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.

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In addition to preserving homeostasis and contributing to immunity, platelets may exhibit a dysregulated state 1,2 in acute respiratory distress syndrome (ARDS) and potentially exacerbate lung injury. [3][4][5] Although thrombocytopenia has been associated with increased mortality in ARDS, 6 and particularly in patients infected with H1N1 influenza, 7 analysis of quantitative changes in platelet activation levels in ARDS and of how these may differ between the various etiologies of ARDS is limited. 3 Coronavirus disease 2019 (COVID-19) is clinically associated with a high incidence of thrombosis [8][9][10] and with a high burden of pulmonary and systemic platelet-rich microthrombi. 11,12 Interestingly, in contrast to a cohort of patients with H1N1-influenza infection with ARDS of equal severity, patients with COVID-19 ARDS displayed a 9 times higher burden of alveolar capillary platelet-rich microthrombi. 11 Patients with COVID-19 who were autopsied demonstrated an abundance of platelet-rich thrombi in the pulmonary and systemic microvasculature despite having received anticoagulation therapy. 12 Clinically, thromboelastography (TEG) studies have also demonstrated a hypercoagulable profile in patients with severe COVID-19 9,13 despite prophylactic anticoagulation. TEG profiles remained hypercoagulable, with parameters suggesting a significant hypercoagulable effect from platelet activity and fibrin. 13 Multiple study groups [14][15][16] including ours 17 have reported dramatically increased platelet activation, platelet reactivity, and platelet-leukocyte aggregates in COVID-19 compared with those in healthy blood donors (controls). In one study, 15 patients with severe COVID-19 harbored a higher degree of platelet activation and platelet-monocyte aggregation compared with patients with COVID-19 that was not severe. In addition, plasma from patients with severe COVID-19 increased the ex vivo activation of platelets and monocytes from healthy controls, a phenomenon inhibited by abciximab, a platelet aggregation inhibitor. Platelet activation correlated with COVID-19 severity in that study. 15 A second study demonstrated an 89-fold increase in platelet hyperreactivity with low-dose stimulation by thromboxane A 2 (TXA 2 ) receptor agonist compared with that in controls. 16 A third study 14 demonstrated increases in platelet activation, platelet reactivity, and platelet-leukocyte aggregates in patients with COVID-19 compared with healthy controls. These studies demonstrate that platelet reactivity is enhanced in patients with COVID-19 and posit that platelet hyperreactivity may be a primary driver of thrombosis in patients with severe COVID-19, contributing to organ failure and death. Whether this degree of platelet hyperreactivity is unique to COVID-19 or is also encountered during ARDS not related to COVID-19 was addressed in our study.COVID-19 patients without (n 5 11) and with ARDS (n 5 9) and patients with ARDS unrelated to COVID-19 etiology (n 5 8) who were admitted to the Cheikh Zaid Hospital of Abulcasis Unive...

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: We document the presence of SARS-CoV-2 RNA in platelets of COVID-19 patients. Exhaustive assessment of cytokines in plasma and in platelets revealed the modulation of platelet-associated cytokine levels in COVID-19, pointing to a direct contribution of platelets to the plasmatic cytokine load. Moreover, we demonstrate that platelets release their alpha- and dense-granule contents and phosphatidylserine-exposing extracellular vesicles. Functionally, platelets were hyperactivated in COVID-19 subjects, with aggregation occurring at suboptimal thrombin concentrations. Furthermore, platelets adhered more efficiently onto collagen-coated surfaces under flow conditions. Conclusions: These data suggest that platelets could participate in the dissemination of SARS-CoV-2 and in the overwhelming thrombo-inflammation observed in COVID-19. Thus, blockade of platelet activation pathways may improve outcomes in this disease.

BACKGROUNDSevere Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent responsible for Coronavirus disease 2019 (COVID-19). While SARS-CoV-2 infections are often benign, there are also severe COVID-19 cases, characterized by severe bilobar pneumonia that can decompensate to an acute respiratory distress syndrome, notably characterized by increased inflammation and a cytokine storm. While there is no cure against severe COVID-19 cases, some treatments significantly decrease the severity of the disease, notably aspirin and dexamethasone, which both directly or indirectly target the biosynthesis (and effects) of numerous bioactive lipids.OBJECTIVEOur working hypothesis was that severe COVID-19 cases necessitating mechanical ventilation were characterized by increased bioactive lipid levels modulating lung inflammation. We thus quantitated several lung bioactive lipids using liquid chromatography combined to tandem mass spectrometry.RESULTSWe performed an exhaustive assessment of the lipid content of bronchoalveolar lavages from 25 healthy controls and 33 COVID-19 patients necessitating mechanical ventilation. Severe COVID-19 patients were characterized by increased fatty acid levels as well as an accompanying inflammatory lipid storm. As such, most quantified bioactive lipids were heavily increased. There was a predominance of cyclooxygenase metabolites, notably TXB2 >> PGE2 ∼ 12-HHTrE > PGD2. Leukotrienes were also increased, notably LTB4, 20-COOH-LTB4, LTE4, and eoxin E4. 15-lipoxygenase metabolites derived from linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acids were also increased. Finally, yet importantly, specialized pro-resolving mediators, notably lipoxin A4 and the D-series resolvins, were also found at important levels, underscoring that the lipid storm occurring in severe SARS-CoV-2 infections involves pro- and anti-inflammatory lipids.CONCLUSIONSOur data unmask the important lipid storm occurring in the lungs of patients afflicted with severe COVID-19. We discuss which clinically available drugs could be helpful at modulating the lipidome we observed in the hope of minimizing the deleterious effects of pro-inflammatory lipids and enhancing the effects of anti-inflammatory and/or pro-resolving lipids.