Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis.
Thromb Res
; 170: 109-118, 2018 10.
Article
en En
| MEDLINE
| ID: mdl-30172129
ABSTRACT
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 ANDMETHODS:
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Plaquetas
/
Inhibidores de Proteínas Quinasas
/
Quinasa Syk
/
Hemostasis
Límite:
Adolescent
/
Adult
/
Humans
/
Middle aged
Idioma:
En
Revista:
Thromb Res
Año:
2018
Tipo del documento:
Article