Circulation, Vol 81, 617-627, Copyright © 1990 by American Heart Association
JK Mickelson, PJ Simpson, M Cronin, JW Homeister, E Laywell, J Kitzen and BR Lucchesi
Coronary artery rethrombosis can complicate initially effective
thrombolytic therapy. Platelets interacting with injured vascular
endothelium in a region along the coronary artery with reduced luminal
cross-sectional area contribute to rethrombosis. The purpose of this study
was to investigate the potential of the F(ab')2 fragment of the murine
monoclonal antibody 7E3 [7E3 F(ab')2] to prevent rethrombosis after
intracoronary clot lysis with recombinant tissue-type plasminogen activator
(rt-PA) in an experimental model. The 7E3 F(ab')2 binds to the platelet
glycoprotein IIb/IIIa complex (GPIIb/IIIa), thereby preventing
platelet-fibrinogen interaction and intravascular thrombus formation.
Experimental coronary artery thrombosis was produced in the anesthetized
dog by application of direct anodal current to the intimal surface of the
left circumflex coronary artery in the region of an external stenosis.
Lysis of the established intracoronary thrombus was achieved with the
intravenous administration of rt-PA (25 mg) after which the animals were
randomized into two groups. Group 1 (n = 10) served as the control,
receiving the saline diluent, and group 2 (n = 9) received 7E3 F(ab')2,
given as a single intravenous injection (0.8 mg/kg). The times required for
occlusive thrombus formation, rt-PA- induced thrombolysis, and rethrombosis
(if it occurred) were similar in the animals treated with saline and those
treated with 7E3 F(ab')2. The initial left circumflex coronary artery blood
flow was similar in both groups but decreased to a negligible level in
group 1. In group 2, left circumflex coronary artery blood flow declined
modestly (24 +/- 2 to 10 +/- 2 ml/min). Rethrombosis occurred in all
animals in group 1 but in only two of nine animals in group 2 (p less than
0.05). Oscillations in coronary blood flow preceded rethrombosis in group
1, whereas 7E3 F(ab')2 stabilized left circumflex coronary artery blood
flow patterns during the course of teh experimental protocol (5.2 +/- 0.9
vs. 0.7 +/- 0.4 oscillations, respectively; p less than 0.05). Thrombus
mass recovered from the left circumflex coronary artery at the conclusion
of each experiment was greater in group 1 as compared with group 2 (7.0 +/-
2.3 vs. 1.5 +/- 0.7 mg, respectively; p less than 0.05). The area of left
ventricle at risk for infarction was similar in both groups but infarct
size, infarction/at risk assessed histochemically, was larger in group 1
than group 2 (35 +/- 9% vs. 6 +/- 4%, respectively; p less than 0.05).
Platelet aggregation induced by ADP and arachidonic acid was similar at
baseline for all of the animals.(ABSTRACT TRUNCATED AT 400 WORDS)
ARTICLES
Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
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