Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 35, Issue 11, Pages 2326-2335Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.115.306130
Keywords
collagen; fibrinogen; hemostasis; ligands; Waldenstrom macroglobulinemia
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Funding
- British Heart Foundation [RG/09/011/28094, PG/13/93/30593]
- British Heart Foundation [PG/13/93/30593, NH/10/2/28425, RG/09/011/28094, PG/11/125/29320, RG/15/2/31224] Funding Source: researchfish
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Objective Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. Approach and Results By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin (IIb3) outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y(12) inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. Conclusions These findings suggest that (1) ibrutinib causes GPVI and integrin (IIb3) platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y(12) antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis.
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