TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia

Meishan Yan; Minghui Xu; Zhanni Li; Yao An; Zelong Wang; Shuli Li; Yingli Chen; Yanshi Xia; Liqiu Wang; Longlong Wang; Shuting Ji; Weijun Dong; Jialan Shi; Chunyan Gao

doi:10.1016/j.bcmd.2022.102666

TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia

Blood Cells Mol Dis. 2022 May 7:96:102666. doi: 10.1016/j.bcmd.2022.102666. Online ahead of print.

Authors

Meishan Yan¹, Minghui Xu¹, Zhanni Li¹, Yao An¹, Zelong Wang¹, Shuli Li², Yingli Chen¹, Yanshi Xia¹, Liqiu Wang³, Longlong Wang², Shuting Ji¹, Weijun Dong⁴, Jialan Shi⁵, Chunyan Gao⁶

Affiliations

¹ Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China.
² Department of Anesthesiology, Daqing Oil Field General Hospital, Daqing, China.
³ Department of Clinical Laboratory, The Fifth Hospital, Harbin Medical University, Daqing, China.
⁴ Department of General Surgery, The Fifth Hospital, Harbin Medical University, Daqing, China.
⁵ Departments of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶ Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China. Electronic address: gaochunyan1234@163.com.

PMID: 35567997
DOI: 10.1016/j.bcmd.2022.102666

Abstract

The link between hyperuricemia (HUA) and the risk of venous thromboembolism (VTE) has been well established. However, the mechanisms of thrombus generation and the effect of HUA on procoagulant activity (PCA) of erythrocytes remain unclear no matter in uremia or hyperuricemia. Here, phosphatidylserine (PS) exposure, microparticles (MPs) release, cytosolic Ca²⁺, TMEM16F expression, reactive oxygen species (ROS) and lipid peroxidation of erythrocyte were detected by flow cytometer. PCA was assessed by coagulation time, purified coagulation complex and fibrin production assays. The fibrin formation was observed by scanning electron microscopy (SEM). We found that PS exposure, MPs generation, TMEM16F expression and consequent PCA of erythrocyte in HUA patients significantly increased compared to those in healthy volunteers. Furthermore, high UA induced PS exposure, and MPs release of erythrocyte in concentration and time-dependent manners in vitro, which enhanced the PCA of erythrocyte and was inhibited by lactadherin, a PS inhibitor. Additionally, using SEM, we also observed compact fibrin clots with highly-branched networks and thin fibers supported by red blood cells (RBCs) and RBC-derived MPs (RMPs). Importantly, we demonstrated UA enhanced the production of ROS and lipid peroxidation and reduced the generation of glutathione (GSH) of erythrocyte, which enhanced TMEM16F activity and followed PS externalization and RMPs formation. Collectively, these results suggest that Ca²⁺-dependent TMEM16F activation may be responsible for UA-induced PS exposure and MPs release of RBC, which thereby contribute to the prothrombotic risk in HUA.

Keywords: Erythrocyte; Hyperuricemia; Phosphatidylserine; TMEM16F; Thrombosis.