation via anodal electrolytic stimulation (100 microA) to the intimal surface of the right carotid artery was initiated 15 minutes after drug administration and continued for 180 minutes. Electrolytic injury to the left carotid artery began 210 minutes after drug administration and continued for 180 minutes. Whole blood cell counts, glycoprotein IIb/IIIa receptor blockade, ex vivo platelet aggregation, template bleeding time, and activated partial thromboplastin time were assessed at various time points throughout the experimental protocol. Hemodynamic and hematologic parameters were comparable among groups at baseline. Treatment with c7E3 Fab inhibited ex vivo platelet aggregation, increased bleeding time, decreased thrombus weight, and increased time to occlusion in a dose-dependent manner in both vessels. Treatment with aspirin, heparin, or the combination of aspirin plus heparin was ineffective for the prevention of carotid artery thrombosis in this model. Inhibition of the platelet glycoprotein IIb/IIIa receptor with c7E3 Fab was found to be safe and effective for the prevention of primary thrombus formation, whereas treatment with either aspirin or heparin or the combination of the two agents failed to protect against occlusive thrombus formation in cynomolgus monkeys.

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Electrical induction of coronary artery thrombosis in the ambulatory canine: A model for evaluation of anti-thrombotic agents

Cited by 162 publications

References 5 publications

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

Acceleration of recombinant tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by the combination of heparin and the Arg-Gly-Asp-containing peptide bitistatin in a canine model of coronary thrombosis.

Chimeric 7E3 prevents carotid artery thrombosis in cynomolgus monkeys.

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