To cite this article: Lhermusier T, van Rottem J, Garcia C, Xuereb JM, Ragab A, Martin V, Gratacap MP, Sié P, Payrastre B. The Syk-kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin-PF4 complex directed antibodies. J Thromb Haemost 2011; 9: 2067-76.Summary. Background: Heparin-induced thrombocytopenia (HIT) is a rare but severe complication of heparin therapy in which immunoglobulin G (IgG) antibodies against the platelet factor 4-heparin complex activate platelets through the FccRIIA receptor. Clustering of FccRIIA initiates signaling cascades involving tyrosine kinases including the spleen tyrosine kinase (Syk). Moreover, besides the critical role of platelets, the expression of tissue factor (TF) by human monocytes triggered by HIT antibodies has been shown to contribute to the hypercoagulability and the thrombotic complications in HIT patients. Objectives: We investigated the effect of R406, a small molecule inhibitor of Syk developed as a potential treatment of autoimmune diseases, allergic disorders and B-cell related hematological malignancies, on FccRIIA-mediated platelet activation. To further assess the potential activity of Syk inhibitors in HIT treatment, the effect of R406 was also evaluated on HIT antibodies-induced expression of TF and procoagulant activity of monocytic cells. Results: We show that R406 is a potent inhibitor of platelet signaling and functions initiated by FccRIIA cross-linking by specific antibodies or by sera from HIT patients. Syk inhibition efficiently prevents FccRIIA-induced LAT phosphorylation and activation of phosphoinositide 3-kinase, Akt, phospholipase Cc2 and p38 MAP-kinase. As a consequence, FccRIIA-induced platelet aggregation, granule secretion and microparticles production are strongly inhibited by R406. Moreover, the Syk inhibitor efficiently impairs the expression of TF and the procoagulant activity of human monocytes triggered by HIT antibodies. Conclusion: Syk inhibitors may be of therapeutic interest in the treatment of HIT by reducing HIT antibodies-mediated platelet activation and monocyte procoagulant activity.