Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis

Introduction: Spleen tyrosine kinase (Syk) mediates signal transduction in multiple hematopoietic cells, including platelets. Syk signals downstream of immunoreceptors and Syk inhibition may ameliorate disease pathology in multiple autoimmune disorders; however, the impact of Syk inhibition in platelets and its potential relevance to bleeding is not fully understood. These studies evaluated the effect of an oral Syk Inhibitor, GS-9876, on platelets in vitro and in vivo, and the impact of GS-9876 plus non-steroidal anti-inflammatory drugs (NSAIDs) on platelet aggregation.

Material and methods: The effect of GS-9876 on platelet activation, aggregation, and binding was characterized by western blotting, aggregometry, fluorescence-activated cell sorting, and microscopy techniques. The effect of GS-9876 on in vivo bleeding time (BT) was determined in cynomolgus monkeys and humans.

Results: GS-9876 inhibited Glycoprotein VI (GPVI)-induced phosphorylation of linker for activation of T cells and Phospholipase Cγ2, platelet activation and aggregation in human whole blood, and platelet binding to collagen under arterial flow. Ex vivo, GPVI-stimulated platelet aggregation was inhibited in GS-9876-treated monkeys without a concomitant increase in BT. Similarly, orally administered GS-9876 did not increase BT in humans. No in vitro additive effects on inhibition of platelet aggregation were observed with GS-9876 plus NSAIDs in human blood.

Conclusions: GS-9876 inhibited Syk activity in platelets via the GPVI receptor without prolonging BT in monkeys or humans. Furthermore, GS-9876 did not increase inhibition of platelet aggregation by NSAIDs in vitro, suggesting that these agents can potentially be combined without increasing bleeding risk in humans.