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Thromb Haemost 2019; 119(03): 397-406
DOI: 10.1055/s-0039-1677744
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Optimizing Platelet GPVI Inhibition versus Haemostatic Impairment by the Btk Inhibitors Ibrutinib, Acalabrutinib, ONO/GS-4059, BGB-3111 and Evobrutinib

Viola Denzinger
1   Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians-University) Munich, Munich, Germany
,
Kristina Busygina
1   Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians-University) Munich, Munich, Germany
,
Janina Jamasbi
1   Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians-University) Munich, Munich, Germany
,
Isabell Pekrul
2   Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University of Munich, Munich, Germany
,
Michael Spannagl
2   Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University of Munich, Munich, Germany
,
Christian Weber
1   Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians-University) Munich, Munich, Germany
3   DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
4   Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
,
Reinhard Lorenz
1   Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians-University) Munich, Munich, Germany
,
Wolfgang Siess
1   Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians-University) Munich, Munich, Germany
3   DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
› Author Affiliations Funding The study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB1123/Z01 and B08) and the August-Lenz foundation.
Further Information

Publication History

24 September 2018

09 December 2018

Publication Date:
27 January 2019 (online)

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Abstract

Ibrutinib and acalabrutinib are approved for B cell malignancies and novel Bruton's tyrosine kinase (Btk) inhibitors undergo clinical testing also in B cell-driven autoimmune disorders. Btk in platelets mediates platelet activation via glycoprotein (GP) VI, which is crucial for atherosclerotic plaque-induced platelet thrombus formation. This can be selectively inhibited by Btk inhibitors. Since patients on second-generation Btk inhibitors apparently show less bleeding than patients on ibrutinib, we compared the effects of ibrutinib and four novel irreversible Btk inhibitors on GPVI-dependent platelet aggregation in blood and in vitro bleeding time. Low concentrations of collagen which induced the same low degree of GPVI-mediated platelet aggregation as atherosclerotic plaque material were applied. IC50 values for collagen (0.2–0.5 µg/mL)-induced platelet aggregation after 15-minute pre-incubation were: ibrutinib 0.12 µM, BGB-3111 0.51 µM, acalabrutinib 1.21 µM, ONO/GS-4059 1.20 µM and evobrutinib 5.84 µM. Peak venous plasma concentrations of ibrutinib (0.5 µM), acalabrutinib (2 µM) and ONO/GS-4059 (2 µM) measured after anti-proliferative dosage inhibited collagen-induced platelet aggregation, but did not increase PFA-200 closure time on collagen/epinephrine. Closure times were moderately increased by 2- to 2.5-fold higher concentrations of these inhibitors, but not by BGB-3111 (1 µM) and evobrutinib (10 µM). Prolonging platelet drug exposure to 60 minutes lowered IC50 values of any Btk inhibitor for GPVI-mediated aggregation by several fold, and 5- to 10-fold below anti-proliferative therapeutic drug plasma levels. In conclusion, low blood concentrations of ibrutinib and the novel Btk inhibitors suffice for GPVI selective platelet inhibition relevant for atherothrombosis but do not impair primary haemostasis.

Keywords

Btk inhibitor - platelet aggregation - bleeding - PFA - GPVI
 

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