Bourne, Joshua H.Smith, Christopher W.Jooss, Natalie J.Di, YingBrown, Helena C.Montague, Samantha J.Thomas, MarkPoulter, Natalie S.Rayes, JulieWatson, Steve P.2023-11-302023-11-302022-10-18Bourne 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-1896-6992.0340-62452567-689X10.1055/a-1896-6992http://hdl.handle.net/20.500.14200/3063C-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.enHaematologyArticle