The GPVI-Fc fusion protein Revacept improves cerebral infarct volume and functional outcome in stroke.

Abstract

OBJECTIVES:

We examined the effect of Revacept, an Fc fusion protein which is specifically linked to the extracellular domain of glycoprotein VI (GPVI), on thrombus formation after vessel wall injury and on experimental stroke in mice.

BACKGROUND:

Several antiplatelet drugs for the treatment of myocardial infarction or ischemic stroke with potent anti-ischemic effects have been developed, but all incur a significant risk of bleeding.

METHODS:

Platelet adhesion and thrombus formation after endothelial injury was monitored in the carotid artery by intra-vital fluorescence microscopy. The morphological and clinical consequences of stroke were investigated in a mouse model with a one hour-occlusion of the middle cerebral artery.

RESULTS:

Thrombus formation was significantly decreased after endothelial injury by 1 mg/kg Revacept i.v., compared to Fc only. 1 mg/kg Revacept i.v. applied in mice with ischemic stroke immediately before reperfusion significantly improved functional outcome, cerebral infarct size and edema compared to Fc only. Also treatment with 10 mg/kg rtPA was effective, and functional outcome was similar in both treatment groups. The combination of Revacept with rtPA leads to increased reperfusion compared to treatment with either agent alone. In contrast to rtPA, however, there were no signs of increased intracranial bleeding with Revacept. Both rtPA and Revacept improved survival after stroke compared to placebo treatment. Revacept and vWF bind to collagen and Revacept competitively prevented the binding of vWF to collagen.

CONCLUSIONS:

Revacept reduces arterial thrombus formation, reduces cerebral infarct size and edema after ischemic stroke, improves functional and prognostic outcome without intracranial bleeding. Revacept not only prevents GPVI-mediated, but probably also vWF-mediated platelet adhesion and aggregate formation. Therefore Revacept might be a potent and safe tool to treat ischemic complications of stroke.

• Authors: Silvia Goebel, Zhongmin Li, Jasmin Vogelmann, Hans-Peter Holthoff, Heidrun Degen, Dirk M Hermann, Meinrad Gawaz, Martin Ungerer, Götz Münch
• Journal: PloS one (PLoS One) Vol. 8 Issue 7 Pg. e66960 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23935828 (Publication Type: Journal Article)

Chemical References

• Glycoproteins
• Immunoglobulin Fc Fragments
• Recombinant Fusion Proteins
• Revacept
• von Willebrand Factor
• Collagen

Topics

• Animals
• Binding, Competitive (drug effects)
• Blood Platelets (drug effects, pathology)
• Cell Communication (drug effects)
• Cerebral Infarction (drug therapy, pathology, physiopathology)
• Collagen (metabolism)
• Disease Models, Animal
• Endothelial Cells (drug effects, pathology)
• Glycoproteins (pharmacology, therapeutic use)
• Humans
• Immunoglobulin Fc Fragments (pharmacology, therapeutic use)
• Infarction, Middle Cerebral Artery (complications, drug therapy, pathology, physiopathology)
• Inflammation (pathology)
• Mice
• Protein Binding (drug effects)
• Recombinant Fusion Proteins (pharmacology, therapeutic use)
• Recovery of Function (drug effects)
• Reperfusion Injury (complications, pathology, physiopathology)
• Stroke (complications, drug therapy, pathology, physiopathology)
• Thrombosis (complications, pathology, physiopathology)
• Treatment Outcome
• Venous Thrombosis (complications, drug therapy, pathology, physiopathology)
• von Willebrand Factor (metabolism)