SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate

Int J Biol Macromol. 2021 Dec 15;193(Pt B):1124-1129. doi: 10.1016/j.ijbiomac.2021.10.112. Epub 2021 Oct 29.


Thrombotic complication has been an important symptom in critically ill patients with COVID-19. It has not been clear whether the virus spike (S) protein can directly induce blood coagulation in addition to inflammation. Heparan sulfate (HS)/heparin, a key factor in coagulation process, was found to bind SARS-CoV-2 S protein with high affinity. Herein, we found that the S protein can competitively inhibit the bindings of antithrombin and heparin cofactor II to heparin/HS, causing abnormal increase in thrombin activity. SARS-CoV-2 S protein at a similar concentration (~10 μg/mL) as the viral load in critically ill patients can cause directly blood coagulation and thrombosis in zebrafish model. Furthermore, exogenous heparin/HS can significantly reduce coagulation caused by S protein, pointing to a potential new direction to elucidate the etiology of the virus and provide fundamental support for anticoagulant therapy especially for the COVID-19 critically ill patients.

Keywords: Anticoagulant therapy; Coagulation; Heparan sulfate; SARS-CoV-2; Spike protein.

MeSH terms

  • Animals
  • Blood Coagulation*
  • Heparitin Sulfate* / chemistry
  • Heparitin Sulfate* / metabolism
  • Humans
  • Mice
  • Protein Binding
  • SARS-CoV-2* / chemistry
  • SARS-CoV-2* / metabolism
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Spike Glycoprotein, Coronavirus* / metabolism
  • Thrombosis / metabolism*


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Heparitin Sulfate