CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear
Bourne, Joshua H. Smith, Christopher W. Jooss, Natalie J. Di, Ying Brown, Helena C. Montague, Samantha J. Poulter, Natalie S. Rayes, Julie Watson, Steve P.
Bourne, Joshua H.
Smith, Christopher W.
Jooss, Natalie J.
Di, Ying
Brown, Helena C.
Montague, Samantha J.
Poulter, Natalie S.
Rayes, Julie
Watson, Steve P.
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 GPIbα-Cre recombinase mouse for more restricted deletion of platelet-CLEC-2 than the previously used PF4-Cre mouse. clec1bfl/flGPIbα-Cre+ mice are born at a 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/flGPIbα-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/flGPIbα-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/flGPIbα-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.
MIDER Authors
Affiliations
University of Birmingham; Maastricht University; University Hospital and Rudolf Virchow Center for Integrative and Translational Bioimaging; Sandwell and West Birmingham NHS Trust; et al.
Citations
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Date
2022-10-18
Type
Article
Subject
Collections
Citation
Bourne JH, Smith CW, Jooss NJ, Di Y, Brown HC, Montague SJ, Thomas MR, Poulter NS, Rayes J, Watson SP. CLEC-2 Supports Platelet Aggregation in Mouse but not Human Blood at Arterial Shear. Thromb Haemost. 2022 Dec;122(12):1988-2000. doi: 10.1055/a-1896-6992.