NOD2-mediated P2Y upregulation increases platelet activation and thrombosis in sepsis.

BACKGROUND

Platelets from septic patients exhibit increased reactivity. However, the underlying mechanism of sepsis-induced platelet hyperactivity is still not completely understood.

OBJECTIVE

P2Y is a central receptor for platelet activation. In this study, we investigated the role of platelet P2Y in platelet hyperactivity during sepsis.

METHODS

We measured platelet P2Y expression and aggregation in response to ADP in septic patients and cecal ligation and puncture (CLP)-treated mice. We also detected the downstream signaling of P2Y in resting platelets from patients and mice with sepsis. The role of nucleotide-binding oligomerization domain 2 (NOD2)/RIP2/NF-κB/P65 pathway in sepsis-induced platelet P2Y high expression was also investigated. Finally, we compared the antiplatelet and antithrombotic effects of clopidogrel, prasugrel, and ticagrelor in experimental sepsis in mice and rats.

RESULTS

Compared to healthy subjects, platelets from septic patients exhibit P2Y hyperactivity and higher P2Y expression. pAkt is enhanced and pVASP is impaired in resting platelets from the patients, indicating the constitutive activation of platelet P2Y receptor. Mouse sepsis model recapitulates the findings in septic patients. NOD2 deficiency attenuates sepsis-induced platelet P2Y high expression, hyperactivity, and thrombosis. Prasugrel and ticagrelor are potent P2Y inverse agonists, and exhibit superior antiplatelet and antithrombotic efficacy over clopidogrel in mice and rats with sepsis.

CONCLUSIONS

NOD2 activation upregulates platelet P2Y expression, which is constitutively activated and contributes to platelet hyperactivity in septic status. Compared to clopidogrel, prasugrel and ticagrelor are potent P2Y inverse agonists with superior antiplatelet and antithrombotic efficacy in experimental sepsis.