Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI
Research output: Contribution to journal › Article
- ACRF Department of Cancer Biology and Therapeutics, John Curt School of Medical Research, Australian National University, Canberra
- University of Cambridge
Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton’s tyrosine kinase used in the treatment of B cell malignancies. They bind irreversibly to cysteine 481 of Bruton’s tyrosine kinase, blocking autophosphorylation on tyrosine 223 and phosphorylation of downstream substrates including phospholipase-ɣ2. In the present study, we demonstrate that concentrations of ibrutinib and acalabrutinib that block Bruton’s tyrosine kinase activity as shown by loss of phosphorylation at tyrosine 223 and phospholipase-ɣ2 delay but do not block aggregation to a maximally-effective concentration of collagen related peptide or collagen. In contrast, 10-20 fold higher concentrations of ibrutinib or acalabrutinib block platelet aggregation to Glycoprotein VI agonists. Ex vivo studies on patients treated with ibrutinib, but not acalabrutinib, show a reduction of platelet aggregation to collagen related peptide indicating that the clinical dose of ibrutinib but not acalabrutinib is supramaximal for Bruton’s tyrosine kinase blockade. Unexpectedly, low concentrations of ibrutinib inhibit aggregation to collagen related peptide in patients deficient in Bruton’s tyrosine kinase. The increased bleeding seen with ibrutinib over acalabrutinib is due to off-target actions of ibrutinib that occur because of unfavourable pharmacodynamics.
|Early online date||19 Jul 2018|
|Publication status||Published - Dec 2018|
- chronic lymphocytic leukemia, platelets, disorders of platelet function