Model Of Coronary Artery Thrombosis Research Articles

Inhibitory role of recombinant neorudin on canine coronary artery thrombosis.

The anticoagulant application is an effective treatment modality for cardiovascular diseases such as coronary heart disease, unstable angina pectoris, and myocardial infarction. In this study, the antithrombotic effect of recombinant neorudin (EPR‐hirudin, EH) was evaluated using a canine model of coronary artery thrombosis. A canine model with platelet thrombosis in the left circumferent branch of the coronary artery was designed using Folt's method, and the anti‐thrombus activity of EH was investigated. Femoral administration of EH intravenously had a significant dose‐dependent inhibitory effect on canine coronary artery thrombosis and the effective rates were 66.7% (p < .05), 83.3% (p < .05), and 100% (p < .01) after injection of 0.3, 1.0, and 3.0 mg/kg EH, respectively. Furthermore, EH demonstrated lower bleeding, with shorter bleeding time and less bleeding loss than low molecular weight heparin (LMWH). Under the similar effect intensity of EH and LMWH (85 IU/kg), the bleeding time of the EH group at 30 min was shorter, and the blood loss at 30–120 min was less than that of LMWH (p < .05 and p < .05–.001, respectively). EH had a significant dose‐dependent inhibitory effect in the dose range of 0.3–3.0 mg/kg on the coronary artery thrombosis and lower bleeding side effects than LMWH with a similar antithrombosis effect.

Molecular Magnetic Resonance Imaging Allows the Detection of Activated Platelets in a New Mouse Model of Coronary Artery Thrombosis

: The final event leading to myocardial infarction is adhesion and activation of platelets after rupture of an atherosclerotic plaque, ending in thrombotic occlusion of the coronary artery. Imaging of imminent vessel occlusion may improve patient care. The feasibility of molecular magnetic resonance imaging (MRI) for the detection of coronary artery thrombosis in mice was examined. : The left anterior descending coronary artery was exposed by lateral thoracotomy and incubated with ferric chloride to induce nonocclusive thrombosis in C57Bl/6 mice. A single chain antibody targeting ligand-induced binding sites (LIBS) of the activated glycoprotein IIb/IIIa or control antibody was conjugated to 1 μm-sized microparticles of iron oxide (MPIOs), resulting in LIBS-MPIO or control-MPIO MRI contrast agent, and injected intravenously. Hearts were subjected to histology and ex vivo MRI at 9.4 Tesla. : Thrombus size was comparable in mice injected with control-MPIO and LIBS-MPIO in histology. Significant binding of MPIOs to thrombi was observed in LIBS-MPIO-injected animals while no binding was observed in control animals (P < 0.05). In MRI, LIBS-MPIO binding to thrombi of the left anterior descending coronary artery resulted in significant MPIO-induced signal void compared with controls (P < 0.05). MRI signal void and the amount of bound contrast agent particles in histology showed a significant positive linear correlation (r = 0.939, P < 0.001). : We established a new mouse model of nonocclusive coronary artery thrombosis. LIBS-MPIO contrast agent binds to activated platelets in this model, allowing molecular MRI of coronary thrombosis. This could have important implications on the timely noninvasive detection of arterial thrombosis, helping to initiate early therapeutic interventions.

Thrombolytic efficacy of recombinant human microplasmin in a canine model of copper coil-induced coronary artery thrombosis

