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

• Published in: EJHaem Vol. 2; no. 4; pp. 685 - 699
• Main Authors: Tullemans, Bibian M.E., Karel, Mieke F.A., Léopold, Valentine, ten Brink, Marieke S., Baaten, Constance C.F.M.J., Maas, Sanne L., Vos, Alex F., Eble, Johannes A., Nijziel, Marten R., Vorst, Emiel P.C., Cosemans, Judith M.E.M., Heemskerk, Johan W.M., Claushuis, Theodora A.M., Kuijpers, Marijke J.E.
• Format: Journal Article
• Language: English
• Published: Hoboken John Wiley & Sons, Inc 01.11.2021; John Wiley and Sons Inc; Wiley
• Subjects: Bleeding; Blood clots; Blood platelets; Bruton tyrosine kinase; Bruton's tyrosine kinase; CLEC‐2; Collagen; glycoprotein VI; Histograms; Patients; Phosphorylation; Plasma; Platelet aggregation; platelets; Protein-tyrosine kinase; Sickle Cell, Thrombosis, and Benign Haematology; Thrombosis; von Willebrand Factor
• ISSN: 2688-6146; 2688-6146
• DOI: 10.1002/jha2.269

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.