Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab

Maudy Walraven, Marjolein Y. V. Homs, Astrid A. M. van der Veldt, Henk Dekker, Jose Koldenhof, Richard Honeywell, Arjan Barendrecht, Silvie A. E. Sebastian, Naomi Parr, Arnold C. Koekman, Emile E. Voest, Mark Roest, Suzanne J. A. Korporaal, Henk M. W. Verheul

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Introduction: At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. Materials and methods: In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA. Results: In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3%, p < 0.001; 25 μM sorafenib: 55.8%, p = 0.042). Sorafenib and sunitinib significantly inhibited P-selectin expression on platelets. Exposure to both TKIs resulted in a reduced tyrosine phosphorylation of c-Src. Ex vivo, within 24 h sunitinib impaired platelet aggregation (83.0%, p = 0.001, N = 8). Plasma concentrations of sunitinib, VEGF, and platelet/EC activation markers were not correlated with disturbed aggregation. In contrast, bevacizumab only significantly impaired platelet aggregation in vitro at high concentrations, but not ex vivo. Conclusion: Sunitinib significantly inhibits platelet aggregation in patients already after 24 h of first administration, whereas bevacizumab had no effect on aggregation. These findings may explain the clinically observed bleedings during treatment with antiangiogenic TKIs.
Original languageEnglish
Pages (from-to)325-334
JournalAngiogenesis
Volume21
Issue number2
DOIs
Publication statusPublished - 2018

Cite this

Walraven, Maudy ; Homs, Marjolein Y. V. ; van der Veldt, Astrid A. M. ; Dekker, Henk ; Koldenhof, Jose ; Honeywell, Richard ; Barendrecht, Arjan ; Sebastian, Silvie A. E. ; Parr, Naomi ; Koekman, Arnold C. ; Voest, Emile E. ; Roest, Mark ; Korporaal, Suzanne J. A. ; Verheul, Henk M. W. / Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab. In: Angiogenesis. 2018 ; Vol. 21, No. 2. pp. 325-334.
@article{5833225c688a458fa23bb84f9e4fa9d7,
title = "Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab",
abstract = "Introduction: At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. Materials and methods: In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA. Results: In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3{\%}, p < 0.001; 25 μM sorafenib: 55.8{\%}, p = 0.042). Sorafenib and sunitinib significantly inhibited P-selectin expression on platelets. Exposure to both TKIs resulted in a reduced tyrosine phosphorylation of c-Src. Ex vivo, within 24 h sunitinib impaired platelet aggregation (83.0{\%}, p = 0.001, N = 8). Plasma concentrations of sunitinib, VEGF, and platelet/EC activation markers were not correlated with disturbed aggregation. In contrast, bevacizumab only significantly impaired platelet aggregation in vitro at high concentrations, but not ex vivo. Conclusion: Sunitinib significantly inhibits platelet aggregation in patients already after 24 h of first administration, whereas bevacizumab had no effect on aggregation. These findings may explain the clinically observed bleedings during treatment with antiangiogenic TKIs.",
author = "Maudy Walraven and Homs, {Marjolein Y. V.} and {van der Veldt}, {Astrid A. M.} and Henk Dekker and Jose Koldenhof and Richard Honeywell and Arjan Barendrecht and Sebastian, {Silvie A. E.} and Naomi Parr and Koekman, {Arnold C.} and Voest, {Emile E.} and Mark Roest and Korporaal, {Suzanne J. A.} and Verheul, {Henk M. W.}",
year = "2018",
doi = "10.1007/s10456-018-9598-5",
language = "English",
volume = "21",
pages = "325--334",
journal = "Angiogenesis",
issn = "0969-6970",
publisher = "Springer Netherlands",
number = "2",

}

Walraven, M, Homs, MYV, van der Veldt, AAM, Dekker, H, Koldenhof, J, Honeywell, R, Barendrecht, A, Sebastian, SAE, Parr, N, Koekman, AC, Voest, EE, Roest, M, Korporaal, SJA & Verheul, HMW 2018, 'Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab' Angiogenesis, vol. 21, no. 2, pp. 325-334. https://doi.org/10.1007/s10456-018-9598-5

Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab. / Walraven, Maudy; Homs, Marjolein Y. V.; van der Veldt, Astrid A. M.; Dekker, Henk; Koldenhof, Jose; Honeywell, Richard; Barendrecht, Arjan; Sebastian, Silvie A. E.; Parr, Naomi; Koekman, Arnold C.; Voest, Emile E.; Roest, Mark; Korporaal, Suzanne J. A.; Verheul, Henk M. W.

In: Angiogenesis, Vol. 21, No. 2, 2018, p. 325-334.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab

AU - Walraven, Maudy

AU - Homs, Marjolein Y. V.

AU - van der Veldt, Astrid A. M.

AU - Dekker, Henk

AU - Koldenhof, Jose

AU - Honeywell, Richard

AU - Barendrecht, Arjan

AU - Sebastian, Silvie A. E.

AU - Parr, Naomi

AU - Koekman, Arnold C.

AU - Voest, Emile E.

AU - Roest, Mark

AU - Korporaal, Suzanne J. A.

AU - Verheul, Henk M. W.

PY - 2018

Y1 - 2018

N2 - Introduction: At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. Materials and methods: In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA. Results: In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3%, p < 0.001; 25 μM sorafenib: 55.8%, p = 0.042). Sorafenib and sunitinib significantly inhibited P-selectin expression on platelets. Exposure to both TKIs resulted in a reduced tyrosine phosphorylation of c-Src. Ex vivo, within 24 h sunitinib impaired platelet aggregation (83.0%, p = 0.001, N = 8). Plasma concentrations of sunitinib, VEGF, and platelet/EC activation markers were not correlated with disturbed aggregation. In contrast, bevacizumab only significantly impaired platelet aggregation in vitro at high concentrations, but not ex vivo. Conclusion: Sunitinib significantly inhibits platelet aggregation in patients already after 24 h of first administration, whereas bevacizumab had no effect on aggregation. These findings may explain the clinically observed bleedings during treatment with antiangiogenic TKIs.

AB - Introduction: At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. Materials and methods: In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA. Results: In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3%, p < 0.001; 25 μM sorafenib: 55.8%, p = 0.042). Sorafenib and sunitinib significantly inhibited P-selectin expression on platelets. Exposure to both TKIs resulted in a reduced tyrosine phosphorylation of c-Src. Ex vivo, within 24 h sunitinib impaired platelet aggregation (83.0%, p = 0.001, N = 8). Plasma concentrations of sunitinib, VEGF, and platelet/EC activation markers were not correlated with disturbed aggregation. In contrast, bevacizumab only significantly impaired platelet aggregation in vitro at high concentrations, but not ex vivo. Conclusion: Sunitinib significantly inhibits platelet aggregation in patients already after 24 h of first administration, whereas bevacizumab had no effect on aggregation. These findings may explain the clinically observed bleedings during treatment with antiangiogenic TKIs.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85043451367&origin=inward

U2 - 10.1007/s10456-018-9598-5

DO - 10.1007/s10456-018-9598-5

M3 - Article

VL - 21

SP - 325

EP - 334

JO - Angiogenesis

JF - Angiogenesis

SN - 0969-6970

IS - 2

ER -