title: Ibrutinib inhibits collagen-mediated but not ADP-mediated platelet aggregation.
abstract: The BTK (Bruton's tyrosine kinase) inhibitor ibrutinib is associated with an increased risk of bleeding. A previous study reported defects in collagen- and adenosine diphosphate (ADP)-dependent platelet responses when ibrutinib was added ex vivo to patient samples. Whereas the collagen defect is expected given the central role of BTK in glycoprotein VI signaling, the ADP defect lacks a mechanistic explanation. In order to determine the real-life consequences of BTK platelet blockade, we performed light transmission aggregometry in 23 patients receiving ibrutinib treatment. All patients had reductions in collagen-mediated platelet aggregation, with a significant association between the degree of inhibition and the occurrence of clinical bleeding or bruising (P=0.044). This collagen defect was reversible on drug cessation. In contrast to the previous ex vivo report, we found no in vivo ADP defects in subjects receiving standard doses of ibrutinib. These results establish platelet light transmission aggregometry as a method for gauging, at least qualitatively, the severity of platelet impairment in patients receiving ibrutinib treatment.
authors.affiliation: Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Kamel
authors.affiliation: Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Horton
authors.affiliation: Département d'Hématologie, IUCT-Oncopole, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Ysebaert
authors.affiliation: 1] Inserm, U1048 and Université Toulouse 3, Toulouse, France [2] Laboratoire d'Hématologie CHU de Toulouse, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Levade
authors.affiliation: Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Burbury
authors.affiliation: Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Cole-Sinclair
authors.affiliation: Faculty of Health, Deakin University, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Filshie
authors.affiliation: Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Schischka
authors.affiliation: Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Khot
authors.affiliation: Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Sandhu
authors.affiliation: Leukemia Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: 1] Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia [2] University of Melbourne, Parkville, Victoria, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Nandurkar
authors.affiliation: 1] Department of Hematology, St Vincent's Hospital, Melbourne, Victoria, Australia [2] Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia [3] University of Melbourne, Parkville, Victoria, Australia.
authors.forename: C S
authors.initials: CS
authors.lastname: Tam
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D010974:Platelet Aggregation / Q000187:drug effects*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects*; D012720:Severity of Illness Index
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000244:Adenosine Diphosphate; D003094:Collagen; D000225:Adenine