Monoclonal antibody-induced inhibition of platelet function: effects on hemostasis and vascular graft thrombosis in baboons.
The usefulness of antiplatelet agents in vascular graft recipients remains controversial because of uncertainties regarding drug mechanisms of action and dose-duration effects. In our study, a well-characterized murine monoclonal antibody (LJ-CP8, 10 mg/kg) was infused into baboons to assess the hemostatic consequences and antithrombotic effectiveness of blocking the platelet glycoprotein IIb-IIIa receptor for fibrinogen and other adhesive glycoproteins. Five treated animals and six control animals were evaluated with serial measurements of platelet count, bleeding time, and platelet aggregation ex vivo (in response to adenosine diphosphate and collagen). Indium 111-labeled platelet deposition onto femoral vascular grafts (4 mm inner diameter Gore-Tex) implanted immediately after antibody infusion was measured by quantitative gamma camera imaging. Although the antibody did not alter circulating platelet counts, bleeding times were immediately prolonged to more than 30 minutes (vs. 4.8 +/- 0.4 minutes pretreatment) with only partial normalization by 48 hours (8.3 +/- 1.0 minutes, p less than 0.05). Platelet aggregation in response to both collagen and adenosine diphosphate was abolished immediately and remained impaired for 48 hours. Despite the profound inhibition of platelet function, graft platelet deposition was equivalent postoperatively in both the treated and untreated groups (p greater than 0.5), averaging approximately 5 x 10(9) platelets per graft. Graft-associated indium 111-labeled platelet activity increased over 48 hours and was not reduced by the antibody treatment (p greater than 0.5 at all times). All grafts were removed at 8 days; only one graft from a treated animal was found patent.(ABSTRACT TRUNCATED AT 250 WORDS)
Torem
S
S
Department of Vascular and Thoracic Surgery, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
Schneider
P A
PA
Hanson
S R
SR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001807:Blood Vessel Prosthesis; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006487:Hemostasis; D008297:Male; D010215:Papio; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D010980:Platelet Membrane Glycoproteins / Q000276:immunology*; D011138:Polytetrafluoroethylene; D013927:Thrombosis / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011138:Polytetrafluoroethylene