GPVI­Fc­PEG improves cerebral infarct volume and cerebral thrombosis in mouse model with cerebral thrombosis.

ABSTRACT

Cerebral thrombosis is one of the most common causes of cerebral infarction, and anticoagulation therapy is a routine treatment in patients with hemorrhagic cerebral venous thrombosis. The hemostatic function of platelets is important for the anticoagulation therapy of thrombosis. Glycoprotein VI (GPVI) is reported as the major signaling receptor for collagen and is exclusively expressed on platelets and megakaryocytes, initiating platelet recruitment at sites of vascular injury and demonstrating numerous beneficial effects for patients with cerebral thrombosis. In the present study, thrombus formation and platelet adhesion following endothelial injury was monitored in the jugular vein by intra­vital fluorescence microscopy. The morphological and clinical observations of cerebral thrombosis were investigated and analyzed in a mouse model with cerebral thrombosis. In addition, the present study investigated the effect of fusion protein GPVI modified with Fc and PEG, which is specifically linked to the extracellular domain of GPVI (GPVI­Fc­PEG), on thrombus formation following vessel wall injury and on experimental mice with cerebral thrombosis. The maximum tolerated dose (MTD) was identified as 0.18 mg. GPVI­Fc­PEG competitively bound to and prevented von Willebrand Factor­collagen interactions. The results of the present study demonstrated that cerebral thrombosis was greatly relieved and improved functional outcomes treatment with an MTD of GPVI­Fc­PEG following endothelial injury, compared with GPVI­Fc­treated mice. In addition, cerebral edema and infarct size was improved compared with GPVI­Fc­treated mice with ischemic stroke immediately prior to reperfusion. Furthermore, treatment of GPVI­Fc­PEG led to increased reperfusion and improved survival following cerebral thrombosis compared with treatment with either single agent alone. Taken together, GPVI­Fc­PEG relieved cerebral thrombosis following ischemic stroke and improved prognostic preclinical outcomes without intracranial bleeding, which suggested that GPVI­Fc­PEG may be a potential candidate for cerebral thrombosis therapy.