Thromb Haemost 2015; 113(05): 1035-1045
DOI: 10.1160/TH14-07-0579
Cellular Haemostasis and Platelets
Schattauer GmbH

Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses

Rahajeng N. Tunjungputri
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
2   Center for Tropical and Infectious Disease (CENTRID), Faculty of Medicine Diponegoro University - Dr. Kariadi Hospital, Semarang, Indonesia
,
Andre J. van der Ven
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
,
Niels Riksen
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
3   Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands
,
Gerard Rongen
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
3   Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands
,
Sabine Tacke
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
,
T. N. A. van den Berg
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
3   Department of Pharmacology-Toxicology, Radboud university medical center, Nijmegen, The Netherlands
,
Rob Fijnheer
4   Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, The Netherlands
,
Marc E. Gomes
5   Department of Cardiology, Canisius Wilhemina Hospital, Nijmegen, The Netherlands
,
Charles A. Dinarello
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
6   Department of Medicine, University of Colorado-Denver, Aurora, Colorado, USA
,
Frank L. van de Veerdonk
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
,
M. Hussein Gasem
2   Center for Tropical and Infectious Disease (CENTRID), Faculty of Medicine Diponegoro University - Dr. Kariadi Hospital, Semarang, Indonesia
,
Mihai G. Netea
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
,
Leo A. B. Joosten
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
,
Philip G. de Groot
4   Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, The Netherlands
,
Quirijn de Mast
1   Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
4   Department of Clinical Chemistry and Haematology, University Medical Center, Utrecht, The Netherlands
› Author Affiliations
Financial support: The study was sponsored by a research grant from AstraZeneca. R.N.T. is a recipient of the DIKTI-NESO PhD Fellowship from the Indonesian Ministry of Education and Culture. M.G.N. was supported by a Vici grant of the Netherlands Organization for Scientific Research and an ERC Consolidator Grant (nr. 310372). F.vd. V was supported by a Veni grant of the Netherlands Organization for Scientific Research. N.P.R. is supported by a Clinical Fellowship of the Netherlands Organisation for Health Research and Development (ZonMw) and a dr. Dekker grant from the Netherlands Heart Foundation. Q.d.M. is supported by the Noaber and Augeo foundations.
Further Information

Publication History

Received: 03 July 2014

Accepted after major revision: 19 February 2014

Publication Date:
24 November 2017 (online)

Zoom Image

Summary

Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.