Silica nanoparticles induced the pre-thrombotic state in rats via activation of coagulation factor XII and the JNK-NF-κB/AP-1 pathway

Abstract

Silica nanoparticles (SiNPs) play a vital role in medical applications such as drug delivery and cancer therapy. SiNPs can translocate into the bloodstream through all the possible routes of entry. However, there have been scarce studies on the pre-thrombotic effect of SiNPs and the mechanism of the pre-thrombotic state in vivo. We specifically focused on the changes of platelet function and blood coagulation in Wistar rats after 7 consecutive days of intravenous injection of SiNPs (52 nm). The platelet aggregation assay, structural changes of platelet membrane glucoproteins, coagulation test, coagulant/anti-coagulant and fibrinolytic factors and the possible molecular mechanism of pre-thrombotic state formation were performed. Our results demonstrated a significant increase in platelet aggregation rate and platelet activation after SiNP exposure. The clotting time was significantly shortened while fibrinogen (FIB) contents were increased. There were sustained increases in coagulation factors and thrombin–antithrombin complex (TAT) expression induced by SiNPs. Antithrombin III (AT-III) of the SiNP-treated groups was significantly decreased while the concentrations of the tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (t-PA) and D-dimer were elevated. The phosphorylation of nuclear factor-κB/p65 (NF-κB/p65) and activator protein-1/c-Jun (AP-1/c-Jun) and the protein levels of JNK were increased after SiNP exposure. In summary, our results revealed that SiNPs induced the hypercoagulable and pre-thrombotic state in rats through the interaction between platelet activation, coagulation system hyperfunction, anti-coagulation and fibrinolytic resistance. Direct interactions between SiNPs and coagulation factor XII (F XII) and the JNK-NF-κB/AP-1 pathway might be involved in the regulation of pre-thrombotic state formation.