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Ibrutinib Inhibits Platelet Integrin αIIbβ3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen
Alexander P Bye1, Amanda J Unsworth1, Sakthivel Vaiyapuri1
1From the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Reading, United Kingdom.
Arteriosclerosis, Thrombosis, and Vascular Biology
|September 12, 2015
Summary
Ibrutinib impairs platelet function by affecting collagen and fibrinogen signaling, leading to unstable thrombi and potential bleeding risk. Combining ibrutinib with P2Y12 inhibitors may worsen bleeding complications.
Area of Science:
- Hematology
- Pharmacology
- Oncology
Background:
- Ibrutinib, a Bruton tyrosine kinase inhibitor, treats certain B-cell malignancies but increases bleeding risk.
- Platelet collagen-evoked signaling is impaired in ibrutinib-treated patients, but its in vivo relevance is unclear.
Purpose of the Study:
- To investigate ibrutinib's effects on platelet function during adhesion to immobilized surfaces.
- To clarify the mechanisms underlying ibrutinib-associated bleeding risk.
Main Methods:
- Compared platelet signaling in suspension versus adhesion to immobilized collagen and fibrinogen.
- Assessed thrombus formation under arterial shear in whole blood treated with ibrutinib.
- Evaluated the combined effect of ibrutinib and a P2Y12 inhibitor (cangrelor).
Main Results:
- Ibrutinib's collagen signaling deficiency is less pronounced during adhesion than in suspension.
- Platelets treated with ibrutinib formed unstable thrombi on collagen under shear.
- Ibrutinib inhibited clot retraction and fibrinogen-evoked signaling, affecting integrin αIIbβ3.
- Combined ibrutinib and cangrelor additively inhibited thrombus formation.
Conclusions:
- Ibrutinib causes GPVI and integrin αIIbβ3 signaling deficiencies, contributing to unstable thrombi and bleeding.
- Concurrent use of ibrutinib and P2Y12 antagonists may adversely impact hemostasis.
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