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(Circulation. 1997;95:1015-1021.)
© 1997 American Heart Association, Inc.

Articles

Effects of GP IIb/IIIa Receptor Monoclonal Antibody (7E3), Heparin, and Aspirin in an Ex Vivo Canine Arteriovenous Shunt Model of Stent Thrombosis

Raj R. Makkar, MD; Frank Litvack, MD; Neal L. Eigler, MD; Masato Nakamura, MD; Pamela A. Ivey, MD; James S. Forrester, MD; Prediman K. Shah, MD; Robert E. Jordan, PhD; Sanjay Kaul, MD

the Cardiovascular Interventional Research Center, the Division of Cardiology, Department of Medicine, The Burns and Allen Research Institute, Cedars-Sinai Medical Center, and UCLA School of Medicine, Los Angeles, Calif, and Centocor Inc, Malvern, Pa (R.E.J.).

Correspondence to Sanjay Kaul, MD, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail kaul@csmc.edu.

	Abstract

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Background Thrombosis is an important limitation of metallic coronary stents, especially in smaller vessels in which shear rates are high. Monoclonal antibody to platelet glycoprotein IIb/IIIa receptor (7E3) has been shown to inhibit shear-induced platelet aggregation. In this study, we compared the effects of 7E3, heparin, and aspirin on stent thrombosis in an ex vivo arteriovenous shunt model of high-shear blood flow.

Methods and Results An ex vivo arteriovenous shunt was created in 10 anesthetized dogs. Control rough-surface slotted-tube nitinol stents (n=72) expanded to 2 mm in diameter in a tubular perfusion chamber were interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100 s^-1 for 20 minutes. The animals were treated with intravenous murine 7E3 (Fab')₂ (0.2, 0.4, and 0.8 mg/kg), heparin (100 U/kg), or aspirin (10 mg/kg). Effects of the test agents on thrombus weight, platelet aggregation, platelet P-selectin expression, bleeding time, and activated clotting time (ACT) were quantified. 7E3 reduced stent thrombosis by 95% (20±1 to 1±1 mg, P<.001) and platelet aggregation by 94% (14±2 to 1±1 , P<.001) at the highest dose (0.8 mg/kg). 7E3 significantly prolonged bleeding time but had no effect on ACT and platelet P-selectin expression. Heparin prolonged ACT but had no significant effect on stent thrombosis or platelet aggregation. Aspirin, although it inhibited platelet aggregation by 65%, had no effect on stent thrombosis (19±2 versus 20±1 mg in controls).

Conclusions 7E3 produced a dose-dependent inhibition of acute stent thrombosis under high-shear flow conditions. Stent thrombosis was resistant to heparin and aspirin. Thus, 7E3 may be an effective agent for preventing stent thrombosis.

Key Words: platelets • angioplasty • thrombosis

	Introduction

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Stent thrombosis is a significant limitation of intracoronary stenting.^{1 2 3 4 5 6 7 8 9} Despite aggressive anticoagulation, the incidence of stent thrombosis is 1% to 17%, depending on the series reported and presence of multiple risk factors.^{1 2 3 4 5 6 7 8 9} Currently used antiplatelet and antithrombotic regimens have limited efficacy in preventing stent thrombosis. A new class of drugs that bind to glycoprotein (GP) IIb/IIIa receptor on activated platelets have potent antiplatelet and antithrombotic effects^{10 11 12 13 14 15} and have demonstrated efficacy in reducing thrombus-related major complications after coronary angioplasty.¹⁶

We recently demonstrated blood shear rate to be an important factor in experimental stent thrombosis.¹⁷ Furthermore, infusion of 7E3, a monoclonal antibody fragment that binds competitively to the glycoprotein IIb/IIIa receptor, has been shown to inhibit shear-induced platelet aggregation and thrombus formation in patients undergoing percutaneous transluminal coronary angioplasty.^{18 19} We therefore hypothesized that this particular GP IIb/IIIa antagonist may be effective in inhibiting shear-induced stent thrombosis.

In this study, we used an ex vivo canine femoral arteriovenous shunt thrombosis model to evaluate the efficacy of 7E3 antibody in inhibiting stent thrombosis. The antithrombotic effects of 7E3 were also compared with those of the conventional antiplatelet and antithrombotic agents aspirin and heparin.

	Methods

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Coronary Stents
The stents (n=72) tested were 7-mm-long slotted-tube-geometry devices made from the nickel-titanium alloy nitinol (Advanced Coronary Technology). They weighed 16±1 mg and had a strut thickness of 0.006 in. They had a silicon carbide grit–blasted surface finish, which creates a uniform roughened surface known to be highly thrombogenic in this model.¹⁷ Stents were expanded on a tapered mandrel to an OD of 2.0 mm before being mounted in the perfusion chamber.

