Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity

Philipp Mourikis; Marcel Benkhoff; Laura Wildeis; Maike Barcik; Carolin Helten; Cristina Coman; Fiorella A Solari; Daniel Krahn; Lisa Dannenberg; Samantha Ahlbrecht; Dorothee Zikeli; Amelie Utz; Kajetan Trojovsky; Hannah Richter; Gabrielle Al Kassis; René M'Pembele; Saif Zako; Tim Huckenbeck; Sofia Bauer; Danny Schmitz; Susanne Pfeiler; Norbert Gerdes; Christof Dücker; Joachim Pircher; Zhang Zhe; Manuela Thienel; Qurrat Ul Ain; Petra Keul; Nicholas Kirkby; Dennis Sohn; Wilfried Budach; Thomas Hohlfeld; Karsten Schrör; Bodo Levkau; Tobias Zeus; Steven H L Verhelst; Robert Ahrends; Albert Sickmann; Jane Mitchell; Samia Mora; JoAnn E Manson; Deepak L Bhatt; Ulf Landmesser; Steffen Massberg; Malte Kelm; Tobias Petzold; Amin Polzin

doi:10.1126/scitranslmed.ado0610

Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity

Philipp Mourikis
, Marcel Benkhoff
, Laura Wildeis
, Maike Barcik
, Carolin Helten
, Cristina Coman
, Fiorella A Solari
, Daniel Krahn
, Lisa Dannenberg
, Samantha Ahlbrecht
, Dorothee Zikeli
, Amelie Utz
, Kajetan Trojovsky
, Hannah Richter
, Gabrielle Al Kassis
, René M'Pembele
, Saif Zako
, Tim Huckenbeck
, Sofia Bauer
, Danny Schmitz

Susanne Pfeiler, Norbert Gerdes, Christof Dücker, Joachim Pircher, Zhang Zhe, Manuela Thienel, Qurrat Ul Ain, Petra Keul, Nicholas Kirkby, Dennis Sohn, Wilfried Budach, Thomas Hohlfeld, Karsten Schrör, Bodo Levkau, Tobias Zeus, Steven H L Verhelst, Robert Ahrends, Albert Sickmann, Jane Mitchell, Samia Mora, JoAnn E Manson, Deepak L Bhatt, Ulf Landmesser, Steffen Massberg, Malte Kelm, Tobias Petzold, Amin Polzin (Corresponding author)

Department of Analytical Chemistry

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)-deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA's inhibitory effects was confirmed by platelet-specific COX-1-deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.

Original language	English
Journal	Science Translational Medicine
Volume	17
Issue number	799
DOIs	https://doi.org/10.1126/scitranslmed.ado0610
Publication status	Published - 21 May 2025

Funding

We thank K. Bartkowski for experimental support. F.A.S. and A.S. thank D. Kopczynski for the development of the bioinformatics platform Innt and S. Ideal for technical support. This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (nos. 46-2016 and 29-2019 to L.D., nos. 16-2014 and 18-2019 to A.P., no. 2020-51 to C.H., and no. 2021-01 to P.M.) and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (grant no. 493659010 to P.M.; grant no. 530690968 to M. Benkhoff; grant no. 236177352-SFB1116; TP B11 to A.P. and TP B11 to B.L.; TP B09 to N.G.; TP B6 and B12 to M.K.; grant nos. 493400536, 413659045, and 510844896 to A.P.; and grant nos. PE2704/3-1, PE2704/4-1, and PE2704/5-1 to T.P.), the Susanne-Bunnenberg-Stiftung at the Duesseldorf Heart Center, the DZHK (German Center for Cardiovascular Research) to A.P. and T.P. (external cooperation grant) and DZHK-BHF-DHF funding (MEGACARDIOCYTE, grant no. 81X2100286) to T.P., the Bundesministerium f\u00FCr Bildung und Forschung (BMBF) (to A.S., F.A.S., D.K., and S.H.L.V.), and the Ministerium f\u00FCr Kultur und Wissenschaft des Landes Nordrhein-Westfalen (to A.S., F.A.S., D.K., and S.H.L.V.). This work was further supported by the British Heart Foundation grants FS/16/1/31699 (to N.K.) and RG/18/4/33541 (to N.K. and J.M.).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

