GPVI-Fc-PEG 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 intra‑vital 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 (GPVI‑Fc‑PEG), 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. GPVI‑Fc‑PEG competitively bound to and prevented von Willebrand Factor‑collagen interactions. The results of the present study demonstrated that cerebral thrombosis was greatly relieved and improved functional outcomes treatment with an MTD of GPVI‑Fc‑PEG following endothelial injury, compared with GPVI‑Fc‑treated mice. In addition, cerebral edema and infarct size was improved compared with GPVI‑Fc‑treated mice with ischemic stroke immediately prior to reperfusion. Furthermore, treatment of GPVI‑Fc‑PEG led to increased reperfusion and improved survival following cerebral thrombosis compared with treatment with either single agent alone. Taken together, GPVI‑Fc‑PEG relieved cerebral thrombosis following ischemic stroke and improved prognostic preclinical outcomes without intracranial bleeding, which suggested that GPVI‑Fc‑PEG may be a potential candidate for cerebral thrombosis therapy.

Selective inhibition of thromboinflammation in COVID-19 by Btk inhibitors

“…As we reported recently, FcγRIIA-stimulated platelet activation (aggregation, secretion, and P-selectin expression) and formation of platelet-neutrophil aggregates were completely suppressed by low concentrations of various Btk-inhibitors in vitro and by a single low oral dose of ibrutinib for several days ex vivo [13]. Further platelet-mediated mechanisms of vascular thrombosis, that are also blocked by Btk-inhibitors, are the activation of platelet glycoprotein (GP) VI by collagen exposed after endothelial injury and of GPIb by von Willebrand factor expressed on inflamed endothelium [14,15,16,17,18,19,20].…”

Modulation of Glycoprotein VI and Its Downstream Signaling Pathways as an Antiplatelet Target

“…Other cases of a modified GPVI-Fc protein were observed in the study performed by Wufuer and collaborators, when GPVI-Fc was linked to polyethylene glycol (PEG), forming the protein GPVI-Fc-PEG (for a better pharmacological release). This molecule is associated with competitive blocking von Willebrand factor (VWF)–collagen interactions [ 118 ]. The administration of GPVI-Fc-PEG (0.18 mg per day) showed an increase in reperfusion and an improvement in the survival following cerebral thrombosis in a murine model, compared with treatment with GPVI alone and without the risk of intracranial bleeding [ 118 ].…”

“…This molecule is associated with competitive blocking von Willebrand factor (VWF)–collagen interactions [ 118 ]. The administration of GPVI-Fc-PEG (0.18 mg per day) showed an increase in reperfusion and an improvement in the survival following cerebral thrombosis in a murine model, compared with treatment with GPVI alone and without the risk of intracranial bleeding [ 118 ].…”

Mir-24 reduces serum lipid levels and inhibits brain tissue cells apoptosis of rats with cerebral infarction

“…Hypertension is an important independent risk factor for cerebral infarction, which can directly cause a wide range of cerebral atherosclerosis (7,11). Thrombosis, which occurs on the basis of atherosclerosis, is one of the most common causes of cerebral infarction (24). It was reported that miR-155 was negatively correlated with elevated blood pressure by acting on the RAAS system.…”