Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19

Abstract

Rationale: In addition to the overwhelming lung inflammation that prevails in COVID-19, hypercoagulation and thrombosis contribute to the lethality of subjects infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Platelets are chiefly implicated in thrombosis. Moreover, they can interact with viruses and are an important source of inflammatory mediators. While a lower platelet count is associated with severity and mortality, little is known about platelet function during COVID-19. Objective: To evaluate the contribution of platelets to inflammation and thrombosis in COVID-19 patients. Methods and Results: Blood was collected from 115 consecutive COVID-19 patients presenting non-severe (n=71) and severe (n=44) respiratory symptoms. We document the presence of SARS-CoV-2 RNA associated with platelets of COVID-19 patients. Exhaustive assessment of cytokines in plasma and in platelets revealed the modulation of platelet-associated cytokine levels in both non-severe and severe COVID-19 patients, pointing to a direct contribution of platelets to the plasmatic cytokine load. Moreover, we demonstrate that platelets release their alpha- and dense-granule contents in both non-severe and severe forms of COVID-19. In comparison to concentrations measured in healthy volunteers, phosphatidylserine-exposing platelet extracellular vesicles were increased in non-severe, but not in severe cases of COVID-19. Levels of D-dimers, a marker of thrombosis, failed to correlate with any measured indicators of platelet activation. Functionally, platelets were hyperactivated in COVID-19 subjects presenting non-severe and severe symptoms, with aggregation occurring at suboptimal thrombin concentrations. Furthermore, platelets adhered more efficiently onto collagen-coated surfaces under flow conditions. Conclusions: Taken together, the data suggest that platelets are at the frontline of COVID-19 pathogenesis, as they release various sets of molecules through the different stages of the disease. Platelets may thus have the potential to contribute to the overwhelming thrombo-inflammation in COVID-19, and the inhibition of pathways related to platelet activation may improve the outcomes during COVID-19.

Circulating Platelet-Derived Extracellular Vesicles Are a Hallmark of Sars-Cov-2 Infection

“…Our findings confirm the suggested relevance of PLT-EVs in Sars-CoV-2 infection as recently shown by Zaid et al [ 22 ].…”

“…In their work, Zaid et al [ 22 ] characterized PLT-EVs starting from manipulated blood, i.e., platelet rich plasma (PRP), after 1000 g centrifugation, in which PLT were subsequently removed to obtain plasma-free-platelet (PFP). PLT-EVs were then identified by FC on forward scatter (FSC) parameter, by using silica beads as a reference to assess their dimension.…”

Platelets are Hyperactivated but Show Reduced Glycoprotein VI Reactivity in COVID-19 Patients

“…The plasma levels of α-granule proteins PF4 and soluble CD40L were higher in COVID-19 patients, further indicating activated platelets in vivo ( Figure 1B). While earlier studies also reported enhanced α granule release 9,10 , our study adds to this that dense granules likely are not affected in COVID-19 patients not requiring intensive care.…”

SARS-CoV-2 RNAemia and proteomic biomarker trajectory inform prognostication in COVID-19 patients admitted to intensive care

“…In this context, circulating SARS-CoV-2 RNA (RNAemia) has been highlighted as a promising prognostic biomarker in hospitalized COVID-19 patients, as it is associated with disease severity 7 and mortality [8][9][10] , with an estimated prevalence of 10% (95% CI 5-18%, random effects model) 7 . Further, we hypothesized that the acute and profound alterations in the innate and adaptive immune system in COVID-19 patients 3,[11][12][13] , especially in RNAemic patients [14][15][16][17][18] , will be accompanied by marked changes in the circulating proteome and interactome and that the proteome in COVID-19 patients will highlight mechanistically relevant signatures and trajectories, when compared to non-COVID-19 sepsis and healthy controls. Thus far, proteomics studies have focused on the determination of protein biomarkers of COVID-19 severity [19][20][21][22] , but have not assessed the longitudinal relationship between proteomic changes, RNAemia and 28-day mortality.…”