P-selectin antagonism causes dose-dependent venous thrombosis inhibition.
Inhibition of P-selectin by antibody or selectin antagonist decreases inflammation and thrombosis. This study evaluates the dose-response relationship using a selectin receptor antagonist. Eight male baboons (Papio anubis) underwent inferior vena caval thrombosis using a 6 h balloon occlusion model. Three animals received 500 microg/kg P-selectin antagonist (rPSGL-Ig) and five 1 mg/kg rPSGL-Ig with or without a non-anticoagulant dose of Dalteparin. These animals were compared to our published results in this model with 4 saline controls and 8 animals that received 4 mg/kg rPSGL-Ig. A statistically significant dose-response relationship existed between rPSGL-Ig dose and thrombosis (p < 0.01), and between rPSGL-Ig dose and spontaneous recanalization (p<0.05). Inflammatory assessment revealed decreased gadolinium enhancement in all rPSGL-Ig groups compared to previously reported control, despite no significant differences in inflammatory cell extravasation. No dose of rPSGL-Ig caused anticoagulation. Selectin antagonism results in a dose-dependent decrease in thrombosis and increase in spontaneous recanalization.
Myers
D D
DD
Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109-0329, USA. ddmyers@umich.edu
Schaub
R
R
Wrobleski
S K
SK
Londy
F J
FJ
Fex
B A
BA
Chapman
A M
AM
Greenfield
L J
LJ
Wakefield
T W
TW
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage; D021721:Balloon Occlusion; D017985:Dalteparin / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage*; D019007:P-Selectin / Q000187:drug effects*; D010215:Papio; D020246:Venous Thrombosis / Q000188:drug therapy / Q000517:prevention & control*
D000925:Anticoagulants; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D017985:Dalteparin