title: Effects of GP IIb/IIIa receptor monoclonal antibody (7E3), heparin, and aspirin in an ex vivo canine arteriovenous shunt model of stent thrombosis.
abstract: 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.
authors.affiliation: Department of Medicine, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Makkar
authors.forename: F
authors.initials: F
authors.lastname: Litvack
authors.forename: N L
authors.initials: NL
authors.lastname: Eigler
authors.forename: M
authors.initials: M
authors.lastname: Nakamura
authors.forename: P A
authors.initials: PA
authors.lastname: Ivey
authors.forename: J S
authors.initials: JS
authors.lastname: Forrester
authors.forename: P K
authors.initials: PK
authors.lastname: Shah
authors.forename: R E
authors.initials: RE
authors.lastname: Jordan
authors.forename: S
authors.initials: S
authors.lastname: Kaul
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D006493:Heparin; D001241:Aspirin; D000077284:Abciximab