Abstract
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.</p>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).</p>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.</p>
Original language | English |
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Article number | 749022 |
Number of pages | 12 |
Journal | Frontiers in Cardiovascular Medicine |
Volume | 8 |
DOIs | |
Publication status | Published - 24 Sept 2021 |
Keywords
- atherothrombosis
- platelet-aggregation
- bleeding
- PFA
- MEA
- BRUTONS TYROSINE KINASE
- X-LINKED AGAMMAGLOBULINEMIA
- THROMBUS FORMATION
- CLOSURE TIME
- ACTIVATION
- ASPIRIN
- PFA-100(TM)
- IBRUTINIB
- ABSENCE
- TRIAL