Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time
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 pla...
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2021-09-01
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doaj-ac46e632b236415080f63ae9ae03dce72021-09-24T06:34:54ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2021-09-01810.3389/fcvm.2021.749022749022Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding TimeRundan Duan0Luise Goldmann1Richard Brandl2Michael Spannagl3Christian Weber4Christian Weber5Christian Weber6Wolfgang Siess7Wolfgang Siess8Philipp von Hundelshausen9Philipp von Hundelshausen10Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, GermanyInstitute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, GermanyInstitute for Vascular Surgery and Phlebology am Marienplatz, Munich, GermanyDepartment of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilians University, Munich, GermanyInstitute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, GermanyGerman Centre for Cardiovascular Research, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, GermanyDepartment of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, NetherlandsInstitute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, GermanyGerman Centre for Cardiovascular Research, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, GermanyInstitute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, GermanyGerman Centre for Cardiovascular Research, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich Heart Alliance, Munich, GermanyBackground: 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 FcγRIIA-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 μM) than rilzabrutinib (IC50 = 0.16 μM). Concentrations of remibrutinib (0.1 μM) and rilzabrutinib (0.5 μM), >80% inhibitory for plaque-induced aggregation, also significantly suppressed (>90%) the Btk-dependent pathways of platelet aggregation upon GPVI, von Willebrand factor/GPIb and FcγRIIA 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 μM) only slightly prolonged closure time and significantly less than rilzabrutinib (0.5 μM).Conclusion: Remibrutinib and rilzabrutinib inhibit Btk-dependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and FcγRIIA 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.https://www.frontiersin.org/articles/10.3389/fcvm.2021.749022/fullatherothrombosisplatelet-aggregationbleedingPFAMEA |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rundan Duan Luise Goldmann Richard Brandl Michael Spannagl Christian Weber Christian Weber Christian Weber Wolfgang Siess Wolfgang Siess Philipp von Hundelshausen Philipp von Hundelshausen |
spellingShingle |
Rundan Duan Luise Goldmann Richard Brandl Michael Spannagl Christian Weber Christian Weber Christian Weber Wolfgang Siess Wolfgang Siess Philipp von Hundelshausen Philipp von Hundelshausen Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time Frontiers in Cardiovascular Medicine atherothrombosis platelet-aggregation bleeding PFA MEA |
author_facet |
Rundan Duan Luise Goldmann Richard Brandl Michael Spannagl Christian Weber Christian Weber Christian Weber Wolfgang Siess Wolfgang Siess Philipp von Hundelshausen Philipp von Hundelshausen |
author_sort |
Rundan Duan |
title |
Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time |
title_short |
Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time |
title_full |
Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time |
title_fullStr |
Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time |
title_full_unstemmed |
Effects of the Btk-Inhibitors Remibrutinib (LOU064) and Rilzabrutinib (PRN1008) With Varying Btk Selectivity Over Tec on Platelet Aggregation and in vitro Bleeding Time |
title_sort |
effects of the btk-inhibitors remibrutinib (lou064) and rilzabrutinib (prn1008) with varying btk selectivity over tec on platelet aggregation and in vitro bleeding time |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cardiovascular Medicine |
issn |
2297-055X |
publishDate |
2021-09-01 |
description |
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 FcγRIIA-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 μM) than rilzabrutinib (IC50 = 0.16 μM). Concentrations of remibrutinib (0.1 μM) and rilzabrutinib (0.5 μM), >80% inhibitory for plaque-induced aggregation, also significantly suppressed (>90%) the Btk-dependent pathways of platelet aggregation upon GPVI, von Willebrand factor/GPIb and FcγRIIA 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 μM) only slightly prolonged closure time and significantly less than rilzabrutinib (0.5 μM).Conclusion: Remibrutinib and rilzabrutinib inhibit Btk-dependent pathways of platelet aggregation upon GPVI, VWF/GPIb, and FcγRIIA 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. |
topic |
atherothrombosis platelet-aggregation bleeding PFA MEA |
url |
https://www.frontiersin.org/articles/10.3389/fcvm.2021.749022/full |
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