Titanium dioxide nanoparticles enhance thrombosis through triggering the phosphatidylserine exposure and procoagulant activation of red blood cells

Yiying Bian,Kyung-Min Lim,Han-Young Chung,Jingbo Pi,Ok-Nam Bae,Jin-Ho Chung

doi:10.1186/s12989-021-00422-1

Abstract

BackgroundExpanding biomedical application of anatase titanium dioxide (TiO2) nanoparticles (NPs) is raising the public concern on its potential health hazards. Here, we demonstrated that TiO2 NPs can increase phosphatidylserine (PS) exposure and procoagulant activity of red blood cells (RBCs), which may contribute to thrombosis.ResultsWe conducted in vitro studies using RBCs freshly isolated from healthy male volunteers. TiO2 NPs exposure (≦ 25 μg/mL) induced PS exposure and microvesicles (MV) generation accompanied by morphological changes of RBCs. While ROS generation was not observed following the exposure to TiO2 NPs, intracellular calcium increased and caspase-3 was activated, which up-regulated scramblase activity, leading to PS exposure. RBCs exposed to TiO2 NPs could increase procoagulant activity as measured by accelerated thrombin generation, and enhancement of RBC-endothelial cells adhesion and RBC-RBC aggregation. Confirming the procoagulant activation of RBC in vitro, exposure to TiO2 NPs (2 mg/kg intravenously injection) in rats increased thrombus formation in the venous thrombosis model.ConclusionCollectively, these results suggest that anatase TiO2 NPs may harbor prothrombotic risks by promoting the procoagulant activity of RBCs, which needs attention for its biomedical application.

Highlights

Expanding biomedical application of anatase titanium dioxide (TiO2) nanoparticles (NPs) is raising the public concern on its potential health hazards
Characterization of TiO2 NPs and transmission electron microscopy (TEM) analysis of TiO2 NPs-exposed red blood cells (RBCs) The size distribution of TiO2 NPs was characterized with scanning electron microscopy (SEM) and dynamic light scattering (DLS)
We could observe that TiO2 NPs penetrates through RBCs membranes and enter into RBCs using transmission electron microscopy (TEM) (Fig. 1c), which matched well the previous findings provided by Li, et al, and Rothen-Rutishauser, et al, [23, 24], indicating that TiO2 NPs exposure may produce significant biological or toxic effects on RBCs

Summary

Introduction

Expanding biomedical application of anatase titanium dioxide (TiO2) nanoparticles (NPs) is raising the public concern on its potential health hazards. We demonstrated that TiO2 NPs can increase phosphatidylserine (PS) exposure and procoagulant activity of red blood cells (RBCs), which may contribute to thrombosis. Participating in thrombosis, RBCs accelerate the cascade of coagulation and the formation of blood clotting through externalization of phosphatidylserine (PS) on the outer membrane providing a procoagulant sites and faciliating thrombin generation [14]. This process is called as the procoagulant activity of RBCs, which is triggered by the perturbation of membrane phospholipid translocases; scramblase and flippase. Perturbation of membrane phospholipid translocases are caused by upstream events of intracelluar calcium increase, caspase activation, ROS production as well as ATP- and thiol-depletion [15,16,17,18,19,20,21]

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Discussion

Conclusion