Combined Administration of the GPVI-Fc Fusion Protein Revacept with Low-Dose Thrombolysis in the Treatment of Stroke

Abstract

BackgroundThrombolytic 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 resultsThe 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.ConclusionsIn 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.

Functional significance of the platelet immune receptors GPVI and CLEC-2

“…GPVI is a key player in the neuronal damage that occurs following cerebral reperfusion in the MCAO model of stroke (96), as shown by the beneficial effect of GPVI antibodies or Revacept (97)(98)(99). The reperfusion triggers an inflammatory response involving platelet adhesion/activation mechanisms, T cells, neutrophils, and monocytes, leading to tissue damage and late-stage thrombus formation.…”

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

“…Few promising entities are in different stages of pre-clinical and clinical testing. Revacept [8], is presently undergoing Phase III trial on patients with symptomatic carotid artery stenosis, TIAs, or stroke [9]. Among small molecule inhibitors, Losartan inhibits platelet activation by blocking GPVI clustering [10].…”

Plasma C‐type lectin‐like receptor 2 as a predictor of death and vascular events in patients with acute ischemic stroke

“…Inhibition of GPVI by GPVI mimics or antibodies showed a protective role in ischaemic stroke mice models. The GPVI‐Fc fusion protein alone or in combination with low‐dose thrombolysis have been reported to reduce arterial thrombus formation, cerebral infarct size and oedema after ischaemic stroke, and improve functional and prognostic outcome without intracranial bleeding . Plasma GPVI has also been reported to be increased in patients with acute coronary syndrome and ischaemic stroke .…”