Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation

Abstract

Coagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood. Here, we report a role of the NETs/ Factor XII (FXII) axis for initiating procoagulant and proinflammatory reactions in COVID-19.Proteomic analysis revealed enrichment of FXII in postmortem lung tissue from COVID-19 patients. Immunofluorescence analysis of COVID-19 lung tissue showed that FXII is activated in the lung parenchyma, within the pulmonary vessel walls and in fibrin-rich alveolar spaces. In particular, activated FXII (FXIIa) colocalized with NETs in COVID-19 lung tissue, indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially caused by impaired NETs clearance via extracellular DNases. In contrast, addition of DNase I improved NETs clearance and reduced FXII activation in vitro. We propose that targeting both, FXIIa and the FXII activator NETs, is therapeutically effective in mitigating thrombo-inflammation in COVID-19.

Thrombotic Events in COVID-19 Are Associated With a Lower Use of Prophylactic Anticoagulation Before Hospitalization and Followed by Decreases in Platelet Reactivity

“…These include plasmin and neutrophil elastase (which can be released during NET formation), which can cleave and truncate the N-terminus of PAR-1 including the thrombin cleavage site, rendering PAR-1 unable to be activated by thrombin (23,24). Both elevated plasmin-α2-antiplasmin complex levels and evidence for neutrophil degranulation and NETs formation have been reported in COVID-19 patient plasma and tissue (25,26). This suggests that PAR-1 desensitization may take place secondary to COVID-19 associated thromboinflammatory events.…”

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications

“…This speculates that either the whole coronaviruses, which contains conserved negatively charged amino acids located within domain III in the carboxyl end of nucleocapsid proteins [ 107 ] or the SARS-CoV-2 RNA that are circulating in the bloodstream [ 108 ] are readily capable of inducing FXII-associated intrinsic coagulation pathway to form a pathological thrombus [ 104 ]. In fact, a pulmonary vessel wall isolated from COVID-19 positive lung tissues exhibited increased expression and activity of FXIIa [ 109 ], showing the commencement of the pathogenic pro-coagulant chain. This FXIIa was activated by an accumulated neutrophil extracellular traps (NETs) indicating an impaired clearance of NETs [ 109 ].…”

“…In fact, a pulmonary vessel wall isolated from COVID-19 positive lung tissues exhibited increased expression and activity of FXIIa [ 109 ], showing the commencement of the pathogenic pro-coagulant chain. This FXIIa was activated by an accumulated neutrophil extracellular traps (NETs) indicating an impaired clearance of NETs [ 109 ]. Further, the coagulation cascade activation is evidenced by increased plasma levels of thrombin-antithrombin-complexes (TAT) and fibrin among COVID-19 patients [ 110 , 111 ], suggesting an activation by FXIIa [ 112 ].…”

Platelet proteome analysis reveals an early hyperactive phenotype in SARS-CoV-2-infected humanized ACE2 mice

“…Similarly, an increase in coagulation factor F12 at 2dpi (Figure 2I) suggests plasma F12 may bind platelets to accelerate activation (contact pathway), and participate in CAC. 17 Furthermore, reduced F5 at 2dpi (Figure 2E) could indicate F5 release to the plasma by activated platelets. On the other hand, we also observed increased anti-coagulation proteins (TFPI, PROC, PROS1, THBD) (Figure 2I), suggesting both pro-coagulant and anticoagulant factors were prominently dysregulated during early SARS-CoV-2 infection.…”