P2Y12 Inhibition Suppresses Proinflammatory Platelet–Monocyte Interactions

Abstract

Consistent with a proinflammatory platelet effector role, MPAs were increased in patients with COVID-19. RNA-Seq revealed a thromboinflammatory monocyte transcriptome upon incubation with platelets. Monocytes aggregated to platelets expressed higher CD40 and tissue factor than monocytes without platelets (<i>p</i> < 0.05 for each). Inhibition with P-selectin (85% reduction) and PSGL1 (87% reduction) led to a robust decrease in MPA. P2Y₁₂ and PAR1 inhibition lowered MPA formation (30 and 21% reduction, <i>p</i> < 0.05, respectively) and decreased monocyte CD40 and TF expression, while GP IIb/IIIa and COX1 inhibition had no effect. Pretreatment of platelets with P2Y₁₂ inhibitors reduced the expression of platelet-mediated monocyte transcription of proinflammatory <i>SOCS3</i> and <i>OSM.</i> CONCLUSIONS: Platelets skew monocytes toward a proinflammatory phenotype. Among traditional APTs, P2Y₁₂ inhibition attenuates platelet-induced monocyte activation.