Ibrutinib Inhibits Platelet Integrin αIIbß3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen.
Arterioscler Thromb Vasc Biol
; 35(11): 2326-35, 2015 Nov.
Article
em En
| MEDLINE
| ID: mdl-26359510
ABSTRACT
OBJECTIVE:
Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH ANDRESULTS:
By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbß3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively.CONCLUSIONS:
These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbß3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Pirimidinas
/
Plaquetas
/
Adesividade Plaquetária
/
Colágeno
/
Complexo Glicoproteico GPIIb-IIIa de Plaquetas
/
Sinalização do Cálcio
/
Inibidores de Proteínas Quinases
/
Hemorragia
/
Hemostasia
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido