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

Abstract

Background

Expanding 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.

Results

We 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.

Conclusion

Collectively, 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.