Ibrutinib, but not zanubrutinib, induces platelet receptor shedding of GPIb-IX-V complex and integrin αIIbβ3 in mice and humans.

Abstract

The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has proven to be efficacious in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and related diseases. However, a major adverse side effect of ibrutinib is bleeding, including major hemorrhages. The bleeding associated with ibrutinib use is thought to be due to a combination of on-target irreversible Btk inhibition, as well as off-target inhibition of other kinases, including EGFR, ITK, JAK3, and Tec kinase. In this study, we investigated the effects of ibrutinib vs zanubrutinib (a more selective Btk inhibitor) on platelet activation, glycoprotein expression, and thrombus formation. Ibrutinib, but not zanubrutinib, induced a time- and dose-dependent shedding of GPIb-IX complex and integrin αIIbβ3, but not of GPVI and GPV, from the platelet surface. The shedding of GPIbα and GPIX was blocked by GM6001 and TAPI-2, an ADAM17 inhibitor but not ADAM10 inhibitor. Ibrutinib but not zanubrutinib treatment of human platelets increased ADAM17 activation. Pretreatment of C57BL/6 mice with ibrutinib (10 mg/kg), but not zanubrutinib (10 mg/kg), inhibited ex vivo and in vivo thrombus growth over time. Platelets from ibrutinib-treated patients with CLL showed reduced GPIb-IX complex and integrin αIIbβ3 surface expression and reduced ex vivo thrombus formation under arterial flow, which was not observed in zanubrutinib-treated patients. In mice, ibrutinib, but not zanubrutinib, led to increased soluble GPIbα and soluble αIIb levels in plasma. These data demonstrate that ibrutinib induces shedding of GPIbα and GPIX by an ADAM17-dependent mechanism and integrin αIIbβ3 by an unknown sheddase, and this process occurs in vivo to regulate thrombus formation.

• Authors: Gasim Dobie, Fahd A Kuriri, Musab M A Omar, Fehaid Alanazi, Ali M Gazwani, Chloe P S Tang, Daniel Man-Yuen Sze, Sasanka M Handunnetti, Constantine Tam, Denise E Jackson
• Journal: Blood advances (Blood Adv) Vol. 3 Issue 24 Pg. 4298-4311 (12 23 2019) ISSN: 2473-9537 [Electronic] United States
• PMID: 31869418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by The American Society of Hematology.

Chemical References

• Biomarkers
• Collagen Type I
• Piperidines
• Platelet Glycoprotein GPIIb-IIIa Complex
• Platelet Glycoprotein GPIb-IX Complex
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• von Willebrand Factor
• ibrutinib
• zanubrutinib
• Adenine

Topics

• Adenine (analogs & derivatives)
• Animals
• Biomarkers
• Blood Platelets (drug effects, metabolism)
• Collagen Type I (metabolism)
• Exocytosis
• Humans
• Mice
• Piperidines (pharmacology)
• Platelet Activation (drug effects)
• Platelet Glycoprotein GPIIb-IIIa Complex (metabolism)
• Platelet Glycoprotein GPIb-IX Complex (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• von Willebrand Factor (metabolism)