期刊
FRONTIERS IN CARDIOVASCULAR MEDICINE
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcvm.2021.749022
关键词
atherothrombosis; platelet-aggregation; bleeding; PFA; MEA
资金
- Deutsche Forschungsgemeinschaft [SFB1123]
- Ludwig-Maximilians-University (LMU)-China Scholarship Council (CSC) program
In this study, two novel BTK inhibitors, remibrutinib and rilzabrutinib, were compared for their effects on platelet aggregation. Both inhibitors were found to inhibit Btk-dependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and Fc gamma RIIA activation, with remibrutinib showing higher potency and less impact on hemostatic impairment compared to rilzabrutinib. This suggests that remibrutinib may be a promising candidate for further development as an antiplatelet drug.
Background: Bruton tyrosine kinase inhibitors (BTKi) are used in B-cell malignancies and in development against various autoimmune diseases. Since Btk is also involved in specific pathways of platelet activation, BTKi might be considered to target platelet GPVI/GPIb-mediated atherothrombosis and platelet Fc gamma RIIA-dependent immune disorders. However, BTKi treatment of patients with B-cell malignancies is frequently associated with mild bleeding events caused possibly by off-target inhibition of Tec. Here, we compared the platelet effects of two novel BTKi that exhibit a high (remibrutinib) or low (rilzabrutinib) selectivity for Btk over Tec. Methods and Results: Remibrutinib and rilzabrutinib were pre-incubated with anticoagulated blood. Platelet aggregation and in vitro bleeding time (closure time) were studied by multiple electrode aggregometry (MEA) and platelet-function analyzer-200 (PFA-200), respectively. Both BTKi inhibited atherosclerotic plaque-stimulated GPVI-mediated platelet aggregation, remibrutinib being more potent (IC50 = 0.03 mu M) than rilzabrutinib (IC50 = 0.16 mu M). Concentrations of remibrutinib (0.1 mu M) and rilzabrutinib (0.5 mu M), >80% inhibitory for plaque-induced aggregation, also significantly suppressed (>90%) the Btk-dependent pathways of platelet aggregation upon GPVI, von Willebrand factor/GPIb and Fc gamma RIIA activation stimulated by low collagen concentrations, ristocetin and antibody cross-linking, respectively. Both BTKi did not inhibit aggregation stimulated by ADP, TRAP-6 or arachidonic acid. Remibrutinib (0.1 mu M) only slightly prolonged closure time and significantly less than rilzabrutinib (0.5 mu M). Conclusion: Remibrutinib and rilzabrutinib inhibit Btk-dependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and Fc gamma RIIA activation. Remibrutinib being more potent and showing a better profile of inhibition of Btk-dependent platelet activation vs. hemostatic impairment than rilzabrutinib may be considered for further development as an antiplatelet drug.
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