Platelet and Endothelial Activation as Potential Mechanisms Behind the Thrombotic Complications of COVID-19 Patients

[Display omitted] •The cytokine storm present in COVID-19 patients induces, together with the imbalance of endothelial functions, a massive cell activation with production of tissue factor, mainly by platelets, granulocytes, and MVs.•Plasma MV-associated thrombin generation is present in patients de...

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Published in:	JACC. Basic to translational science Vol. 6; no. 3; pp. 202 - 218
Main Authors:	Canzano, Paola, Brambilla, Marta, Porro, Benedetta, Cosentino, Nicola, Tortorici, Elena, Vicini, Stefano, Poggio, Paolo, Cascella, Andrea, Pengo, Martino F., Veglia, Fabrizio, Fiorelli, Susanna, Bonomi, Alice, Cavalca, Viviana, Trabattoni, Daniela, Andreini, Daniele, Omodeo Salè, Emanuela, Parati, Gianfranco, Tremoli, Elena, Camera, Marina
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01.03.2021 Elsevier
Subjects:	antiplatelet drugs Cardiovascular circulating microvesicles Clinical Research COVID-19 IL-6 platelet activation tissue factor CRP IL-6R NO IL PS tissue factor PLA PGI2 CAD MV HS ADP IL-6 platelet activation COVID-19 LMWH SARS-CoV-2 TF NOS antiplatelet drugs GPA circulating microvesicles MPA coronary artery disease microvesicle C-reactive protein platelet–leukocyte aggregates PGI 2 monocyte–platelet aggregates adenosine diphosphate low-molecular-weight heparin nitric oxide synthase interleukin coronavirus disease-2019 nitric oxide granulocyte–platelet aggregates prostacyclin interleukin-6 receptor phosphatidylserine severe acute respiratory syndrome-coronavirus-2 healthy subject PLA, platelet–leukocyte aggregates GPA, granulocyte–platelet aggregates HS, healthy subject NOS, nitric oxide synthase CAD, coronary artery disease PS, phosphatidylserine ADP, adenosine diphosphate NO, nitric oxide COVID-19, coronavirus disease-2019 IL, interleukin MV, microvesicle SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2 TF, tissue factor IL-6R, interleukin-6 receptor LMWH, low-molecular-weight heparin CRP, C-reactive protein PGI2, prostacyclin MPA, monocyte–platelet aggregates
ISSN:	2452-302X, 2452-302X
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Summary:	[Display omitted] •The cytokine storm present in COVID-19 patients induces, together with the imbalance of endothelial functions, a massive cell activation with production of tissue factor, mainly by platelets, granulocytes, and MVs.•Plasma MV-associated thrombin generation is present in patients despite prophylactic anticoagulation.•COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to what is observed in vivo. This effect is blunted by pre-incubation with tocilizumab, giving insights into the IL-6–mediated platelet activation that triggers the hypercoagulable state in COVID-19, suggesting the potential effectiveness of anti–IL-6 antibodies and antiplatelet drugs.•Our data provide the bench-to-clinic rationale behind the ongoing clinical trial assessing the potential effectiveness of antiplatelet drugs and IL-6R antagonists in the treatment of COVID-19 patients. The authors hypothesized that the cytokine storm described in COVID-19 patients may lead to consistent cell-based tissue factor (TF)-mediated activation of coagulation, procoagulant microvesicles (MVs) release, and massive platelet activation. COVID-19 patients have higher levels of TF+ platelets, TF+ granulocytes, and TF+ MVs than healthy subjects and coronary artery disease patients. Plasma MV-associated thrombin generation is present in prophylactic anticoagulated patients. A sustained platelet activation in terms of P-selectin expression and platelet–leukocyte aggregate formation, and altered nitric oxide/prostacyclin synthesis are also observed. COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to that observed in vivo. This effect was blunted by pre-incubation with tocilizumab, aspirin, or a P2Y12 inhibitor.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Drs. Tremoli and Camera contributed equally to this work, and are joint senior authors. Drs. Canzano and Brambilia contributed equally to this work and are joint first authors.
ISSN:	2452-302X 2452-302X
DOI:	10.1016/j.jacbts.2020.12.009