Experimental Model
All procedures were approved by the Institutional Animal Care and Use Committee and conformed to the American Heart Association guidelines for animal research. A previously described ex vivo extracorporeal perfusion system²⁰ was adapted to study acute stent thrombosis (Fig 1).

View larger version (23K): [in this window] [in a new window]   Figure 1. Schematic of extracorporeal perfusion system to study platelet-thrombus formation on stents. Expanded stents were mounted in tubular perfusion chamber and exposed to flowing blood (70 mL/min) from femoral artery of dogs at a shear rate of 2100 s-1. Blood was returned to femoral vein by a peristaltic pump.

Experiments were performed in 10 dogs weighing 18 to 22 kg. After overnight fasting, dogs were sedated with phenobarbital (5 mg/kg), and anesthesia was maintained with 1% isoflurane after endotracheal intubation. The right femoral artery and vein were isolated and cannulated with 8F sheaths to establish an extracorporeal circuit. Arterial blood gases and pH were monitored periodically and maintained at normal levels by adjustment of the ventilation rate and tidal volume. Invasive arterial pressure measurement, oxygen saturation, ECG, and rectal temperature were monitored continuously. A thermostatically controlled blanket was used to maintain temperature at 37°C.

Venous blood was collected for baseline platelet aggregation, platelet flow cytometry, complete blood cell count, and activated clotting time (ACT) measurements. After this, all animals received heparin at a dose of 10 U/kg as a bolus before the study to prevent thrombotic occlusion of catheters and tubing. Each dog received an average of 200 U heparin, an amount that produces negligible effects on thrombus formation at high-shear conditions in this model (data not shown).

At the conclusion of the experiment, blood was collected for complete blood cell counts, the femoral artery and vein were ligated, and the animals were allowed to recover from anesthesia before being returned to the vivarium.

Extracorporeal Shunt
A schematic of the extracorporeal shunt system is shown in Fig 1. A tubular Badimon perfusion chamber²⁰ with an ID of 2.0 mm was used for perfusion experiments. Expanded stents were mounted in the chamber, and the tops of the stents were covered with 1.0x2.5-cm sterile Hemashield graft strips (Medtronic Corp) to obtain a watertight seal to prevent blood from leaking. The arterial cannula was connected to the inlet of the perfusion chamber, and the outlet was connected to the venous catheter through a variable-speed peristaltic pump (Masterflex, Cole-Palmer Instrument Co). A transit-time Doppler flow probe (Transonic System Inc) was interposed in the circuit after the pump to document continuous blood flow through the circuit. The chamber and part of the tubing were placed in a water bath maintained at 37°C.

Perfusion Protocol
The perfusion protocol is illustrated in Fig 2. After a 60-minute stabilization period, stents were mounted in the tubular chamber and perfused with Krebs solution for 60 seconds at 37°C. With a switch valve used to prevent stasis, blood was circulated through the system, and flow was regulated at 70 mL/min for 20 minutes. This flow rate generates a wall shear rate of 1486 s^-1 at the chamber surface and 2100 s^-1 at the stent surface. The shear rates were calculated according to the formula for laminar flow of homogeneous newtonian fluid in a cylindrical tube: shear rate=4·Q/p·R³, where Q is volume flow and r is radius. At high shear rates, as used in this study, blood is considered to be essentially a newtonian fluid.²¹ At the end of the perfusion period, Krebs buffer was circulated through the chamber for 30 seconds at 40 mL/min to wash off unattached cells and blood from the stent and the perfusion system.

View larger version (19K): [in this window] [in a new window]   Figure 2. Perfusion protocol. Animals were divided into two groups: group A animals were treated with intravenous 7E3 in cumulative doses of 0.2, 0.4, and 0.8 mg/kg and group B animals with intravenous heparin (100 U/kg), aspirin (10 mg/kg), and 7E3 (0.4 mg/kg) in stepwise fashion. In each animal, one or two stents were perfused before administration of any drug to obtain control thrombus weight. Perfusion studies were performed 30, 15, and 60 minutes after administration of 7E3, heparin, and aspirin, respectively. Numbers in parentheses indicate total number of stents perfused in study at each step.

At the completion of each perfusion period, the stents were removed from the chamber, dried, and weighed. The perfusion chamber and ex vivo system were perfused with normal saline for several minutes to clear any visible blood before another stent was mounted. Digital images of stents were obtained at x15 magnification in side and end views with a video microscope, PC frame grabber, and image analysis software (Bioscan, Optimas Corp).

