Immunothrombosis in COVID-19: Implications of Neutrophil Extracellular Traps

Abstract

SARS-CoV-2 is a member of the family of coronaviruses associated with severe outbreaks of respiratory diseases in recent decades and is the causative agent of the COVID-19 pandemic. The recognition by and activation of the innate immune response recruits neutrophils, which, through their different mechanisms of action, form extracellular neutrophil traps, playing a role in infection control and trapping viral, bacterial, and fungal etiological agents. However, in patients with COVID-19, activation at the vascular level, combined with other cells and inflammatory mediators, leads to thrombotic events and disseminated intravascular coagulation, thus leading to a series of clinical manifestations in cerebrovascular, cardiac, pulmonary, and kidney disease while promoting severe disease and mortality. Previous studies of hospitalized patients with COVID-19 have shown that elevated levels of markers specific for NETs, such as free DNA, MPO, and H3Cit, are strongly associated with the total neutrophil count; with acute phase reactants that include CRP, D-dimer, lactate dehydrogenase, and interleukin secretion; and with an increased risk of severe COVID-19. This study analyzed the interactions between NETs and the activation pathways involved in immunothrombotic processes in patients with COVID-19.

Keywords: CID; COVID-19; SARS-CoV-2; immunothrombosis; neutrophil extracellular traps.

Figure 1

Proposed model of hypercoagulability in patients with COVID-19. 1. Increased secretion of inflammatory interleukins and chemokines recruits neutrophils to the site of infection. 2. Unable to eliminate the virus by activation of TLR-2, and -4, the neutrophils release their extracellular traps by NETosis. 3. NETs are rich in histones, free DNA, and MPO acting as DAMPs, amplifying the inflammatory response and leading to endothelial damage. 4. The previous step leads to platelet aggregation, clot formation, and stabilization. 5. Histones H3 and H4 present in NETs activate the intrinsic coagulation pathway through their interaction with FXI and XII, and they downregulate thrombomodulin, inducing a procoagulant state. 6. Endothelial injury leads to the activation of the extrinsic pathway by the expression of TFIII, which binds to FVII, triggering the coagulation cascade. 7. Thrombin, FXa, and the TFIII–FVII complex interact with protease activated receptors (PARs), causing platelet activation and aggregation with the subsequent release of their granular content, such as p-selectin. 8. p-selectin favors the activation and migration of additional PMNs that easily bind to the endothelium through adhesion molecules—leukocyte function antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). 9. Meanwhile, the complement system activates thrombin by binding C3a and C5a. 10. Perpetuating thrombus formation.