CLEC-2 supports platelet aggregation in mouse but not human blood at arterial shear

Joshua Bourne, Christopher Smith, Natalie Jooss, Ying Di, Helena Brown, Samantha Montague, Mark Thomas, Natalie Poulter, Julie Rayes, Steve P. Watson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
24 Downloads (Pure)

Abstract

C-type lectin-like receptor 2 (CLEC-2) is highly expressed on platelets and a subpopulation of myeloid cells, and is critical in lymphatic development. CLEC-2 has been shown to support thrombus formation at sites of inflammation, but to have a minor/negligible role in hemostasis. This identifies CLEC-2 as a promising therapeutic target in thromboinflammatory disorders, without hemostatic detriment. We utilized a GPIb-Cre recombinase mouse for more restricted deletion of platelet-CLEC-2 than the previously used PF4-Cre mouse. CLEC1bfl/flGPIb-Cre+ mice are born at Mendelian ratio, with a mild reduction in platelet count, and present with reduced thrombus size post-FeCl3-induced thrombosis, compared to littermates. Antibody-mediated depletion of platelet count in C57BL/6 mice, to match CLEC1bfl/flGPIb-Cre+ mice, revealed that the reduced thrombus size post-FeCl3-injury was due to the loss of CLEC-2, and not mild thrombocytopenia. Similarly, CLEC1bfl/flGPIb-Cre+ mouse blood replenished with CLEC-2-deficient platelets ex vivo to match littermates had reduced aggregate formation when perfused over collagen at arterial flow rates. In contrast, platelet-rich thrombi formed following perfusion of human blood under flow conditions over collagen types I or III, atherosclerotic plaque or inflammatory endothelial cells were unaltered in the presence of CLEC-2-blocking antibody, AYP1, or recombinant CLEC-2-Fc. The reduction in platelet aggregation observed in CLEC1bfl/flGPIb-Cre+ mice during arterial thrombosis is mediated by the loss of CLEC-2 on mouse platelets. In contrast, CLEC-2 does not support thrombus generation on collagen, atherosclerotic plaque or inflamed endothelial cells in human at arterial shear.

Original languageEnglish
Pages (from-to)1988-2000
Number of pages13
JournalThrombosis and Haemostasis
Volume122
Issue number12
Early online date11 Jul 2022
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 Georg Thieme Verlag.

Keywords

  • CLEC-2
  • thrombosis
  • platelets
  • AYP1
  • thromboinflammation

ASJC Scopus subject areas

  • Hematology

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