Silver nanoparticles (AgNP) are widely used in medical practices owing to their distinct antibacterial, antiviral and anticancer activities. However, with increasing use of AgNP, concerns over its potential toxicity are also escalating. Here, we demonstrated the potential thrombotic effect of AgNP which was mediated by the procoagulant activity of red blood cells (RBCs). In freshly isolated human RBCs, AgNP, but not silver microparticles (AgMP), elicited morphological changes, phosphatidylserine (PS) exposure and microvesicles (MV) generation, the key indicators of procoagulant activity in RBCs at concentration ranges (≤ 100 μg/mL) that were free of significant hemolysis. In line with this, AgNP potentiated thrombin generation and adherence of RBCs to endothelial cells, while AgMP did not. Oxidative stress, intracellular calcium increase and ATP depletion were found to underlie the procoagulant effects of AgNP, which led to altered activity of membrane aminophospholipid translocases. These in vitro findings were well reproduced in rat in vivo, where intravenously exposure to AgNP promoted venous thrombosis significantly. Of note, RBCs isolated from cancer patients, who inherently convey the risk of thrombogenesis, were more sensitive to the procoagulant effects of AgNP. In addition, AgNP significantly potentiated the procoagulant effects of a chemotherapeutic drug, paclitaxel. Collectively, these results suggest that AgNP may have prothrombotic risks by promoting procoagulant activity of RBCs and caution shall be taken for its use in the population sensitive to thrombosis like cancer patients.

中文翻译：

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银纳米颗粒可促进红细胞的促凝血活性：易感人群有血栓形成的潜在风险

银纳米颗粒（AgNP）由于其独特的抗菌，抗病毒和抗癌活性而被广泛用于医疗实践。但是，随着AgNP用量的增加，对其潜在毒性的关注也在增加。在这里，我们证明了由红细胞（RBCs）的促凝活性介导的AgNP的潜在血栓形成作用。在新鲜分离的人类RBC中，AgNP而非银微粒（AgMP）引起形态变化，磷脂酰丝氨酸（PS）暴露和微囊泡（MV）生成，这是浓度范围（≤100μg/ mL）的RBC中促凝活性的关键指标没有明显的溶血。与此相一致，AgNP增强了凝血酶的生成和RBC对内皮细胞的粘附，而AgMP则不然。氧化应激 发现细胞内钙增加和ATP消耗是AgNP促凝血作用的基础，这导致膜氨基磷脂转位酶活性的改变。这些体外发现在大鼠体内得到了很好的再现，其中静脉内暴露于AgNP可以显着促进静脉血栓形成。值得注意的是，固有地具有血栓形成风险的从癌症患者中分离出的RBC对AgNP的促凝作用更为敏感。另外，AgNP显着增强了化疗药物紫杉醇的促凝作用。总体而言，这些结果表明，AgNP可能通过促进RBC的促凝血活性而具有血栓形成风险，因此在癌症患者等对血栓形成敏感的人群中使用AgNP时应谨慎。