A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissue-type plasminogen activator in baboons.
Inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor with the murine monoclonal antibody 7E3 abolishes ex vivo platelet aggregation, reduces thrombogenicity, and sustains arterial recanalization with recombinant tissue-type plasminogen activator (rt-PA). A chimeric murine/human Fab fragment of 7E3 (c7E3-Fab) has a markedly reduced immunogenicity, but its potency as an adjunct for thrombolysis with rt-PA has not been evaluated. The effects of a single intravenous bolus injection of aspirin (17 mg/kg) or c7E3-Fab (0.45 mg/kg) on thrombolysis and reocclusion induced with rt-PA were studied in groups of six baboons with femoral arterial thrombosis and superimposed high-grade stenosis. This dose of c7E3-Fab blocked 96 +/- 1% of the platelet GPIIb/IIIa receptors and abolished ADP-induced platelet aggregation. Bolus intravenous injections of rt-PA (0.25 mg/kg) were repeated at 15-minute intervals until reperfusion occurred (maximum of four injections). In the aspirin group, reperfusion was obtained within 51 +/- 16 minutes (mean +/- SD) but was rapidly followed by reocclusion within 6 +/- 9 minutes and by cyclic reflow and reocclusion. In the c7E3-Fab group, reperfusion was obtained within 25 +/- 8 minutes (P < .01 versus aspirin group) and was associated with a delayed reocclusion of 63 +/- 63 minutes (P < .05 versus aspirin group). Template bleeding times remained unchanged in the aspirin/rt-PA group but were markedly prolonged (to > 30 minutes) in the c7E3-Fab/rt-PA group.(ABSTRACT TRUNCATED AT 250 WORDS)
Kohmura
C
C
Cardiac Unit, Massachusetts General Hospital, Boston 02114.
Gold
H K
HK
Yasuda
T
T
Holt
R
R
Nedelman
M A
MA
Guerrero
J L
JL
Weisman
H F
HF
Collen
D
D
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D005260:Female; D005263:Femoral Artery / Q000473:pathology / Q000503:physiopathology; D006487:Hemostasis; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D010215:Papio; D010980:Platelet Membrane Glycoproteins / Q000276:immunology*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000627:therapeutic use; D015424:Reperfusion; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D007140:Immunoglobulin Fab Fragments; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D001241:Aspirin