title: Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions.
abstract: The oral Bruton's tyrosine kinase inhibitor, ibrutinib, has recently demonstrated high efficiency in patients with relapsed B-cell malignancies. Occurrence of bleeding events has been reported in a subgroup of ibrutinib-treated patients. We demonstrate that ibrutinib selectively inhibits platelet signaling and functions downstream of the collagen receptor glycoprotein VI and strongly affects firm platelet adhesion on von Willebrand factor (VWF) under arterial flow. A longitudinal study of 14 patients indicated a correlation between occurrence of bleeding events and decreased platelet aggregation in response to collagen in platelet-rich plasma and firm adhesion on VWF under arterial flow. The addition of 50% untreated platelets was sufficient to efficiently reverse the effects of ibrutinib, and platelet functions recovered after treatment interruption as physiological platelet renewal occurred. These data have important clinical implications and provide a basis for hemostasis management during ibrutinib treatment.
authors.affiliation: INSERM, U1048 and Université Toulouse 3, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Laboratoire d'Hématologie Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Levade
authors.affiliation: Laboratoire d'Hématologie Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
authors.forename: Elodie
authors.initials: E
authors.lastname: David
authors.affiliation: Laboratoire d'Hématologie Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
authors.forename: Cédric
authors.initials: C
authors.lastname: Garcia
authors.affiliation: INSERM, U1048 and Université Toulouse 3, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Laurent
authors.affiliation: Laboratoire d'Hématologie Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
authors.forename: Sarah
authors.initials: S
authors.lastname: Cadot
authors.affiliation: Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France;
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Michallet
authors.affiliation: Laboratoire d'Hémostase, Centre Hospitalier Universitaire Hôpital Edouard Herriot, Lyon, France;
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Bordet
authors.affiliation: Department of Hematology, Peter MacCallum Cancer Center, East Melbourne, VIC, Australia; and.
authors.forename: Constantine
authors.initials: C
authors.lastname: Tam
authors.affiliation: INSERM, U1048 and Université Toulouse 3, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Laboratoire d'Hématologie Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Sié
authors.affiliation: Service d'Hématologie Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Ysebaert
authors.affiliation: INSERM, U1048 and Université Toulouse 3, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Laboratoire d'Hématologie Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects; D003094:Collagen / Q000737:chemistry*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D006487:Hemostasis; D006493:Heparin / Q000737:chemistry; D006801:Humans; D008137:Longitudinal Studies; D051966:Phospholipase C gamma / Q000737:chemistry; D010766:Phosphorylation; D010880:Piperidines; D015539:Platelet Activation; D010973:Platelet Adhesiveness; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D033081:Shear Strength; D014841:von Willebrand Factor / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D014841:von Willebrand Factor; C551803:ibrutinib; D006493:Heparin; D003094:Collagen; D051966:Phospholipase C gamma; D000225:Adenine; D004121:Dimethyl Sulfoxide