title: Ibrutinib Inhibits Platelet Integrin αIIbβ3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen.
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.
  
  
  RESULTS
  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 αIIbβ3 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 αIIbβ3 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.
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Bye
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Unsworth
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Vaiyapuri
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Stainer
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fry
authors.affiliation: From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom. j.m.gibbins@reading.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gibbins
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000077329:Agammaglobulinaemia Tyrosine Kinase; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced*; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D010880:Piperidines; D010973:Platelet Adhesiveness / Q000187:drug effects*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000097:blood; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011720:Pyrazoles / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D012307:Risk Factors; D013997:Time Factors
chemical_list: D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D047428:Protein Kinase Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000249:Adenosine Monophosphate; C117446:cangrelor; D005340:Fibrinogen; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine
keywords: Waldenstrom macroglobulinemia; collagen; fibrinogen; hemostasis; ligands