TY - JOUR
T1 - Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment
AU - Tullemans, B.M.E.
AU - Veninga, A.
AU - Fernandez, D.I.
AU - Aarts, M.J.B.
AU - Eble, J.A.
AU - van der Meijden, P.E.J.
AU - Heemskerk, J.W.M.
AU - Kuijpers, M.J.E.
N1 - Funding Information:
Funding: J.A.E. was financially supported by the Interdisciplinary Centre for Clinical Research (IZKF) of Münster University (grant: Ebl/009/21). D.I.F. was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Slodowska–Curie grant agreement number 766118 and is enrolled in a joint PhD program at the Universities of Maastricht (the Netherlands) and Santiago de Compostela (Spain). A.V. was supported by the Dutch Landsteiner Foundation for Blood Transfusion Research (grant: 1711).
Funding Information:
J.A.E. was financially supported by the Interdisciplinary Centre for Clinical Research (IZKF) of M?nster University (grant: Ebl/009/21). D.I.F. was supported by the European Union?s Horizon 2020 research and innovation program under the Marie Slodowska?Curie grant agreement number 766118 and is enrolled in a joint PhD program at the Universities of Maastricht (the Netherlands) and Santiago de Compostela (Spain). A.V. was supported by the Dutch Landsteiner Foundation for Blood Transfusion Research (grant: 1711).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10-50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (> 90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.
AB - Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10-50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (> 90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.
KW - platelet activation
KW - aggregation
KW - bleeding
KW - thrombus formation
KW - tyrosine kinase inhibitors
KW - antiplatelet treatment
KW - IN-VIVO DEPLETION
KW - GLYCOPROTEIN-VI
KW - THROMBUS FORMATION
KW - RECEPTOR CLEC-2
KW - ACTIVATION
KW - GPVI
KW - EXPRESSION
KW - DEFICIENT
KW - INTEGRIN
KW - BLOOD
U2 - 10.3390/ijms222011199
DO - 10.3390/ijms222011199
M3 - Article
C2 - 34681859
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 20
M1 - 11199
ER -