Inhibition of platelet glycoprotein Ib, glycoprotein IIb/IIIa, or both by monoclonal antibodies prevents arterial thrombosis in baboons.
The antithrombotic efficacy of the monoclonal antibodies 6B4-Fab and MA-16N7C2 against platelet glycoprotein (GP) Ib and GP IIb/IIIa, respectively, on acute platelet-mediated thrombosis was evaluated in a baboon model of femoral artery stenosis, which is a modification of the original Folts model: platelet thrombi form on the injured stenosed artery, producing cyclic flow reductions (CFRs). A dose of 0.6 mg/kg 6B4-Fab significantly reduced the CFRs by 59 +/- 15%, whereas 2 mg/kg 6B4-Fab completely abolished the CFRs without prolongation of the bleeding time. MA-16N7C2 inhibited CFRs by 43 +/- 8% at a dose of 0.1 mg/kg and abolished the CFRs at a dose of 0.3 mg/kg but with a significant prolongation of the bleeding time. Finally, the combination of 0.6 mg/kg 6B4-Fab and 0.1 mg/kg MA-16N7C2 fully prevented the CFRs without prolongation of the bleeding time. The present study demonstrates that the inhibition of platelet GP Ib function by 6B4-Fab is a powerful intervention to prevent platelet thrombus formation in injured arteries without prolongation of the bleeding time; the latter is in contrast to the result after the inhibition of GP IIb/IIIa. Moreover, we demonstrate that combining a GP Ib blocker with a GP IIb/IIIa blocker can achieve a strong antithrombotic effect without increasing the bleeding time. This provides new information that will be beneficial in designing clinical therapeutic approaches.
Wu
Dongmei
D
Laboratory for Thrombosis Research, Interdisciplinary Research Center, KU Leuven Campus Kortrijk, Kortrijk, Belgium.
Meiring
Muriel
M
Kotze
Harry F
HF
Deckmyn
Hans
H
Cauwenberghs
Nancy
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000494:pharmacology*; D001798:Blood Proteins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005263:Femoral Artery; D008297:Male; D010215:Papio; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D001798:Blood Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; C024875:platelet adhesion inhibitor