Manchester Metropolitan University's Research Repository

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

Crescente, Marilena and Armstrong, Paul C and Kirkby, Nicholas S and Edin, Matthew L and Chan, Melissa V and Lih, Fred B and Jiao, Jing and Maffucci, Tania and Allan, Harriet E and Mein, Charles A and Gaston-Massuet, Carles and Cottrell, Graeme S and Mitchell, Jane A and Zeldin, Darryl C and Herschman, Harvey R and Warner, Timothy D (2020) Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34 (8). pp. 10027-10040. ISSN 0892-6638


Available under License Creative Commons Attribution.

Download (1MB) | Preview


Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A<sub>2</sub> , 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 TxA<sub>2</sub> , prostaglandin (PG) F<sub>2α</sub> , 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 PGI<sub>2</sub> metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA<sub>2</sub> and PGE<sub>2</sub> . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI<sub>2</sub> and PGD<sub>2</sub> 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.

Impact and Reach


Activity Overview

Additional statistics for this dataset are available via IRStats2.


Actions (login required)

View Item View Item