We investigated the in vitro fibrinolytic properties of microplasmin, the isolated proteinase domain of plasmin, and its thrombolytic efficacy in a coronary artery thrombosis model in dogs. The amidolytic and fibrinolytic activity of recombinant microplasmin was compared with natural human plasmin. The thrombolytic efficacy of microplasmin was studied in a canine model of copper coil induced coronary artery thrombosis. Animals were randomly assigned to one of six treatment regimens, each with five animals per cohort. Four treatment groups received an intravenous bolus of microplasmin followed by an intravenous infusion of microplasmin for 1 h (1 mg/kg + 1.5 mg/kg/h with or without abciximab or 2 mg/kg + 3 mg/kg/h). In two treatment groups, microplasmin was administered intracoronary. Bolus administration was followed by a 1-h infusion if coronary flow was incompletely restored after the initial bolus administration (1 mg/kg + 1.5 mg/kg/h or 2 mg/kg + 3 mg/kg/h, respectively). The thrombolytic efficacy was documented by repeated angiographies and the coronary perfusion was assessed with the Thrombolysis in Myocardial Infarction (TIMI) grading. No significant differences between plasmin and microplasmin were observed with respect to the catalytic efficiencies towards the synthetic chromogenic substrates S-2403 or S-2444. The concentration required for 50% lysis of purified fibrin clots in 3 h, was approximately 100 nM for microplasmin compared to 20 nM for natural plasmin. Intravenous bolus administration of microplasmin restored TIMI 3 coronary flow in 0/5, 0/5, 1/5 and 2/5, respectively, whereas intracoronary bolus administration restored TIMI 3 coronary flow in 1/5 and 4/5 (1 mg/kg and 2 mg/kg, respectively) (ANOVA P < 0.05). TIMI 3 coronary flow was obtained in 0/5, 2/5, 2/5 and 3/5, respectively, during subsequent intravenous administration and in 5/5 and 4/5 in case of intracoronary administration (ANOVA P < 0.05). When compared to natural plasmin, the catalytic efficiency of microplasmin towards chromogenic substrates was similar, but the fibrinolytic potency of microplasmin towards fibrin clots was lower. Intracoronay administration of microplasmin effectively lysed coronary thrombosis.

RO3244794, an IP receptor antagonist, shortens the time to occlusion in a canine model of coronary artery thrombosis

RO3244794, an IP receptor antagonist, shortens the time to occlusion in a canine model of coronary artery thrombosis

Preclinical Evaluation of S18886 in an Experimental Model of Coronary Arterial Thrombosis

The specific thromboxane receptor antagonist, S18886, was evaluated for prevention of coronary arterial thrombosis and myocardial ischemia-reperfusion in anesthetized canines. For the primary thrombosis study in left circumflex (LCX) coronary artery, 26 dogs were randomized to receive either vehicle (n = 7) or intravenous S18886 (0.3 mg/kg, n = 6; 1.0 mg/kg, n = 6; and 3.0 mg/kg, n = 7). The respective times to occlusion after S18886 were as follows: 56.8 +/- 9.3, 83.5 +/- 14.9, and 92.4 +/- 15.7 minutes compared to 43.3 +/- 8.2 minutes after vehicle. S18886 caused a minimal increase in tongue bleeding time and a significant decrease in ex vivo platelet aggregation to arachidonic acid or U46619. Another 37 dogs were randomized to receive placebo (n = 12), clopidogrel 1.0 mg/kg p.o. QDX3 (n = 9), clopidogrel + S18886 0.3 (n = 9) or 1.0 (n = 7) mg/kg intravenous. Clopidogrel produced a 50% reduction in adenosine diphosphate-induced platelet aggregation and a slight increase in the time to occlusion. However, clopidogrel + S18886 1.0 mg/kg prevented occlusive thrombus formation in most of the coronary vessels over 6 hours. S18886 did not alter myocardial infarct size in the ischemia-reperfusion model. In conclusion, S18886 alone caused a dose-dependent prolongation in the time to primary occlusive coronary artery thrombosis, whereas S18886 + clopidogrel displayed effective in preventing occlusive thrombus formation with only a moderate increase of tongue-bleeding time.

Pharmacologic inhibition of platelet vWF-GPIbα interaction prevents coronary artery thrombosis

Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibalpha, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIb alpha interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 microg/kg, n=6; 500 microg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105+/-34 and 156+/-23 (p<0.05) min, respectively compared to the saline treated control group (32+/-6 min, n=6). Patency of the injured vessel was sustained in 1/6 (100 microg/kg) and 3/6 vessels (500 microg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 microg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day -2 followed by 1.1 mg/kg daily for 2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure. The PTR and LDR clopidogrel treatments prolonged TTO to 98.2+/-30.0 min and 136.1+/-39.5 min (p<0.05), and sustained patency in 1/6 and 4/8 vessels, respectively. However, template bleeding time in the LDR clopidogrel group was sustained higher than the control group. The combination of PTR clopidogrel and GPG-290 (100 microg/kg) prolonged TTO equivalent to LDR clopidogrel alone (141.4 +/- 35.1 min) and sustained patency in 3/7 dogs, without increased bleeding while LDR clopidogrel combined with 100 microg/kg GPG-290 prevented occlusion in 5/8 dogs and further prolonged TTO (173.5+/-32.6 min) but was associated with increased bleeding compared to control. GPG-290 is an antithrombotic agent that may be combined with lower doses of clopidogrel to yield similar antithrombotic efficacy as higher loading doses.

