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

https://doi.org/10.1016/j.jacbts.2020.12.009 Get rights and content
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Highlights

  • 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.

Summary

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.

Key Words

antiplatelet drugs
circulating microvesicles
COVID-19
IL-6
platelet activation
tissue factor

Abbreviations and Acronyms

ADP
adenosine diphosphate
CAD
coronary artery disease
COVID-19
coronavirus disease-2019
CRP
C-reactive protein
GPA
granulocyte–platelet aggregates
HS
healthy subject
IL
interleukin
IL-6R
interleukin-6 receptor
LMWH
low-molecular-weight heparin
MPA
monocyte–platelet aggregates
MV
microvesicle
NO
nitric oxide
NOS
nitric oxide synthase
PGI2
prostacyclin
PLA
platelet–leukocyte aggregates
PS
phosphatidylserine
SARS-CoV-2
severe acute respiratory syndrome-coronavirus-2
TF
tissue factor

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The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center .

Drs. Canzano and Brambilia contributed equally to this work and are joint first authors.

Drs. Tremoli and Camera contributed equally to this work, and are joint senior authors.