(Stroke. 2000;31:1402.)
© 2000 American Heart Association, Inc.
Original Contributions |
Integrin 
IIbß3 Inhibitor Preserves Microvascular Patency in Experimental Acute Focal Cerebral Ischemia
Presented in part at a meeting of the International Society of Thrombosis and Haemostasis, Washington, DC, August 14–21, 1999.
From the Department of Molecular and Experimental Medicine (T.A., B.R.C., J.A.K., G.J.d.Z.), The Scripps Research Institute, La Jolla, Calif; the Department of Surgery (R.F.), University of Adelaide, The Queen Elizabeth Hospital, Woodville, Australia; and the Integra LifeSciences Corp (C.M., J.F.T., M.P.), Corporate Research Center, San Diego, Calif.
Correspondence to Gregory J. del Zoppo, MD, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd, MEM 132, La Jolla, CA 92037. E-mail grgdlzop{at}hermes.scripps.edu
Background and
Purpose—Platelets become activated and accumulate in
brain microvessels of the ischemic microvascular bed after
experimental focal cerebral ischemia. The binding of
glycoprotein IIb/IIIa (integrin
IIbß3) on platelets to fibrinogen is
the terminal step in platelet adhesion and aggregation. This study
tests the hypothesis that inhibition of platelet-fibrin(ogen)
interactions may prevent microvascular occlusion after experimental
middle cerebral artery occlusion (MCA:O).
Methods—TP9201 is a novel Arg-Gly-Asp (RGD)-containing integrin
IIbß3 inhibitor. Microvascular
patency after 3-hour MCA:O and 1-hour reperfusion within the
ischemic and nonischemic basal ganglia was compared in
adolescent male baboons who received high-dose TP9201 (group A:
IC80 in heparin, n=4), low-dose TP9201 (group B:
IC30 in heparin, n=4), or no treatment (group C: n=4)
before MCA:O.
Results—After MCA:O, microvascular patency decreased
significantly in group C. However, in the ischemic zones of
groups A and B compared with group C, patencies were significantly
greater in the 4.0- to 7.5-µm-diameter (capillary) and 7.5- to
30.0-µm-diameter vessels (2P<0.05). A dose-dependent
increase in hemorrhagic transformation was seen in group A (3 of 4
animals) compared with group B (1 of 4 animals), and no
hemorrhage was visible in group C (
2
analysis for trend, P<0.05).
Conclusions—Platelet activation contributes significantly to
ischemic microvascular occlusion. Occlusion formation may be
prevented by this RGD–integrin IIbß3
inhibitor at a dose that does not produce clinically
significant parenchymal hemorrhage. The effect of microvascular
patency on neuron recovery can now be tested.
Editorial Comment
Presented in part at a meeting of the International Society of Thrombosis and Haemostasis, Washington, DC, August 14–21, 1999.
Department of Anesthesiology/Critical Care Medicine Johns Hopkins Medical Institutions Baltimore, Maryland
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