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

The objective of this study was to test the hypothesis if thrombolysis induced by recombinant tissue-type plasminogen activator, (rt-PA) could be facilitated by inhibiting carboxypeptidase U (CPU, active Thrombin Activatable Fibrinolysis Inhibitor, TAFIa) activity. The efficacy of rt-PA alone, or in combination with the carboxypeptidase inhibitor MERGETPA, was compared in a dog model of coronary artery thrombosis. Twenty dogs were randomised in two groups, one received rt-PA, 1 mg kg −1, as intravenous infusion over 20 min starting 30 min after thrombus formation, and the other group received rt-PA, 1 mg kg −1, as group one with the addition of MERGEPTA 5 mg kg −1 starting 25 min prior to coronary artery occlusion and followed by infusion of 5 mg kg −1 h −1 until the end of experiment. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Both groups had similar baseline characteristics with respect to haemodynamic parameters, i.e., heart rate, blood pressure and coronary artery blood flow. Coadministration of rt-PA and MERGETPA resulted in significant decrease in time to lysis (15±1.5 min vs. 20±1.7 min, p=0.03), increased patency time (87±16 min vs. 46±12 min, p=0.047) and increased coronary blood flow during patency (1131 mL h −1 vs. 405 mL h −1, p=0.015), compared to rt-PA alone. These results indicate that an inhibitor of CPU activity may have a beneficial effect in patients undergoing thrombolytic therapy by attaining shorter time to reperfusion and improved coronary patency.

Encapsulation of a plasminogen activator speeds reperfusion, lessens infarct and reduces blood loss in a canine model of coronary artery thrombosis.

In the present study, a polymer-encapsulated plasminogen activator was investigated as an alternative to restore blood flow more effectively than free plasminogen activator. While current fibrinolytic agents have limited efficacy, attributable to delayed onset of sustained reperfusion and bleeding complications, encapsulated plasminogen activators have shown promise in addressing these shortcomings. A polymer-encapsulated plasminogen activator could offer an effective formulation with a prolonged shelf-life. In this study, coronary artery thrombosis was produced in the anesthetized dog by the injection of thrombin + whole blood, and then one of five randomly selected formulations was administered intravenously: saline, blank microcapsules, free streptokinase (FREE SK), streptokinase and blank microcapsules (FREE SK + BLANK), or streptokinase entrapped in polymer microcapsules (MESK). MESK significantly accelerated the time to reperfusion compared to FREE SK or FREE SK + BLANK. Additionally, substantial reductions were observed in residual clot mass, infarct mass, reocclusion episodes, fibrinogen depletion and blood loss with MESK compared to FREE SK. The results of this study demonstrate that MESK accelerates thrombolysis and the restoration of blood flow compared to identical dosages of FREE SK while also reducing systemic fibrinogenolysis and blood loss. Microencapsulation may produce an improved dosage form for restoring arterial blood flow and reducing bleeding complications with thrombolytic therapy.

Endothelial COX-2 inhibition

Endothelial COX-2 inhibition

Effect of a humanized monoclonal antibody to von Willebrand factor in a canine model of coronary arterial thrombosis

The purpose of this study was to investigate the antithrombotic effect and bleeding time prolongation of AJW200, a humanized monoclonal antibody to von Willebrand factor (vWF), in a canine model of coronary arterial thrombosis. AJW200 significantly inhibited cyclic flow reductions, as well as botrocetin-induced platelet aggregation, at 0.1 mg/kg. A significant prolongation of bleeding time was observed at 0.3–1 mg/kg. Approximately 50% occupancy of vWF (approximately 0.7 μg/ml AJW200 in plasma) and 80–100% occupancy (approximately 20 μg/ml AJW200 in plasma) were needed for the antithrombotic effect and the extensive prolongation of bleeding time, respectively. On the contrary, the minimal effective dose of abciximab (0.8 mg/kg) was associated with a significant prolongation of bleeding time. These results suggest that the pharmacological blockade of platelet glycoprotein (GP) Ib-vWF interaction with AJW200 results in a safer antithrombotic profile than platelet GPIIb/IIIa blockade with abciximab in dogs.

