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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 language | English |
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Pages (from-to) | 1988-2000 |
Number of pages | 13 |
Journal | Thrombosis and Haemostasis |
Volume | 122 |
Issue number | 12 |
Early online date | 11 Jul 2022 |
DOIs | |
Publication status | Published - 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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H2020_ITN_TAPAS_Coordinator
Poulter, N., Tomlinson, M. & Watson, S.
European Commission, European Commission - Management Costs
1/01/18 → 30/06/22
Project: Research