Department of Vascular Thyroid Surgery, Gastrointestinal Vascular Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China.
The First Department of Pediatric Surgery, Gastrointestinal Vascular Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China.
Mol Med Rep. 2017 Nov;16(5):7561-7568. doi: 10.3892/mmr.2017.7556. Epub 2017 Sep 20.
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.
脑血栓形成是脑梗死最常见的原因之一，抗凝治疗是出血性脑静脉血栓形成患者的常规治疗方法。血小板的止血功能对于血栓的抗凝治疗很重要。糖蛋白 VI（GPVI）被报道为胶原蛋白的主要信号受体，它仅在血小板和巨核细胞上表达，在血管损伤部位启动血小板募集，并对脑血栓形成患者表现出许多有益的作用。在本研究中，通过活体荧光显微镜监测颈静脉内皮损伤后的血栓形成和血小板黏附。在脑血栓形成小鼠模型中观察和分析了脑血栓形成的形态学和临床观察。此外，本研究还研究了与 GPVI 细胞外结构域特异性连接的 Fc 和 PEG 修饰的融合蛋白 GPVI（GPVI-Fc-PEG）对血管壁损伤后血栓形成以及实验性脑血栓形成小鼠的影响。确定最大耐受剂量（MTD）为 0.18mg。GPVI-Fc-PEG 竞争性结合并阻止 von Willebrand 因子-胶原蛋白相互作用。本研究结果表明，与 GPVI-Fc 处理的小鼠相比，内皮损伤后给予 MTD 的 GPVI-Fc-PEG 治疗可大大缓解和改善脑血栓形成的功能结果。此外，与缺血性脑卒中即刻再灌注的 GPVI-Fc 处理的小鼠相比，脑水肿和梗死面积得到改善。此外，与单独使用单一药物治疗相比，GPVI-Fc-PEG 治疗可增加脑血栓形成后的再灌注和存活率。综上所述，GPVI-Fc-PEG 可缓解缺血性脑卒中后的脑血栓形成，并改善预后的临床前结局，且无颅内出血，这表明 GPVI-Fc-PEG 可能是脑血栓形成治疗的潜在候选药物。