Preparation and Administration of Drugs
m7E3 F(ab')₂ was supplied by Centocor Inc as a filtered, sterile, nonpyrogenic, 2-mg/mL solution in 0.01 mol/L sodium phosphate/0.001% polysorbate 80, pH 7.2. The antibody was kept refrigerated at 4°C until immediately before use. The maximum dose of 7E3 used in this study is "pharmacologically equivalent" to the standard dose (0.25 mg/kg) used clinically in humans.^{22 23} Aspirin (Bayer AG) was dissolved in distilled water just before use as instructed by the manufacturer. All drugs were administered intravenously as a bolus.

Platelet Studies
Platelet Aggregation Assay
Thirty minutes after administration of the drug, 3 mL venous blood was collected in a siliconized test tube containing 0.3 mL of 0.129 molar sodium citrate (Becton Dickinson Vacutainer System). Whole blood aggregometry (Chronolog Corp) was used to measure collagen 5 µg/mL–induced platelet aggregation. Blood (0.5 mL) was diluted 1:1 in sterile physiological saline and incubated at 37°C for 3 minutes before aggregation was estimated. Aggregation was expressed as maximal increase in electrical impedance measured in ohms at 6 minutes after the addition of collagen.

Flow Cytometry
Aliquots of control and treated venous blood were collected in 0.3 mL 0.129 molar sodium citrate solution and incubated with saturating concentrations of phycoerythrin (PE)-conjugated CD61 and FITC-conjugated CD62 (Becton Dickinson) monoclonal antibodies for 20 minutes. Specimens were fixed with 1% formaldehyde and analyzed in a FACScan flow cytometer (Becton Dickinson Immunocytometry Systems).²⁴ The light channels were set at logarithmic gain. Platelets were identified from other cells on the basis of their CD61-PE profiles. Activated degranulating platelets were identified from the CD62-FITC profile as a measure of P-selectin activity.²⁵ P-selectin expression was measured at baseline and after activation with ADP (1 µmol/L).

Bleeding and ACT
Bleeding time was measured from an incision on the ventral surface of the thigh with a No. 11 surgical knife. The time between incision and cessation of bleeding was recorded as bleeding time. ACT was performed with a Hemochron 400 (International Technidyne Corp) machine in standard fashion.²⁶

Scanning Electron Microscopy
For electron microscopy studies, four control stents and four stents treated with 0.8 mg/kg 7E3 were immediately fixed in 1% glutaraldehyde-cacodylate, dehydrated in increasing concentrations of ethanol, and dried overnight at room temperature. The dried stents were cut open carefully and mounted on aluminum stubs with the inner surface of the stent facing up. Stents were spray-coated with gold in a Polaron G-5000 sputter coater, and care was taken not to dislodge any thrombus. Scanning was performed at x50 to x2000 with a Hitachi S-450 electron microscope operated at 20 kV.

Statistical Analysis
Data are presented as mean±SD. The statistical difference between means was determined by single-factor ANOVA. If means were shown to be significantly different, multiple comparisons by pairs were performed by the Tukey test (Instat version 1.2). Probability values of P<.05 were considered to indicate statistical significance.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Stent Thrombosis
Administration of 7E3 produced a dose-dependent inhibition of thrombus weight (Fig 3). Effects of treatment with 7E3, aspirin, and heparin on acute stent thrombosis are quantified in Fig 4. Stent thrombus weight was reduced by 95% at the highest dose, 0.8 mg/kg (from 20±1 to 1±1 mg, P<.001). Aspirin and heparin had no significant effects on thrombus formation on stents. Treatment with aspirin+7E3 (0.4 mg/kg) produced a slightly greater but statistically insignificant reduction in thrombus weight compared with 7E3 alone (from 20±1 to 2±1 versus 20±1 to 4±2 mg, respectively, P=.5, n=9).

View larger version (82K): [in this window] [in a new window]   Figure 3. Photomicrographs (x15) demonstrating effects of m7E3 dosages on stent thrombosis: side view (left) and end view (right). Control stent is totally occluded with thrombus weighing 18 mg; stent treated with 0.2 mg/kg 7E3 has 14-mg thrombus; stent treated with 0.4 mg/kg has 3-mg thrombus; and stent treated with 0.8 mg/kg 7E3 has 1-mg thrombus.

View larger version (19K): [in this window] [in a new window]   Figure 4. Effects of 7E3, heparin (hep), aspirin (asa), and m7E3+aspirin (asa+7E3) on thrombus weight. Values are mean±SD. *P<.001 vs control; P<.001 vs 7E3 0.2 mg/kg; n=No. of stents.

