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Viper venoms drive the macrophages and hepatocytes to sequester and clear platelets: novel mechanism and therapeutic strategy for venom-induced thrombocytopenia

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Abstract

Venomous snakebites cause clinical manifestations that range from local to systemic and are considered a significant global health challenge. Persistent or refractory thrombocytopenia has been frequently reported in snakebite patients, especially in cases caused by viperidae snakes. Viper envenomation-induced thrombocytopenia may persist in the absence of significant consumption coagulopathy even after the antivenom treatment, yet the mechanism remains largely unknown. Our study aims to investigate the mechanism and discover novel therapeutic targets for coagulopathy-independent thrombocytopenia caused by viper envenomation. Here we found that patients bitten by Protobothrops mucrosquamatus and Trimeresurus stejnegeri, rather than Naja. atra may develop antivenom-resistant and coagulopathy-independent thrombocytopenia. Crude venoms and the derived C-type lectin-like proteins from these vipers significantly increased platelet surface expression of neuraminidase and platelet desialylation, therefore led to platelet ingestion by both macrophages and hepatocytes in vitro, and drastically decreased peripheral platelet counts in vivo. Our study is the first to demonstrate that desialylation-mediated platelet clearance is a novel mechanism of viper envenomation-induced refractory thrombocytopenia and C-type lectin-like proteins derived from the viper venoms contribute to snake venom-induced thrombocytopenia. The results of this study suggest the inhibition of platelet desialylation as a novel therapeutic strategy against viper venom-induced refractory thrombocytopenia.

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Acknowledgements

This work was supported by grants from the Heart and Stroke Foundation of Ontario, Canada, the Canadian Institutes of Health Research Foundation [389035] and Health Commission of Guangxi Zhuang autonomous region [Z20200287].

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Author notes

  1. Chuanbin Shen and Ming Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Chuanbin Shen, Zi Yan Chen, Danielle Karakas, June Li, Peter A. A. Norris & Heyu Ni

  2. Department of Laboratory Medicine, LKSKI-Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, and Toronto Platelet Immunobiology Group, Toronto, ON, M5B 1W8, Canada

    Chuanbin Shen, Daniel Thomas Mackeigan, Zi Yan Chen, Pingguo Chen, Danielle Karakas, June Li, Peter A. A. Norris & Heyu Ni

  3. Department of Molecular and Cell Biology, School of Life Sciences, University of Science and Technology of China, Hefei, 230027, Anhui, China

    Ming Liu

  4. Department of Physiology, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Daniel Thomas Mackeigan & Heyu Ni

  5. Canadian Blood Services Centre for Innovation, Toronto, ON, M5G 2M1, Canada

    Zi Yan Chen, Pingguo Chen, June Li, Peter A. A. Norris & Heyu Ni

  6. Hospital of Traditional Chinese Medicine of Wuzhou City, Wuzhou, 543002, Guangxi, China

    Jiayao Li & Yanling Deng

  7. Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, 650223, Yunnan, China

    Chengbo Long & Ren Lai

  8. KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China

    Chengbo Long & Ren Lai

  9. Department of Medicine, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Heyu Ni

  10. Department of Laboratory Medicine and Pathobiology, Department of Medicine and Department of Physiology, University of TorontoCanadian Blood Services Centre for Innovation, St. Michael’s Hospital, Room 421, LKSKI - Keenan Research Centre, 209 Victoria Street, Toronto, ON, M5B 1W8, Canada

    Heyu Ni

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  1. Chuanbin Shen
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  2. Ming Liu
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Contributions

C.S. and M.L. performed experiments, created figures, analyzed data. J.L. and Y.D. provided medical records of snakebite patients. D.T.M, Z.C., P.C., D.K., J.L., P.A.A.N., C.L. and R.L. provided valuable suggestions and contributed to paper writing. C.S. wrote the manuscript. H.N. supervised the research and wrote the paper.

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Correspondence to Ren Lai or Heyu Ni.

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Shen, C., Liu, M., Mackeigan, D.T. et al. Viper venoms drive the macrophages and hepatocytes to sequester and clear platelets: novel mechanism and therapeutic strategy for venom-induced thrombocytopenia. Arch Toxicol 95, 3589–3599 (2021). https://doi.org/10.1007/s00204-021-03154-5

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