Breakthrough infections after Covid-19 vaccinations do not elicit platelet hyper-activation and associate with high platelet-lymphocyte and low platelet-neutrophil aggregates

Background. Severe coronavirus disease 2019 (COVID-19) is associated with an excessive immunothrombotic response and thromboinflammatory complications. Vaccinations effectively reduce the risk of severe clinical outcomes in COVID-19 patients, but their impact on platelet activation and on immunothrombosis during breakthrough infections are not known. Objective. To investigate how pre-emptive vaccinations modify the platelet-immune crosstalk during COVID-19 infections. Methods and patients. Cross-sectional flow cytometry study of the phenotype and interactions of platelets circulating in vaccinated (n=21) and unvaccinated COVID-19 patients, either admitted to the intensive care unit (ICU, n=36) or not (non-ICU, n=38), in comparison to matched SARS-CoV-2-negative patients (n=48). Results. In the circulation of unvaccinated non-ICU COVID-19 patients, we detected hyper-active and hyper-responsive platelets and platelet aggregates with adaptive and innate immune cells. In unvaccinated ICU COVID-19 patients, most of whom had severe acute respiratory distress syndrome (ARDS), platelets had high P-selectin and phosphatidylserine exposure but low capacity to activate integrin αIIbβ3, dysfunctional mitochondria, and reduced surface glycoproteins. In addition, in the circulation of ICU patients we detected microthrombi and platelet aggregates with innate, but not with adaptive, immune cells. In vaccinated COVID-19 patients, who had no ARDS, platelets had surface receptor levels comparable to controls, did not form microthrombi or platelet-granulocyte aggregates, but aggregated avidly with adaptive immune cells. Conclusions. Our study provides evidence that vaccinated COVID-19 patients are not associated with platelet hyper-activation and are characterized by platelet-leukocyte aggregates that foster immune protection but not excessive immunothrombosis. These findings advocate for the importance of vaccination in preventing severe COVID-19.