Platelet Studies
Effects of 7E3, heparin, and aspirin on collagen-induced platelet aggregation are shown in Fig 5. 7E3 produced a dose-dependent inhibition of platelet aggregation with virtual elimination of platelet aggregation (from 14±2 to 1±1 , P<.001) at a dose of 0.8 mg/kg. Heparin had no significant effects on platelet aggregation in response to collagen. Although aspirin did not affect stent thrombosis, platelet aggregation was reduced significantly, by 65% (from 14±2 to 6±2 , P<.01).

View larger version (18K): [in this window] [in a new window]   Figure 5. Effects of 7E3, heparin (hep), aspirin (asa), and m7E3+aspirin (asa+7E3) on collagen 5 mg/mL–induced platelet aggregation and bleeding time. Values are mean±SD. *P<.05 vs control; P<.001 vs control; n=No. of observations.

Resting and ADP-stimulated platelet P-selectin expression (a marker of platelet activation) were not significantly affected by administration of 7E3, heparin, or aspirin (Table 1).

View this table: [in this window] [in a new window]   Table 1. Effects on Platelet P-Selectin Expression

Hematological Studies
The effects of study drugs on bleeding and ACTs are shown in Figs 5 and 6, respectively. 7E3 produced a dose-dependent prolongation of bleeding time but had virtually no effect on ACT. Bleeding time was prolonged from 3±1 to 24±3 minutes (n=9; P<.001) at the highest dose, 0.8 mg/kg. Heparin had no effects on bleeding time but prolonged ACT. Aspirin had no significant effects on either bleeding or ACT. There were no episodes of significant bleeding in any of the animals studied. Treatment with 7E3, heparin, and aspirin had no significant effects on either platelet or white blood cell counts or hematocrit (Table 2).

View larger version (20K): [in this window] [in a new window]   Figure 6. Effects of 7E3, heparin (hep), and aspirin (asa) on activated clotting time. Values are mean±SD. *P<.01 vs control; n=No. of observations.

View this table: [in this window] [in a new window]   Table 2. Effects on Platelets, WBC, and Hematocrit

Scanning Electron Microscopy
Control stents revealed large amounts of organized thrombus and platelet clumps with no visible bare stent surface. Stents treated with 0.8 mg/kg 7E3 had virtually no visible thrombus macroscopically but showed fibrinous material coating the stent surface, with adherent platelets and leukocytes. The bare stent surface was not visible because of protein and platelet coating.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Using a canine arteriovenous shunt model to study high shear rate–mediated stent thrombosis, we have demonstrated that m7E3, a murine monoclonal antibody to platelet GP IIb/IIIa receptor, profoundly inhibits stent thrombosis, whereas treatment with the conventional antiplatelet and antithrombotic agents aspirin and heparin does not. The antithrombotic effects of 7E3 are rapid in onset, dose-dependent, and associated with significant inhibition of platelet aggregation and prolongation of bleeding time. The profound inhibition of stent thrombosis was obtained by doses of murine 7E3 that are equivalent to routinely used doses of chimeric 7E3 in clinical practice.

Despite the expanding role of stents in the interventional treatment of coronary artery disease, subacute thrombosis remains an important limitation of intracoronary stenting, especially in nonelective cases or in smaller vessels. Conventionally used antiplatelet and anticoagulant agents such as aspirin, heparin, and warfarin have been ineffective in reducing stent thrombosis.^{2 4 6 9} More recently, a combination of aspirin, ticlopidine, and high-pressure stent deployment has been reported to reduce the incidence of stent thrombosis in large vessels.²⁷ Also, heparin-coated stents have been found to be effective in reducing stent thrombosis in animal²⁸ and human²⁹ studies. At this time, however, no data are available on the efficacy of this approach in small (<2.5-mm) vessels or other high-risk clinical situations. In addition, the 48- to 72-hour delay in onset of the antiplatelet effects of ticlopidine limits its use for stent implantation in acute ischemic syndromes with preexisting thrombus. Treatment with ticlopidine is also associated with neutropenia in 1% to 2% of patients.³⁰

The ex vivo extracorporeal perfusion chamber system used in this study has been used extensively to study mechanisms and treatment of vascular platelet-thrombus formation in experimental animals.²⁰ Other investigators have validated similar models to study the thrombogenicity of endovascular stents.^{31 32} We specifically studied stent thrombosis at higher shear rates (2100 s^-1) to simulate the high-risk clinical situation of inadequate stent deployment or stenting in a smaller-diameter vessel. Although the relevance of this model to clinical stent thrombosis remains to be defined, its simplicity, reproducibility, and ability to study multiple stents and drug types in the same experiment makes it attractive in the study of the interaction of blood elements with stent surfaces.

