The Syk‐kinase inhibitor R406 impairs platelet activation and monocyte tissue factor expression triggered by heparin‐PF4 complex directed antibodies

摘要: 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 FcγRIIA receptor. Clustering initiates signaling cascades involving tyrosine kinases including spleen kinase (Syk). Moreover, besides critical role platelets, expression tissue (TF) by human monocytes triggered HIT has been shown to contribute hypercoagulability and thrombotic complications patients. Objectives We investigated effect R406, small molecule inhibitor Syk developed as potential treatment autoimmune diseases, allergic disorders B-cell related hematological malignancies, on FcγRIIA-mediated activation. To further assess activity inhibitors treatment, R406 was also evaluated antibodies-induced TF procoagulant monocytic cells. Results show that potent functions initiated cross-linking specific or sera from inhibition efficiently prevents FcγRIIA-induced LAT phosphorylation activation phosphoinositide 3-kinase, Akt, phospholipase Cγ2 p38 MAP-kinase. As consequence, aggregation, granule secretion microparticles production are strongly inhibited R406. impairs antibodies. Conclusion may be therapeutic interest reducing antibodies-mediated monocyte activity.