Platelet P2Y₁₂ Receptor Deletion or Pharmacological Inhibition does not Protect Mice from Sepsis or Septic Shock

Abstract

Introduction Platelets are increasingly appreciated as key effectors during sepsis, raising the question of the usefulness of antiplatelet drugs to treat patients with sepsis.

Objective Evaluate the potential contribution of the platelet P2Y₁₂ receptor in the pathogenesis of polymicrobial-induced sepsis and septic shock in mice.

Methods The effects of P2Y₁₂ inhibition using clopidogrel treatment and of platelet-specific deletion of the P2Y₁₂ receptor in mice were examined in two severity grades of cecal ligation and puncture (CLP) leading to mild sepsis or septic shock.

Results Twenty hours after induction of the high grade CLP, clopidogrel- and vehicle-treated mice displayed a similar 30% decrease in mean arterial blood pressure (MAP) characteristic of shock. Septic shock-induced thrombocytopenia was not modified by clopidogrel treatment. Plasma concentrations of inflammatory cytokines and myeloperoxidase (MPO) were similarly increased in clopidogrel- and vehicle-treated mice, indicating comparable increase in systemic inflammation. Thrombin-antithrombin (TAT) complexes and the extent of organ damage were also similar. In mild-grade CLP, clopidogrel- and vehicle-treated mice did not display a significant decrease in MAP, while thrombocytopenia and plasma concentrations of TNFα, IL6, IL10, MPO, TAT and organ damage reached similar levels in both groups, although lower than those reached in the high grade CLP. Similarly, mice with platelet-specific deletion of the P2Y₁₂ receptor were not protected from CLP-induced sepsis or septic shock.

Conclusion The platelet P2Y₁₂ receptor does not contribute to the pathogenesis of sepsis or septic shock in mice, suggesting that P2Y₁₂ receptor antagonists may not be beneficial in patients with sepsis or septic shock.

Keywords

sepsis - septic shock - P2Y12 receptor - clopidogrel treatment - antiplatelet drug

Addendum

B. Hechler and C. Gachet designed the research; Y. Rabouël, S. Magnenat and B. Hechler performed experiments; Y. Rabouël, X. Delabranche and B. Hechler analyzed data; B. Hechler wrote the manuscript; All authors critically reviewed the manuscript and contributed to the final manuscript.

^* These authors share last co-authorship.

Publikationsverlauf

Eingereicht: 13. März 2021

Angenommen: 06. Juli 2021

Artikel online veröffentlicht:
24. August 2021

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