At the maximum dose of 0.8 mg/kg used in this study, m7E3 produces 85% GP IIb/IIIa receptor blockade in canine platelets.²² This effect equals in magnitude the degree of blockade (85%) attained by chimeric 7E3 at the standard dose (0.25 mg/kg) in human platelets.²³ The difference in dose-response relationships of 7E3 in canine and human platelets is due to weaker binding of 7E3 to canine platelets than to human platelets. Therefore, the higher dose of murine 7E3 used in this study is "pharmacologically equivalent" to the dose of chimeric 7E3 used in clinical practice.

Mechanism of Action
Platelets seem to play a crucial role in stent thrombosis.³³ Thrombus formation on bioprostheses such as stents most likely involves four steps: (1) surface coating by plasma proteins, particularly fibrinogen and von Willebrand factor; (2) platelet adhesion to these proteins; (3) activation of adhered platelets; and finally, (4) formation of large platelet aggregates mediated by GP IIb/IIIa receptors through fibrinogen cross-links between activated platelets.

This study provides some clues as to the mechanism of the inhibitory effects of 7E3 on stent thrombosis. Scanning electron microscopy of 7E3-treated stents showed the stent surface to be extensively coated with plasma proteins (most likely fibrinogen) and platelets, suggesting that fibrinogen binding and platelet adhesion to stents are not eliminated by 7E3. Platelet activation, as measured by P-selectin expression, was also unaffected by 7E3. P-selectin is released from the platelets during platelet activation, which occurs during platelet adhesion and aggregation. Our data are consistent with the observations of Turner et al,¹⁸ who demonstrated that 7E3 inhibits shear-induced platelet aggregation while producing little effect on adhesion. It is conceivable that plasma proteins and GP IIb/IIIa receptor–blocked platelets adherent to the stent "passivate" the surface by blocking further platelet aggregation on the stent. These findings therefore suggest that 7E3 inhibits stent thrombosis predominantly by preventing large platelet aggregates, either by blocking the exposed GP IIb/IIIa receptors on platelets adherent to the stent surface or by a more systemic inhibition of the final common pathway of platelet aggregation.

Limitations
Several limitations of this study preclude making direct inferences to the clinical situation of stent thrombosis. This was an ex vivo study that examined acute thrombus formation on stents over a short period of time (20 minutes), whereas in the clinical setting, stent thrombosis peaks around 3 to 5 days after stenting. The high-shear conditions used in this model generated large quantities of thrombus, a situation generally not encountered in large, adequately stented vessels. We purposely tested such high-shear conditions to simulate clinical situations of inadequate stent expansion, small-vessel stenting, and stenting in the presence of thrombus, conditions that are all associated with increased incidence of stent thrombosis. The ex vivo model also excludes underlying vascular injury or the effect of drugs on the vessel wall, both of which may potentially affect stent thrombosis.³⁴

Implications
Although 7E3 antibody has been assessed in clinical trials of angioplasty^{35 36} and thrombolysis,³⁷ very little information is available regarding the effects of 7E3 on stent thrombosis. We have shown that 7E3, a potent GP IIb/IIIa antagonist, produces marked inhibition of acute platelet-dependent stent thrombosis under high-shear flow conditions in an ex vivo canine arteriovenous shunt thrombosis model compared with heparin and aspirin. Recent randomized trials have shown that 7E3 reduces ischemia, myocardial infarction, refractory angina, death, and clinical restenosis in patients undergoing angioplasty in the setting of unstable ischemic syndromes. Our study supports a potential beneficial role of 7E3 in preventing stent thrombosis under high-shear flow conditions in vessels <2.5 mm, when stents are inadequately deployed, and in the presence of thrombus. The present study suggests a properly designed clinical trial to evaluate the role of 7E3 in patients at high risk for stent thrombosis.

	Acknowledgments

 
This research was supported in part by grants from the Rose and Richard Miller Family Fund and Cedars-Sinai Grand Foundation. The authors wish to thank Susan Schauer, MS, Hao Zeng, MD, and Adrian Glenn for technical assistance and Juan J. Badimon, PhD, for generously providing the perfusion chamber.

	Footnotes

 
Drs Eigler, Litvack, and Forrester have a financial interest in Advanced Coronary Technology, the manufacturers of the nitinol stent used in this study.

Received May 14, 1996; revision received September 23, 1996; accepted October 7, 1996.

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