The GPVI-Fc Fusion Protein Revacept Improves Cerebral Infarct Volume and Functional Outcome in Stroke

Abstract

ObjectivesWe 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.BackgroundSeveral 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.MethodsPlatelet 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.ResultsThrombus formation was significantly decreased after endothelial injury by 1 mg/kg Revacept IV, compared to Fc only. 1 mg/kg Revacept IV 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.ConclusionsRevacept 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.

Targeting Glycoprotein VI and the Immunoreceptor Tyrosine-Based Activation Motif Signaling Pathway

“…In mouse models of thrombosis, pretreatment with this protein, called Revacept, was reported to prevent occlusive thrombus formation 52 and reduce infarction size after ischemic stroke. 53 These results were in agreement with those seen in GPVI-deficient mouse models, albeit less pronounced, indicating the potential efficacy of this approach. 6 Revacept is now under phase II trial (clinicaltrials.gov: NCT01645306) after phase I indicated that it is safe in healthy subjects.…”

Glycoprotein VI in securing vascular integrity in inflamed vessels

“…Consistent with observations made in GPVI‐deficient patients, inhibition, immunodepletion, or genetic deletion of GPVI in animals only had minor consequences on primary hemostasis . In contrast to its limited impact on primary hemostasis, GPVI deficiency conferred remarkable protection against thrombosis in a variety of in vitro and in vivo experimental models, including flow chamber‐based assays using human atherosclerotic plaque material . For these reasons, and despite some controversies, GPVI has been proposed as a promising target for antithrombotic therapy with reduced bleeding risk as compared to current antiplatelet therapies based on administration of aspirin and/or P2Y12 inhibitors …”

ADPase CD39 Fused to Glycoprotein VI‐Fc Boosts Local Antithrombotic Effects at Vascular Lesions

“…We showed previously that GPVI‐Fc inhibits platelet‐induced thrombus formation at sites of vascular injury . Administration of GPVI‐Fc improved myocardial ischemia and cerebral infarction without affecting bleeding time and inhibited progression of atherosclerosis . GPVI‐Fc also inhibited collagen‐induced aggregation in humans in a phase 1 study …”