SARS-CoV-2 infection induces the activation of tissue factor-mediated coagulation via activation of acid sphingomyelinase

Blood. 2021 Jul 29;138(4):344-349. doi: 10.1182/blood.2021010685.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with the hypercoagulable state. Tissue factor (TF) is the primary cellular initiator of coagulation. Most of the TF expressed on cell surfaces remains cryptic. Sphingomyelin (SM) is responsible for maintaining TF in the encrypted state, and hydrolysis of SM by acid sphingomyelinase (ASMase) increases TF activity. ASMase was shown to play a role in virus infection biology. In the present study, we investigated the role of ASMase in SARS-CoV-2 infection-induced TF procoagulant activity. Infection of human monocyte-derived macrophages (MDMs) with SARS-CoV-2 spike protein pseudovirus (SARS-CoV-2-SP-PV) markedly increased TF procoagulant activity at the cell surface and released TF+ extracellular vesicles. The pseudovirus infection did not increase either TF protein expression or phosphatidylserine externalization. SARS-CoV-2-SP-PV infection induced the translocation of ASMase to the outer leaflet of the plasma membrane, which led to the hydrolysis of SM in the membrane. Pharmacologic inhibitors or genetic silencing of ASMase attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Inhibition of the SARS-CoV-2 receptor, angiotensin-converting enzyme-2, attenuated SARS-CoV-2-SP-PV-induced increased TF activity. Overall, our data suggest that SARS-CoV-2 infection activates the coagulation by decrypting TF through activation of ASMase. Our data suggest that the US Food and Drug Administration-approved functional inhibitors of ASMase may help treat hypercoagulability in patients with COVID-19.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Angiotensin-Converting Enzyme 2 / physiology
  • COVID-19 / blood*
  • COVID-19 / complications
  • Cell-Derived Microparticles
  • Enzyme Activation
  • Humans
  • Hydrolysis
  • Macrophages / enzymology
  • Macrophages / virology*
  • Membrane Proteins / physiology*
  • Molecular Targeted Therapy
  • Plasmids
  • Protein Transport
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Virus / physiology
  • SARS-CoV-2*
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Sphingomyelin Phosphodiesterase / physiology*
  • Sphingomyelins / physiology
  • Spike Glycoprotein, Coronavirus / physiology*
  • Thrombophilia / blood
  • Thrombophilia / drug therapy
  • Thrombophilia / enzymology
  • Thrombophilia / etiology*
  • Thromboplastin / physiology*


  • Membrane Proteins
  • RNA, Small Interfering
  • Receptors, Virus
  • Sphingomyelins
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Thromboplastin
  • SMPD1 protein, human
  • Sphingomyelin Phosphodiesterase
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2