Ibrutinib Inhibits Platelet Integrin a αIIbβ3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen
Ibrutinib Inhibits Platelet Integrin a αIIbβ3 Outside-In Signaling and Thrombus Stability But Not Adhesion to Collagen
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DOI：
10.1161/atvbaha.115.306130
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发表时间：
2015-11-01
影响因子：
8.7
通讯作者：
Gibbins, Jonathan M.
中科院分区：
文献类型：
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作者：
Bye, Alexander P.;Unsworth, Amanda J.;Gibbins, Jonathan M.
目的伊曲替尼是一种不可逆的布鲁顿酪氨酸激酶抑制剂，已被批准用于治疗Waldenstrom巨球蛋白血症、慢性淋巴细胞白血病和套细胞淋巴瘤，这些疾病增加了患者的出血风险。伊匹替尼治疗患者的血小板在悬浮液中表现出胶原诱发信号传导的缺陷;然而，由于血小板在体内遇到固定的胶原，因此该观察结果的意义及其与出血风险的关系尚不清楚。我们试图澄清伊布替尼对血小板功能的影响，以更好地了解潜在的出血risk.Approach和结果的机制通过比较信号在悬浮液中，并在粘附固定化配体，我们发现，由伊布替尼引起的胶原蛋白信号传导缺陷是温和的粘附固定化胶原蛋白。我们还发现，用伊布替尼处理的全血中的血小板在动脉剪切下粘附于胶原蛋白，但形成不稳定的血栓，这表明由伊布替尼引起的胶原蛋白信号传导缺陷可能不是体内出血的主要原因。然而，血栓收缩和血小板粘附到固定的纤维蛋白原引起的信号传导也被伊布替尼抑制，这表明除了GPVI信号传导之外，整联蛋白（IIb 3）由外向内的信号传导也受到影响。结论：（1）伊鲁替尼可导致GPVI和整合素（IIb 3）血小板信号传导缺陷，导致不稳定血栓的形成，并可能导致体内观察到的出血;（2）伊鲁替尼与P2 Y（12）拮抗剂联用，其也抑制血栓稳定性，可能对止血有不利影响。
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.