Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin

FASEB J. 2020 Aug;34(8):10027-10040. doi: 10.1096/fj.202000312R. Epub 2020 Jun 27.


Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2 , a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2 , prostaglandin (PG) F , 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2 . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.

Keywords: antithrombotic therapy; aspirin; eicosanoid profiling; endothelium; platelets.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acid / administration & dosage
  • Aspirin / pharmacology*
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Cyclooxygenase 1 / physiology*
  • Cyclooxygenase Inhibitors / pharmacology*
  • Eicosanoids / metabolism*
  • Female
  • Male
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Thrombosis / drug therapy
  • Thrombosis / metabolism*
  • Thrombosis / pathology


  • Cyclooxygenase Inhibitors
  • Eicosanoids
  • Membrane Proteins
  • Arachidonic Acid
  • Cyclooxygenase 1
  • Ptgs1 protein, mouse
  • Aspirin