TY - JOUR AU - Phillip L.R. Nicolson, AU - Craig E. Hughes, AU - Stephanie Watson, AU - Sophie H. Nock, AU - Alexander T. Hardy, AU - Callum N. Watson, AU - Samantha J. Montague, AU - Hayley Clifford, AU - Aarnoud P. Huissoon, AU - Jean-Daniel Malcor, AU - Mark R. Thomas, AU - Alice Y. Pollitt, AU - Michael G. Tomlinson, AU - Guy Pratt, AU - Steve P. Watson, PY - 2018/11/30 Y2 - 2024/03/29 TI - Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI JF - Haematologica JA - haematol VL - 103 IS - 12 SE - Articles DO - 10.3324/haematol.2018.193391 UR - https://haematologica.org/article/view/8706 SP - 2097-2108 AB - Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton tyrosine kinase used in the treatment of B-cell malignancies. They bind irreversibly to cysteine 481 of Bruton tyrosine kinase, blocking autophosphorylation on tyrosine 223 and phosphorylation of downstream substrates including phospholipase C-γ2. In the present study, we demonstrate that concentrations of ibrutinib and acalabrutinib that block Bruton tyrosine kinase activity, as shown by loss of phosphorylation at tyrosine 223 and phospholipase C-γ2, delay but do not block aggregation in response to a maximally-effective concentration of collagen-related peptide or collagen. In contrast, 10- to 20-fold higher concentrations of ibrutinib or acalabrutinib block platelet aggregation in response to glycoprotein VI agonists. Ex vivo studies on patients treated with ibrutinib, but not acalabrutinib, showed a reduction of platelet aggregation in response to collagen-related peptide indicating that the clinical dose of ibrutinib but not acalabrutinib is supramaximal for Bruton tyrosine kinase blockade. Unexpectedly, low concentrations of ibrutinib inhibited aggregation in response to collagen-related peptide in patients deficient in Bruton tyrosine kinase. The increased bleeding seen with ibrutinib over acalabrutinib is due to off-target actions of ibrutinib that occur because of unfavorable pharmacodynamics. ER -