title: Recombinant leech antiplatelet protein prevents collagen-mediated platelet aggregation but not collagen graft thrombosis in baboons.
abstract: Leech antiplatelet protein (LAPP) is a specific inhibitor of collagen-induced human platelet aggregation and adhesion to collagen under static conditions. Recombinant LAPP (rLAPP) and L-366,763 (acetylated-Cys-Asn-Pro-Arg-Gly-Asp-Cys-NH2), a peptidyl fibrinogen receptor antagonist, were evaluated in an anesthetized baboon thrombosis model using a collagen-coated graft segment of an arteriovenous shunt to elicit thrombus formation. Animals were randomized to receive systemic intravenous administration of rLAPP (100 micrograms.kg-1 x min-1; n = 5), L-366,763 (8.5 micrograms.kg-1 x min-1; n = 3), or saline (n = 3). Despite complete and selective inhibition of type I collagen-induced ex vivo aggregation of platelets, rLAPP had no significant effect on the rate or the extent of 111-In-labeled platelet deposition onto the collagen graft and no effect on template bleeding time. In contrast, L-366,763 completely prevented platelet deposition, maintained blood flow, and significantly prolonged bleeding time at the dosage that inhibited ex vivo aggregation in response to all agonists studied. In this study, the absence of an antithrombotic benefit of rLAPP contrasted sharply with the efficacy of the fibrinogen receptor antagonist. These results demonstrate that specific inhibition of collagen-mediated platelet aggregation alone is not sufficient to prevent platelet-dependent thrombosis in this baboon model.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486.
authors.forename: L W
authors.initials: LW
authors.lastname: Schaffer
authors.forename: J T
authors.initials: JT
authors.lastname: Davidson
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
authors.forename: R J
authors.initials: RJ
authors.lastname: Gould
authors.forename: R F
authors.initials: RF
authors.lastname: Nutt
authors.forename: S F
authors.initials: SF
authors.lastname: Brady
authors.forename: T M
authors.initials: TM
authors.lastname: Connolly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001760:Bleeding Time; D003094:Collagen / Q000494:pharmacology*; D005344:Fibrinopeptide A / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010215:Papio; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012471:Salivary Proteins and Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: C073760:LAPP protein, Haementeria officinalis; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D012471:Salivary Proteins and Peptides; C084022:L 366763; D005344:Fibrinopeptide A; D003094:Collagen