SARS-CoV-2 spike protein potentiates platelet aggregation via upregulating integrin αIIbβ3 outside-in signaling pathway

Platelet hyperreactivity is one of the crucial causes of coagulative disorders in patients with COVID-19. Few studies have indicated that integrin αIIbβ3 may be a potential target for spike protein binding to platelets. This study aims to investigate whether spike protein interacts with platelet integrin αIIbβ3 and upregulates outside-in signaling to potentiate platelet aggregation. In this study, we found that spike protein significantly potentiated platelet aggregation induced by different agonists and platelet spreading in vitro. Mechanism studies revealed that spike protein upregulated the outside-in signaling, such as increased thrombin-induced phosphorylation of β3, c-Src. Moreover, using tirofiban to inhibit spike protein binding to αIIbβ3 or using PP2 to block outside-in signaling, we found that the potentiating effect of spike protein on platelet aggregation was abolished. These results demonstrate that SARS-CoV-2 spike protein directly enhances platelet aggregation via integrin αIIbβ3 outside-in signaling, and suggest a potential target for platelet hyperreactivity in patients with COVID-19.

SARS-CoV-2 spike protein interacts with platelet integrin αIIbβ3, upregulating the outside-in signaling pathway and subsequently potentiating platelet aggregation.

• Spike protein potentiates platelet aggregation and upregulates αIIbβ3 outside-in signaling.

• Spike protein interacts with integrin αIIbβ3 to potentiate platelet aggregation.

• Blocking outside-in signaling abolishes the effect of spike protein on platelets.