Local proCPU (TAFI) Activation during Thrombolytic Treatment in a Dog Model of Coronary Artery Thrombosis can be Inhibited with a Direct, Small Molecule Thrombin Inhibitor (Melagatran)

To test the hypothesis that the direct thrombin inhibitor, melagatran is able to inhibit local pro-carboxypeptidase U (proCPU) activation that occurs during thrombolytic treatment, t-PA alone, or in combination with melagatran, was given to dogs with a coronary artery thrombosis. Blood samples from the great cardiac vein and aorta were collected at baseline, during thrombus formation, throughout the t-PA+/-melagatran infusion and during the patency period, for analysis of CPU activity using a novel assay. A higher CPU activity in venous compared to arterial blood (V-A difference) indicates CPU activation in coronary vessels. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Dogs (n = 26) were randomized to receive either 1) t-PA, 1 mg/kg as an intravenous 20-min infusion; 2) t-PA as in group 1, +melagatran bolus, 0.3 mg/kg, followed by a 3-h infusion (0.15 mg/kg per h); 3) sham-operated but no coronary thrombus, and administered t-PA as for Group 1. All groups had similar baseline characteristics. Significant increases in CPU activity were observed in Groups 1 and 2 during thrombus formation, with V-A differences of 5.5 and 4.5 U/L, respectively. No significant V-A difference was observed in the sham-operated group. CPU activity increased in Group 1 during the t-PA infusion (V-A difference 15.9 U/L), whereas the V-A difference in Group 2 decreased to 2.6 U/L following melagatran treatment. These results demonstrate that melagatran attenuates generation of CPU in the coronary circulation. The mechanism is probably indirect, via inhibition of thrombin-mediated activation of proCPU.

Risk of Recurrent Venous Thomboembolism – Expanding the Frontier

Local proCPU (TAFI) Activation during Thrombolytic Treatment in a Dog Model of Coronary Artery Thrombosis can be Inhibited with a Direct, Small Molecule Thrombin Inhibitor (Melagatran) C. Mattsson, J. A. Bjorkman, T. Abrahamsson, V. Nerme, K. Schatteman, J. Leurs, S. Scharpe, D. Hendriks _________________ 557 Prothrombotic Genotypes Are not Associated with Pre-eclampsia and Gestational Hypertension: Results from a Large Population-based Study and Systematic Review E. R. Morrison, Z. H. Miedzybrodzka, D. M. Campbell, N. E. Haites, B. J. Wilson, M. S. Watson, M. Greaves, M. A. Vickers ______________ 779

Thrombostatin Inhibits Cyclic Flow Variations in Stenosed Canine Coronary Arteries

Thrombostatins are a group of compounds based upon a breakdown product of bradykinin, RPPGF. They inhibit alpha-thrombin-induced platelet activation by binding to protease activated receptor 1 and, at a lower affinity, by interacting with thrombin's active site. After a single intravenous infusion of MAP4-RPPGF (11.58 mg/kg), its t1/2alpha was 4.5 min with a clearance of 2.0 ml/min. MAP4-RPPGF administration had a sustained antiplatelet effect, preventing gamma-thrombin-induced (12.5 nM) platelet activation for 4 h. Its antiplatelet effect summated with that of aspirin and/or clopidogrel. MAP4-RPPGF was compared with aspirin and clopidogrel in the Folts model of coronary artery thrombosis. Dogs were randomized to 3 treatment groups: aspirin 1.14 mg/kg i.v., clopidogrel 0.5 mg/kg i.v., or MAP4-RPPGF 0.77 mg/kg i.v. Cyclic flow variations (CFV) were recorded in 5 untreated dogs hourly for 3 successive hours and for 1 h before (all groups >11 CFV/h), and for 2 h after drug infusion in each of the 3 treatment groups. After 1 h drug treatment, all groups of animals had <6 CFV/h; after 2 h treatment, all had <1 CFV/h. All agents significantly reduced CFV from control at each hour, but none was significantly better than any other. Thrombostatin was as effective as aspirin or clopidogrel in inhibiting coronary artery thrombosis in this canine model.

