SLAP/SLAP2 prevent excessive platelet (hem)ITAM signaling in thrombosis and ischemic stroke in mice

In this study, we show that platelets expressed both SLAP isoforms and that overexpression of either protein in a heterologous cell line almost completely inhibited glycoprotein VI and C-type lectin-like receptor 2 signaling. In mice, single deficiency of SLAP or SLAP2 had only moderate effects on platelet function, whereas double deficiency of both adapters resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity, and thrombin generation in response to (hem)ITAM-coupled, but not G protein-coupled, receptor activation. In vivo, constitutive SLAP/SLAP2 knockout mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. This was attributed to the absence of both adapter proteins in platelets, as demonstrated by adoptive transfer of Slap–/–/Slap2–/– platelets into wild-type mice. Our results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.

Source: Blood - January 1, 2015 Category: Hematology Authors: Cherpokova, D., Bender, M., Morowski, M., Kraft, P., Schuhmann, M. K., Akbar, S. M., Sultan, C. S., Hughes, C. E., Kleinschnitz, C., Stoll, G., Dragone, L. L., Watson, S. P., Tomlinson, M. G., Nieswandt, B. Tags: Free Research Articles, Platelets and Thrombopoiesis, Thrombosis and Hemostasis Source Type: research