TABLE 5.

Effects of ibrutinib and acalabrutinib on megakaryocytes and platelets.

Cells	Inhibitor	Target	Signaling pathway	Effects	References
Megakaryocytes	Ibrutinib		Unclear	Impairs the proliferation of progenitor cells during early stage megakaryopoiesis	Huang et al., 2021
				Decreases the number of colony-forming units of megakaryocytes (CFU-MKs) derived from HSCs	Huang et al., 2021
				Enhances the differentiation and ploidy of megakaryocytes and the formation of proplatelets during late-stage megakaryopoiesis	Huang et al., 2021
				Increases the expression of integrin αIIbβ3 on megakaryocytes	Huang et al., 2021
				Induces thrombocytopenia in the bone marrow of mice	Huang et al., 2021
		SRC/BTK	αIIbβ3-SRC-SYK-BTK-PLCγ2-AKT/ERK1/2	Impairs megakaryocyte adhesion and spreading on immobilized fibrinogen	Huang et al., 2021
				Inhibits the integrin αIIbβ3 outside-in signaling in megakaryocytes	Huang et al., 2021
Platelets	Acalabrutinib IC50 1.85 μM	BTK	αIIbβ3-SYK-PI3K-BTK-PLCγ2	Inhibits platelet spreading on fibrinogen, cytoskeletal assembly and platelet aggregation	Zheng et al., 2021
			GPIb-IX-SYK-LAT-PI3K-BTK-PLCγ2	Inhibits ristocetin- or VWF-induced platelet adhesion and aggregation	Denzinger et al., 2019
			CLEC-2-SYK-LAT-BTK-PLCγ2-NFAT	Blocks CLEC-2-mediated platelet activation and granule secretion	Nicolson et al., 2021
				Platelets from acalabrutinib-treated CLL patients do not aggregate in response to rhodocytin or podoplanin	Nicolson et al., 2021
			FcγRIIA-BTK-PLCγ2	Inhibits FcγRIIA-mediated platelet aggregation, ATP secretion, P-selectin expression and platelet-neutrophil complex formation	Goldmann et al., 2019
		BTK/TEC	GPVI-FcRγ-SYK-LAT-PI3K-BTK/TEC-PLCγ2-PKC	Delays collagen- or CRP-induced platelet aggregation, granule secretion and inside-out activation of αIIbβ3	Bye et al., 2017; Nicolson et al., 2018,Chen et al., 2018; Zheng et al., 2021,Denzinger et al., 2019
				Inhibits plaque-induced platelet aggregation in blood under static condition	Busygina et al., 2018
				Prevents platelet thrombus formation in arterially flowing blood on human atherosclerotic plaque homogenates and plaque tissue sections	Busygina et al., 2018
	Ibrutinib IC50 0.35 μM		Unclear	Induces shedding of GPIb-IX complex and αIIbβ3 from the platelet surface	Dobie et al., 2019
				Increases membrane fluidity and ROS production of platelets	Popov et al., 2020
		BTK	αIIbβ3-SYK-PI3K-BTK-PLCγ2	Inhibits platelet spreading on fibrinogen, cytoskeletal assembly and platelet aggregation	Dobie et al., 2019; Zheng et al., 2021,Denzinger et al., 2019
			GPIb-IX-SYK-LAT-PI3K-BTK-PLCγ2	Inhibits ristocetin- or VWF-induced platelet adhesion and aggregation	Denzinger et al., 2019; Dobie et al., 2019
			CLEC-2-SYK-LAT-BTK-PLCγ2-NFAT	Inhibits rhodocytin-induced platelet activation and granule secretion	Manne et al., 2015; Dobie et al., 2019
					Nicolson et al., 2021
				Reduces the prevalence of CLEC-2-dependent deep vein thrombosis in a mouse model of inferior vena cava stenosis	Nicolson et al., 2021
			FcγRIIA-BTK-PLCγ2	Inhibits FcγRIIA-mediated platelet aggregation, ATP secretion, P-selectin expression and platelet-neutrophil complex formation	Goldmann et al., 2019
				Prevents in vivo platelet aggregation stimulated by CD32 cross-linking in 3 healthy physicians	Goldmann et al., 2019
		BTK/TEC	GPVI-FcRγ-SYK-LAT-PI3K-BTK/TEC-PLCγ2-PKC	Delays collagen- or CRP-induced platelet aggregation, granule secretion and inside-out activation of αIIbβ3	Bye et al., 2017; Nicolson et al., 2018,Chen et al., 2018; Zheng et al., 2021,Denzinger et al., 2019
				Inhibits plaque-induced platelet aggregation in blood under static condition	Busygina et al., 2018
				Prevents platelet thrombus formation in arterially flowing blood on human atherosclerotic plaque homogenates and plaque tissue sections	Busygina et al., 2018
		SRC family	GPVI-FcRγ-SRC family kinases	Inhibits thrombus formation in blood from healthy donors on collagen under arterial shear conditions	Bye et al., 2017; Dobie et al., 2019