Antiplatelet and Antithrombotic Activity of SL65.0472, a Mixed 5-HT1B/5-HT2A Receptor Antagonist

The antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-di-hydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 microM 5-HT + threshold concentrations of ADP (0.5-1 microM) or collagen (0.3 microg/ml) with mean IC50 values of 49 +/- 13 and 48 +/- 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p.o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p.o. SL65.0472 (30 microg/kg i.v.) virtually abolished coronary cyclic flow variations (7.2 +/- 1.0/h to 0.6 +/- 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 +/- 0.8 ml/min to 31.8 +/- 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p.o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.

Effect of time of 7E3 administration on rt-PA-induced reperfusion: study in a canine model of thrombus-based occlusion–reperfusion

Chimeric version of the murine monoclonal antibody, 7E3 has been proposed for the early restoration of coronary artery patency during thrombolytic therapy. We determined the optimal time for administration of 7E3 during recombinant tissue plasminogen activator (rt-PA)-induced thrombolysis using a canine model of coronary artery thrombosis. After 30 min of thrombotic occlusion, microspheres were injected to assess regional myocardial blood flow, followed by a 90-min rt-PA infusion. Dogs were randomized to three groups wherein 7E3 (0.8 mg kg −1, i.v.) was administered either 5 min before rt-PA (Group I), at the first evidence of thrombolysis (Group II), or after the completion of rt-PA infusion (Group III). Hemodynamic parameters were monitored for 6 h after which infarct size was estimated. Time to occlusion/reperfusion was similar in all groups. In the rt-PA alone group, 78% arteries reoccluded after 60 min of reperfusion. The incidence of reocclusion was lower in Groups II (25%, P=0.04) and III (0%, P<0.01). All arteries (100%) were patent at the end of the protocol in Group III vs 50% remaining patent in Group I ( P=0.01). Arterial patency was maintained longer in Group III (301 min, n=10), compared with Groups I (124 min, n=5) and II (124 min, n=6). Arterial flow was greater in Group III (82%) compared with Groups I (27%) and II (35%) ( P<0.01). Regional myocardial blood flow and infarct size were similar in all groups. The data indicate that the time of administration of 7E3 in conjunction with rt-PA-induced thrombolysis influences patency status. The experimental results suggest that in the absence of aspirin and heparin, optimal thrombolysis is obtained when 7E3 is administered after the completion of rt-PA infusion regimen.

Temporary and partial inhibition of platelets by SM-20302 prevents coronary artery thrombosis in a chronic canine model

We proposed that temporary and partial platelet inhibition by a GPIIb/IIIa receptor antagonist, SM-20302, would provide sustained antithrombotic efficacy in a chronic model of coronary artery thrombosis. Instrumented, conscious dogs received vehicle (Group I, n=7), low dose SM-20302 (30 μg/kg bolus+1 μg/kg/min infusion for 6 h) (Group II, n=7), or high dose SM-20302 (100 μg/kg bolus+1 μg/kg/min infusion for 6 h) (Group III, n=7). Thrombosis was initiated by electrolytic injury to the circumflex coronary artery. Coronary blood flow was monitored for 6 h on day 1 and days 2–6. Platelet aggregation was performed in platelet-rich plasma prepared from citrated or heparinized blood. At 6 h, both doses of SM-20302 inhibited adenosine diphosphate-induced platelet aggregation completely (>90%) in citrated platelet-rich plasma, but incompletely (57–59%) in heparinized platelet-rich plasma. Platelet reactivity returned to baseline values at 24 h. Control animals developed thrombotic occlusion on Day 1. Both doses of SM-20302 maintained vessel patency during the infusion period (Day 1) and the subsequent 5 days. Myocardial infarct size and mortality in the drug treated groups were reduced compared to the vehicle group. Thus, temporary inhibition of platelet reactivity by SM-20302 is associated with sustained prevention of primary thrombus formation, and reduction in infarct size and mortality.

