Table 2.

Btk-inhibitors (BTKi): Comparison of IC50 values for inhibition of Btk-dependent platelet aggregation (PA) by GPVI or FcγRIIa stimulation of blood, therapeutic plasma concentrations and blood concentrations which increase bleeding time in vitro.

BTKi	Dosage	GPVI—Mediated PA *, IC50, µM	FcγRIIa-Mediated PA ** IC50, µM	Plasma Concentration (Cmax)	Increased Bleeding Time In Vitro ***		Ref.
					µM	fold ****
Irreversible BTKi
Ibrutinib	420 mg QD	0.025	0.08	0.31	1	40	13, 41, 75
Acalabrutinib	100 mg BID	0.372	0.38	1.78	5	13	13, 41, 78
Zanubrutinib	160 mg BID	0.094	0.11	1.4	nd		13, 41, 86
Tirabrutinib	480 mg QD	0.268	0.42	2.36	5	18	13, 41, 91
Evobrutinib	75 mg QD 75 mg BID	1.2	1.13	not known	nd		13, 41
Reversible BTKi
Fenebrutinib	150 mg BID	0.013	0.011	0.6	no		13, 111

* Hirudin-anticoagulated blood was pre-incubated with the BTKi for 60 min before stimulation with low collagen concentrations (0.2–0-5 µg/mL) inducing the same degree of submaximal platelet aggregation as maximal concentrations of atherosclerotic plaque homogenate or with plaque homogenate (after fenebrutinib pre-incubation). Platelet aggregation was measured in blood by multiple electrode aggregometry (MEA) [42,43]. ** Hirudin-anticoagulated blood was pre-incubated with the BTKi for 60 min before CD32 cross-linking. ***, closure time was measured with the platelet-function analyzer (PFA; collagen/epinephrine cartridge) [48]. ****, x-fold over the IC50 for inhibition of GPVI-mediated aggregation. nd: not detected, no increase of closure time was observed by testing less than 10-fold higher concentrations of zanubrutinib (1 µM) and evobrutinib (10 µM). Higher concentrations were not tested. no: no increase of closure time was observed by testing up to 78,000-fold higher concentrations of fenebrutinib.