Combined administration of the GPVI-Fc fusion protein Revacept with low-dose thrombolysis in the treatment of stroke

Overview

Background. Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) remains the only approved
medication for acute ischemic stroke, but incurs significant bleeding risks. Therefore, approaches to
combine lower doses of thrombolytic therapy with other effective drugs aim at improving efficacy and reducing
bleeding rates. We examined the safety and therapeutic effects of various dosings of rtPA, either alone or combined
with glycoprotein VI-Fc fusion protein (GPVI-Fc, Revacept) on experimental stroke in mice.
Methods and results. The effect of filament-induced intracerebral thrombus formation and embolization was
investigated after a one-hour occlusion of the middle cerebral artery.
In accordance with previous studies, treatment with 10 mg/kg rtPA significantly improved functional outcome, cerebral
infarct size and edema, but also resulted in markedly increased intracranial bleeding volumes. In contrast, low
doses of rtPA (0.1 or 0.35 mg/kg body weight) did not change outcome parameters. However, addition of 1 mg/kg
Revacept to 0.35 mg/kg rtPA led to improved reperfusion compared to rtPA alone. Moreover, these combined treatments
resulted in improved grip strength, compared to the respective dose of rtPA alone. Infarct-surrounding edema
improved after combined treatments, but not after respective single rtPA dosings. Intracranial bleeding volumes were
below controls after all low-dose rtPA therapies, given either alone or combined with Revacept.
Conclusions. In contrast to using the equally effective full dose of rtPA, intracranial bleeding was not increased by
low-dose rtPA combined with Revacept. Therefore, addition of Revacept to low-dose rtPA does not incur safety
risks, but improves efficacy of treatment.

Keywords

Glycoprotein VI, Middle cerebral artery occlusion, Platelet aggregation, Stroke

Disclosure

Financial support: This study was supported by a grant from the Bavarian
Research Foundation (Bayerische Forschungsstiftung), grant
# 1145-14.

Correspondence

Martin Ungerer AdvanceCOR GmbH – Procorde Fraunhofer Str. 9a 82152 Martinsried, Germany ungerer@advancecor.com; Meinrad Gawaz University of Tübingen Otfried-Müller-Str. 10 72076 Tübingen, Germany meinrad.gawaz@med.uni-tuebingen.de

Acknowledgements

We acknowledge the excellent technical assistance of Isabel Fodor.