Reduction in the size of myocardial infarction with YM866, a modified Tissue-type plasminogen activator, in a rat model of coronary artery thrombosis.

Reduction in the size of myocardial infarction with YM866, a modified Tissue-type plasminogen activator, in a rat model of coronary artery thrombosis.

P–223 - Subacute-stage prognosis after treatment with a modified tissue-type plasminogen activator, YM866 in a canine coronary artery thrombosis model.

P–223 - Subacute-stage prognosis after treatment with a modified tissue-type plasminogen activator, YM866 in a canine coronary artery thrombosis model.

Myocardial Perfusion Abnormalities by Intravenous Administration of the Contrast Agent NC100100 in an Experimental Model of Coronary Artery Thrombosis and Reperfusion.

The aim of this study was to evaluate a second-generation echo contrast agent (NC100100) for the study of myocardial perfusion. In eight anesthetized open-chest dogs, this agent was injected intravenously under baseline conditions, during acute coronary thrombosis, and after reperfusion, using both fundamental (FI) and harmonic (HI) imaging, both continuous and intermittent imaging, and both ultrasound (US) and integrated backscatter (IBS) imaging. Contrast injections did not modify the hemodynamic parameters. With all imaging modalities, myocardial contrast enhancement (MCE) was higher with intermittent than with continuous imaging (134 vs 82 gray level/pixel using FI, P = 0.02; 62 vs 32 acoustic units using US HI, P = 0.02; and 52 vs 12 dB using IBS, P = 0.05). MCE equally increased using either US or IBS imaging. The accuracy of MCE in detecting perfusion defects during coronary occlusion and myocardial reperfusion after thrombolysis was very good (sensitivity and specificity = 93% and 95% and 89% and 93%, respectively). The extent of myocardial perfusion defects by echo contrast showed a closer correlation with microspheres using HI (r = 0.82) than FI (r = 0.53). Thus, the intravenous administration of NC100100 during intermittent HI allows myocardial perfusion abnormalities to be accurately detected during acute myocardial infarction.

Intravenous Administration of the Glycoprotein IIb-IIIa Receptor Antagonist 7E3 Induces Reperfusion of an Acute Thrombotic Occlusion of the Canine Coronary Artery

The ability of the F(ab’) 2 fragment of the murine monoclonal antibody 7E3 directed against the platelet glycoprotein IIb-IIIa receptor complex, to cause reperfusion of a totally occluding coronary artery thrombus was examined alone and in combination with aspirin and heparin in a canine model of coronary artery thrombosis. A localized thrombus was produced in the left circumflex coronary artery in open-chest dogs by electrolytic injury of the endothelium. Intravenous administration of a single injection of 5.0 mg/kg aspirin and heparin (80 U/kg bolus plus 30 U/kg/hr×2hr) maintained vessel patency for approximately 101±15 minutes. After vessels had been completely occluded for 5 minutes (in the presence of aspirin+heparin), a single intravenous injection of saline (10 ml) or 0.8 mg/kg 7E3 was administered. Reperfusion was observed in all dogs (6 of 6) receiving 7E3; 4 of 6 dogs maintained vessel patency throughout the course of the 2 hour observation period. Activated partial thromboplastin and thrombin times were elevated 1.4 and 9 fold, respectively, in groups that received heparin. Template bleeding times were significantly elevated in the groups receiving 7E3. In the control group, 2 of 5 dogs reperfused briefly, however neither were patent at the end of the observation period. A third group of 4 dogs which did not receive the aspirin+heparin regimen was allowed to occlude and 5 minutes later received a single intravenous injection of 0.8 mg/kg 7E3. None of the 4 dogs in this group reperfused at any time during the study. There were no significant differences between groups in regards to hematological or hemodynamic measurements during the experiment. We concluded from these findings that the monoclonal antibody, 7E3 can promote the dissolution of friable coronary artery thrombi that evolve during standard anticoagulant and antiplatelet therapy.