Comparison of inhibitory effects of irreversible and reversible Btk inhibitors on platelet function

eJHaem

article

Bibian M.E. Tullemans¹  Mieke F.A. Karel¹  Valentine Léopold²  Marieke S. ten Brink²  Constance C.F.M.J. Baaten¹  Sanne L. Maas⁴  Alex F. de Vos²  Johannes A. Eble⁶  Marten R. Nijziel⁷  Emiel P.C. van der Vorst⁴  Judith M.E.M. Cosemans¹  Johan W.M. Heemskerk¹  Theodora A.M. Claushuis⁷  Marijke J.E. Kuijpers¹ 

[1] Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University;Center for Experimental and Molecular Medicine, Amsterdam University Medical Centres, Academic Medical Centre, University of Amsterdam;Hopital Lariboisiere, Department of Anaesthesiology and Critical Care;Institute for Molecular Cardiovascular Research ,(IMCAR), University Hospital Aachen;Interdisciplinary Center for Clinical Research ,(IZKF), RWTH Aachen University;Institute of Physiological Chemistry and Pathobiochemistry, University of Münster;Department of Haematology, Catharina Hospital Eindhoven;Department of Pathology, Cardiovascular Research Institute Maastricht ,(CARIM), Maastricht University Medical Centre;Institute for Cardiovascular Prevention ,(IPEK), Ludwig-Maximilians-University Munich;Both the authors contributed equally to this work.;Thrombosis Expertise Centre, Heart and Vascular Centre, Maastricht University Medical Centre

关键词: bleeding;    Bruton tyrosine kinase;    CLEC-2;    glycoprotein VI;    platelets;    von Willebrand Factor;   

DOI  :  10.1002/jha2.269

来源: Wiley

【 摘 要 】

All irreversible Bruton tyrosine kinase (Btk) inhibitors including ibrutinib and acalabrutinib induce platelet dysfunction and increased bleeding risk. New reversible Btk inhibitors were developed, like MK-1026. The mechanism underlying increased bleeding tendency with Btk inhibitors remains unclear. We investigated the effects of ibrutinib, acalabrutinib and MK-1026 on platelet function in healthy volunteers, patients and Btk-deficient mice, together with off-target effects on tyrosine kinase phosphorylation. All inhibitors suppressed GPVI- and CLEC-2-mediated platelet aggregation, activation and secretion in a dose-dependent manner. Only ibrutinib inhibited thrombus formation on vWF-co-coated surfaces, while on collagen this was not affected. In blood from Btk-deficient mice, collagen-induced thrombus formation under flow was reduced, but preincubation with either inhibitor was without additional effects. MK-1026 showed less off-target effects upon GPVI-induced TK phosphorylation as compared to ibrutinib and acalabrutinib. In ibrutinib-treated patients, GPVI-stimulated platelet activation, and adhesion on vWF-co-coated surfaces were inhibited, while CLEC-2 stimulation induced variable responses. The dual inhibition of GPVI and CLEC-2 signalling by Btk inhibitors might account for the increased bleeding tendency, with ibrutinib causing more high-grade bleedings due to additional inhibition of platelet-vWF interaction. As MK-1026 showed less off-target effects and only affected activation of isolated platelets, it might be promising for future treatment.

【 授权许可】

Unknown