A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

Dorien Kiers; Wouter A van der Heijden; Lisa van Ede; Jelle Gerretsen; Quirijn de Mast; André J van der Ven; Saloua El Messaoudi; Gerard A Rongen; Marc Gomes; Matthijs Kox; Peter Pickkers; Niels P Riksen

doi:10.1160/TH16-10-0799

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia

Thromb Haemost. 2017 Aug 30;117(9):1798-1807. doi: 10.1160/TH16-10-0799. Epub 2017 Jul 6.

Authors

Dorien Kiers¹, Wouter A van der Heijden, Lisa van Ede, Jelle Gerretsen, Quirijn de Mast, André J van der Ven, Saloua El Messaoudi, Gerard A Rongen, Marc Gomes, Matthijs Kox, Peter Pickkers, Niels P Riksen

Affiliation

¹ Prof. N. P. Riksen, Dept. of Internal Medicine 463, Radboud University Medical Center, PO Box 9101, 6500HB Nijmegen, The Netherlands, Tel.: +31 24 3618819, Fax: +31 24 3616519, E-mail: [email protected].

PMID: 28692111
DOI: 10.1160/TH16-10-0799

Abstract

The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y₁₂ inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y₁₂ antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y₁₂ inhibition impaired platelet reactivity, there was no correlation with cytokine responses.

Keywords: Acetylsalicylic acid; clopidogrel; endotoxaemia; platelet inhibition; ticagrelor.

Publication types

Randomized Controlled Trial

MeSH terms

Adenosine / adverse effects
Adenosine / analogs & derivatives*
Adenosine / therapeutic use
Administration, Intravenous
Adolescent
Adult
Aspirin / adverse effects
Aspirin / therapeutic use*
Cells, Cultured
Clopidogrel
Cytokines / blood
Drug Therapy, Combination
Endotoxemia / blood
Endotoxemia / diagnosis
Endotoxemia / drug therapy*
Endotoxins / administration & dosage
Healthy Volunteers
Humans
Inflammation / blood
Inflammation / diagnosis
Inflammation / drug therapy*
Inflammation Mediators / blood
Male
Netherlands
Platelet Activation / drug effects*
Platelet Aggregation Inhibitors / adverse effects
Platelet Aggregation Inhibitors / therapeutic use*
Prospective Studies
Purinergic P2Y Receptor Antagonists / adverse effects
Purinergic P2Y Receptor Antagonists / therapeutic use*
Ticagrelor
Ticlopidine / adverse effects
Ticlopidine / analogs & derivatives*
Ticlopidine / therapeutic use
Time Factors
Treatment Outcome
Young Adult

Substances

Cytokines
Endotoxins
Inflammation Mediators
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
endotoxin, Escherichia coli
Clopidogrel
Ticagrelor
Adenosine
Ticlopidine
Aspirin