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  • The anti platelet functions of ZGR were

    2021-11-25

    The anti-platelet functions of ZGR were confirmed by the mechanistic studies such as the activation of PKC, intracellular Ca2+ mobilization, and the expressions of P-selectin and PAC-1. Further, rivaroxaban prolonged the generation of thrombin and reduced the thrombin burst produced in the propagation phase (Perzborn et al., 2010) whereas ZGR did not affect the generation and activity of thrombin. Therefore, as ZGR selectively inhibited FXa amidolytic activity without affecting the function of thrombin in the circulation system, it should have a minimal effect on normal hemostatic responses and regulatory processes, indicating that ZGR has favorable benefits compared to rivaroxaban. The mode of the anti-platelet action of ZGR involved inhibiting (1) platelet aggregation, (2) phosphorylation of MARCKS via the PKC pathway, (3) cytosolic Ca2+ mobilization, (4) activation and production of thrombin and FXa, (5) coagulation times, and (6) expression of P-selectin and PCA-1. The mechanism of coagulation involved the activation, adhesion, and aggregation of platelets (Dahlback, 2000, Furie and Furie, 2005, Sim et al., 2005). Coagulation begins almost instantly after an injury to the blood vessel damages the endothelial lining. Exposure of blood to the space under the endothelium initiates two processes: changes in platelets and the exposure of subendothelial tissue factor (TF) to factor VII (FVII), which ultimately leads to fibrin formation (Dahlback, 2000, Furie and Furie, 2005, Sim et al., 2005). Disruption of the endothelium exposes platelets to collagen in the vessel wall and FVIIa to TF. Subsequently, the propagation of the thrombus involves the recruitment of additional platelets and amplification of the coagulation cascade by the intrinsic pathway of blood coagulation, which includes the hemophilia factors FVIII and FIX (Dahlback, 2000). Importantly, platelets and endothelial hcv protease inhibitors play a critical role in the amplification of the coagulation cascade by providing a thrombogenic surface. Therefore, the activation and behavior of platelets are the mechanistic targets of both pathways of coagulation and aggregation, suggesting that the inhibitory effects of ZGR on the activation and behavior of platelets could be the most important functions of the anti-thrombotic and anti-platelet effects of ZGR. The ex vivo antithrombotic effects of ZGR were observed in a pulmonary thrombosis model. Results of studies using pulmonary thrombosis models are reliable and reproducible. A platelet activator is used to induce the formation of thrombi characterized by massive activation of circulating platelets and widespread formation of platelet thrombi in mice (Izuhara et al., 2008, Sachs and Nieswandt, 2007). The FeCl3-induced carotid artery thrombosis mouse model is well-established and produces arterial thrombosis and, therefore, it is commonly used to determine the efficacy of novel antithrombotic drugs in vivo (Izuhara et al., 2008, Sachs and Nieswandt, 2007). A hallmark of the FeCl3-injury model is the development of thrombi in which large platelet aggregates adhere to the thrombogenic silk thread surrounded by erythrocytes and fibrin (Izuhara et al., 2008, Sachs and Nieswandt, 2007). In this study, ZGR suppressed the formation of stable occlusive thrombi that were otherwise quickly formed in the FeCl3-injury model (Table 3). Very recently, Hemalatha and Stanely Mainzen Prince reported the anti-thrombotic effects of ZGR in a rat model of myocardial infarction, in which ZGR treatment (via P.O.) decreased the expressions of inflammatory genes such as tumor necrosis factor-α, interleukin-1β (IL-1β) and IL-6 (Hemalatha and Stanely Mainzen Prince, 2016). Although they did not show the direct results of anti-thrombotic effects of ZGR in isoproterenol induced myocardial infarcted mouse model (Hemalatha and Stanely Mainzen Prince, 2016), our results showed that injected ZGR (i.v.) showed the direct inhibitory effects on arterial thrombosis and acute thrombosis animal model, confirming that ZGR was a promising novel anti-thrombotic mediator.