Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI

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Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI. / Nicolson, Phillip; Hughes, Craig E; Watson, Stephanie; Nock, Sophie H; Hardy, Alexander; Watson, Callum N; Montague, Samantha J; Malcor, Jean-Daniel; Thomas, Mark R.; Pollitt, Alice Y; Tomlinson, Michael; Pratt, Guy; Watson, Steve.

In: Haematologica, Vol. 103, No. 12, 12.2018, p. 2097-2108.

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Nicolson, Phillip ; Hughes, Craig E ; Watson, Stephanie ; Nock, Sophie H ; Hardy, Alexander ; Watson, Callum N ; Montague, Samantha J ; Malcor, Jean-Daniel ; Thomas, Mark R. ; Pollitt, Alice Y ; Tomlinson, Michael ; Pratt, Guy ; Watson, Steve. / Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI. In: Haematologica. 2018 ; Vol. 103, No. 12. pp. 2097-2108.

Bibtex

@article{dbf88eee07464a1881e888a03b783f76,
title = "Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI",
abstract = "Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton{\textquoteright}s tyrosine kinase used in the treatment of B cell malignancies. They bind irreversibly to cysteine 481 of Bruton{\textquoteright}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{\textquoteright}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{\textquoteright}s tyrosine kinase blockade. Unexpectedly, low concentrations of ibrutinib inhibit aggregation to collagen related peptide in patients deficient in Bruton{\textquoteright}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.",
keywords = "chronic lymphocytic leukemia, platelets, disorders of platelet function",
author = "Phillip Nicolson and Hughes, {Craig E} and Stephanie Watson and Nock, {Sophie H} and Alexander Hardy and Watson, {Callum N} and Montague, {Samantha J} and Jean-Daniel Malcor and Thomas, {Mark R.} and Pollitt, {Alice Y} and Michael Tomlinson and Guy Pratt and Steve Watson",
year = "2018",
month = dec,
doi = "10.3324/haematol.2018.193391",
language = "English",
volume = "103",
pages = "2097--2108",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "12",

}

RIS

TY - JOUR

T1 - Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI

AU - Nicolson, Phillip

AU - Hughes, Craig E

AU - Watson, Stephanie

AU - Nock, Sophie H

AU - Hardy, Alexander

AU - Watson, Callum N

AU - Montague, Samantha J

AU - Malcor, Jean-Daniel

AU - Thomas, Mark R.

AU - Pollitt, Alice Y

AU - Tomlinson, Michael

AU - Pratt, Guy

AU - Watson, Steve

PY - 2018/12

Y1 - 2018/12

N2 - 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.

AB - 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.

KW - chronic lymphocytic leukemia

KW - platelets

KW - disorders of platelet function

U2 - 10.3324/haematol.2018.193391

DO - 10.3324/haematol.2018.193391

M3 - Article

C2 - 30026342

VL - 103

SP - 2097

EP - 2108

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 12

ER -