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

Abstract

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.

TULA-2 (T-Cell Ubiquitin Ligand-2) Inhibits the Platelet Fc Receptor for IgG IIA (FcγRIIA) Signaling Pathway and Heparin-Induced Thrombocytopenia in Mice

“…Recent studies have discovered the importance of monocyte activation in HIT pathogenesis, in which HIT antibodies stimulate monocyte FcγRIIA-mediated tissue factor production and further facilitates coagulation cascade activation and thrombosis. 48,49 Further experiments are necessary to determine whether TULA-2 regulates monocyte activation via FcγRIIA.…”

New Fundamentals in Hemostasis

“…The low-affinity IgG receptor Fc␥RIIa, which contains one ITAM, also evokes Syk-dependent signaling pathways in human platelets that are enforced by autocrine stimulation (159). Signaling via Fc␥RIIa is induced by clustering of two or more receptor chains, e.g., by autoimmune antibodies against the complex of platelet factor 4 and heparin, leading to heparin-induced thrombocytopenia.…”

How I treat heparin-induced thrombocytopenia

“…64 Examples include a desulfated form of heparin with minimal anticoagulant activity 92 ; PF4 antagonists, which interfere with formation of PF4/heparin complexes 93 ; inhibitors of Fc␥RIIA-mediated platelet activation by HIT immune complexes; and inhibitors of splenic tyrosine kinase (Syk) and Ca 2ϩ and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), which disrupt intracellular transduction triggered by immune complex binding. [94][95][96] Finally, there is growing appreciation of the financial burden of HIT, a major driver of which is cost of approved agents and the increased length of hospital stay their use entails. 97 Future studies of therapeutics should include economic analyses that consider not only direct drug costs, but also costs associated with monitoring, length of stay, and toxicity.…”