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  • NETosis activation of Factor VII-activating protease (FSAP): A predictive role in SARS-COV-2 infection thrombosis
  • mahin behzadifard,1,* roqaye karimi,2
    1. de
    2. Tarbiat Modares univercity


  • Introduction: Multiple factors such as inflammatory cytokines and neutrophil extracellular traps (NETs) formation, NETosis, are involved in coagulation activation(1, 2). During inflammation and viral infection NETs actively released from neutrophils into the extracellular space(3). NETs act as a part of innate immunity, and thought to be responsible for inflammation and host defense(4). Pathogens such as respiratory viruses, induce NETs formation that physically immobilize pathogens and kill the microbes(5, 6). The NETosis contributes in sepsis and acute respiratory distress syndrome(ARDS) pathogenesis and causing vascular tissue damage , thrombosis, multiorgan failure and death(7, 8). Increased NETs formation correlates with COVID-19 related ARDS and is a potential biomarker for the disease severity(5, 9). SARS-COV-2 may directly infect monocytes/ macrophages and tissue factor (TF) expression/release from these cells that may play a critical role in the development of COVID-19 coagulopathy (10). NETs particularly by histone component lead to platelets adhesion and activation and may bind to von Willebrand factor (VWF) and fibrinogen(11). Neutrophils and platelets release microparticles that contain TF and to be trapped by NETs, TF has been detected in NETs inside venous thrombi in vivo as a factor of induce thrombosis (12, 13). NETs used several pathways that support fibrin formation, and enhance platelets activation and thrombosis by involvement in fibrinolysis inhibition, activation of contact-pathway of coagulation, and triggering coagulation initiation(14). NETs induce tissue factor pathway inhibitor (TFPI) degradation and increase blood coagulation(15). Additionally, to activation of extrinsic pathway, NETs promote intrinsic coagulation cascade by activation of FXII by nucleic acids and phosphates and may inhibit fibrinolysis by tissue plasminogen activator(tPA) inhibition and increase fibrin formation(16). FSAP is a serine protease produced mainly by liver and is present in the circulation in the form of zymogen (pro-FSAP). Histones and nucleosomes released from NETs can activate circulating pro-FSAP. The released histones degraded by FSAP and histone cytotoxicity towards endothelial cells was neutralized by FSAP. This activation of FSAP may be important in diminishing the cytotoxic effect of histones, thus limiting the damaging effect of NETosis (17). The first initially known described roles of FSAP was involvement in activation of FVII, fibrinolysis as an activator of pro-urokinase (18).
  • Methods: To provide a better prospect representing the prognostic value of alteration in NETosis and coagulation pathway in COVID-19, we searched national library of medicine Medline/PubMed and google scholar by using the keywords “coagulation” OR “coagulopathy” AND “COVID-19” OR “coronavirus 2019” OR “2019-nCoV” OR “SARSCoV-2” AND 'NETosis" between December, 2019 and the time of our analysis (i.e., May 25, 2021), without any restriction.
  • Results: FSAP bounds to NETs, colocalization of FSAP-NETs was reported in coronary thrombi from patients with acute myocardial infarction (19). Additionally, FSAP can inhibit TFPI and increase the chance of thrombosis. Increased FSAP activity is demonstrated in pregnancy(20), the use of oral contraceptives(21), deep vein thrombosis (19) or coronary heart disease as compared with health controls (22). More recently reports have been shown FVII is a poor FSAP substrate and TFPI was identified as a novel substrate and impaired FSAP modulation of TFPI levels was suggested as an explanation for the thrombus formation observed in FSAP deficient mice (FSAP−/−) (23). RNA and DNA components of nucleosomes could promote FSAP auto-activation, and inhibition of TFPI may contribute to prothrombotic actions and support arterial thrombosis (22, 23). COVID-19 patients seem especially prone to lead excessive NETs release, disease severity and survival parallel increasing markers of NETs formation (6, 9). Raised protein levels of FSAP was reported in the lungs of patients with ARDS (24). This may represent a novel pathological mechanism which contributes to pulmonary extravascular fibrin deposition and may also modulate inflammation in the acutely injured lung via hemostasis independent cellular activities of FSAP(18).
  • Conclusion: Because of the similarity of ARDS in COVID-19 infection with other infectious respiratory syndromes that is related to dysregulated immune response, releasing of inflammatory cytokines, and development of pathogenic microvascular thrombi, NETs formation may induce thrombosis and activate FSAP as a thrombosis inducer that may have a predictive role in SARS-COV-2 thrombosis, using the NETs inhibitors may dampen the severity of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection.
  • Keywords: Thrombosis, SARS-CoV-2, COVID-19, Angiotensin converting enzyme, NETosis,