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Blocking Early Steps in Platelet Aggregation Reduces Stroke Infarct Size Without Increasing Intracerebral Hemorrhage (ICH)

May 11, 2007

By Laurie Brunette and Asher Kimchi M.D.

Würzburg, Germany- Ischemic stroke is the third leading cause of death and permanent disability in industrialized countries. Currently, the anticoagulant therapies available to treat ischemic stroke offer moderate benefit on stroke progression and recurrence, but this is outweighed by a significant increase in the rate of ICH. During ischemia, platelets can adhere to hypoxic endothelial cells by binding of their glycoprotein (GP) Ib receptor to von Willebrand factor (vWF) on the endothelial surface. Additionally, subendothelial matrix proteins are exposed, allowing firm attachment of platelets to the vessel by binding of collagens to their GPVI receptor. These processes lead to activation of platelet GPIIb/IIIa and platelet aggregation. Christoph Kleinschnitz, MD et al from the University of Würzburg in Würzburg, Germany tested the hypothesis that blocking platelet aggregation and activation at various steps in these pathways may reduce infarct size following ischemic stroke. Their results, published in the May 1, 2007 issue of Circulation, showed that targeting platelet GPIb or GPVI receptors protects mice from ischemic brain injury in an experimental stroke model without increasing bleeding complications. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa antibodies had no positive effect on stroke outcome and dose-dependently raised the incidence of ICH and mortality.

Complete blockade of GPIbα receptors was achieved by intravenous injection of 100 µg Fab fragments of the monoclonal antibody p0p/B to mice undergoing 1 hour of transient middle cerebral artery (MCA) occlusion. This was administered in one group 1 hour before the induced ischemia, and in another group, it was given 1 hour after the induction of the ischemia. GPIIb/IIIa receptors were blockaded by injection of 100 µg, 20 µg, or 10µg. JON/A F(ab)2 IV 1 hour before the start of the experiment. GPVI function was inhibited by 100 µg JAQ1 IP 5 days before infarct induction. The tMCAO model was used to induce focal cerebral ischemia. This involved inserting a silicon rubber-coated 6.0 nylon monofilament into the right common carotid artery and advancing it to occlude the MCA. After one hour, the occluding filament was removed. After recovery from anesthesia and again after 24 hours, neurological function was assessed. At 24 hours after transient MCA occlusion, cerebral infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining. Magnetic resonance imaging (MRI) was performed repeatedly at 24 hours and at 7 days after stroke on a 1.5-T MR unit in order to assess the frequency of ICH over time.

In mice treated with anti-GPIb Fabα 1 hour before MCA occlusion, ischemic lesions were reduced to ≈40% compared with controls (28.5±12.7 versus 73.9±17.4 mm3, respectively; P<0.001). Application of anti-GPIbα Fab 1 hour after MCA occlusion also reduced brain infarct volumes (24.5±7.7 mm3; P<0.001) and improved the neurological status. Similarly, depletion of GPVI significantly diminished the infarct volume but to a lesser extent (49.4±19.1 mm3; P<0.05). Additionally, the disruption of early steps of platelet activation was not accompanied by an increase in bleeding complications as revealed by serial magnetic resonance imaging. In contrast, blockade of the final common pathway of platelet aggregation with anti-GPIIb/IIIa F(ab)2 fragments did not reduce stroke size and functional outcome but increased the incidence of ICH and mortality after transient MCA occlusion in a dose-dependent manner.

These results show that inhibition of early steps of platelet adhesion to the ischemic endothelium and the subendothelial matrix diminishes infarct development without causing ICH. Thus, selective blocking of platelet receptor GPIb may offer a novel and safe treatment strategy for acute stroke in humans in the future.  

Co-authors: Miroslava Pozgajova, PhD; Mirko Pham, MD; Martin Bendszus, MD; Bernhard Nieswandt, PhD; Guido Stoll, MD


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