Effects of GP IIb/IIIa receptor monoclonal antibody (7E3), heparin, and aspirin in an ex vivo canine arteriovenous shunt model of stent thrombosis.
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.


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 2100s-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 omega, 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.
Makkar
R R
RR
Department of Medicine, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Litvack
F
F
Eigler
N L
NL
Nakamura
M
M
Ivey
P A
PA
Forrester
J S
JS
Shah
P K
PK
Jordan
R E
RE
Kaul
S
S
D000077284:Abciximab; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001166:Arteriovenous Shunt, Surgical; D001241:Aspirin / Q000494:pharmacology*; D001760:Bleeding Time; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D004285:Dogs; D005112:Extracorporeal Circulation; D006493:Heparin / Q000494:pharmacology*; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D015607:Stents / Q000009:adverse effects*; D013927:Thrombosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D014914:Whole Blood Coagulation Time
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D006493:Heparin; D001241:Aspirin; D000077284:Abciximab