301303 Medical biochemistry
301304 Medical biology

Keywords

Animals
Cyclooxygenase 1/metabolism
Thrombosis/drug therapy
Eicosapentaenoic Acid/pharmacology
Humans
Blood Platelets/drug effects
Platelet Aggregation/drug effects
Mice
Male
Platelet Adhesiveness/drug effects
Mice, Inbred C57BL
Arteries/pathology

Access to Document

10.1126/scitranslmed.ado0610

Cite this

Mourikis, P., Benkhoff, M., Wildeis, L., Barcik, M., Helten, C., Coman, C., Solari, F. A., Krahn, D., Dannenberg, L., Ahlbrecht, S., Zikeli, D., Utz, A., Trojovsky, K., Richter, H., Al Kassis, G., M'Pembele, R., Zako, S., Huckenbeck, T., Bauer, S., ... Polzin, A. (2025). Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity. Science Translational Medicine, 17(799). https://doi.org/10.1126/scitranslmed.ado0610

@article{6f79bec9e33947a180f3947bb31f1aff,

title = "Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity",

abstract = "Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)-deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA's inhibitory effects was confirmed by platelet-specific COX-1-deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.",

keywords = "Animals, Cyclooxygenase 1/metabolism, Thrombosis/drug therapy, Eicosapentaenoic Acid/pharmacology, Humans, Blood Platelets/drug effects, Platelet Aggregation/drug effects, Mice, Male, Platelet Adhesiveness/drug effects, Mice, Inbred C57BL, Arteries/pathology",

author = "Philipp Mourikis and Marcel Benkhoff and Laura Wildeis and Maike Barcik and Carolin Helten and Cristina Coman and Solari, \{Fiorella A\} and Daniel Krahn and Lisa Dannenberg and Samantha Ahlbrecht and Dorothee Zikeli and Amelie Utz and Kajetan Trojovsky and Hannah Richter and \{Al Kassis\}, Gabrielle and Ren{\'e} M'Pembele and Saif Zako and Tim Huckenbeck and Sofia Bauer and Danny Schmitz and Susanne Pfeiler and Norbert Gerdes and Christof D{\"u}cker and Joachim Pircher and Zhang Zhe and Manuela Thienel and \{Ul Ain\}, Qurrat and Petra Keul and Nicholas Kirkby and Dennis Sohn and Wilfried Budach and Thomas Hohlfeld and Karsten Schr{\"o}r and Bodo Levkau and Tobias Zeus and Verhelst, \{Steven H L\} and Robert Ahrends and Albert Sickmann and Jane Mitchell and Samia Mora and Manson, \{JoAnn E\} and Bhatt, \{Deepak L\} and Ulf Landmesser and Steffen Massberg and Malte Kelm and Tobias Petzold and Amin Polzin",

note = "Accession Number WOS:001491858400002 PubMed ID 40397711",

year = "2025",

month = may,

day = "21",

doi = "10.1126/scitranslmed.ado0610",

language = "English",

volume = "17",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "AMER ASSOC ADVANCEMENT SCIENCE",

number = "799",

}

Mourikis, P, Benkhoff, M, Wildeis, L, Barcik, M, Helten, C, Coman, C, Solari, FA, Krahn, D, Dannenberg, L, Ahlbrecht, S, Zikeli, D, Utz, A, Trojovsky, K, Richter, H, Al Kassis, G, M'Pembele, R, Zako, S, Huckenbeck, T, Bauer, S, Schmitz, D, Pfeiler, S, Gerdes, N, Dücker, C, Pircher, J, Zhe, Z, Thienel, M, Ul Ain, Q, Keul, P, Kirkby, N, Sohn, D, Budach, W, Hohlfeld, T, Schrör, K, Levkau, B, Zeus, T, Verhelst, SHL, Ahrends, R, Sickmann, A, Mitchell, J, Mora, S, Manson, JE, Bhatt, DL, Landmesser, U, Massberg, S, Kelm, M, Petzold, T & Polzin, A 2025, 'Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity', Science Translational Medicine, vol. 17, no. 799. https://doi.org/10.1126/scitranslmed.ado0610

TY - JOUR

T1 - Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity

AU - Mourikis, Philipp

AU - Benkhoff, Marcel

AU - Wildeis, Laura

AU - Barcik, Maike

AU - Helten, Carolin

AU - Coman, Cristina

AU - Solari, Fiorella A

AU - Krahn, Daniel

AU - Dannenberg, Lisa

AU - Ahlbrecht, Samantha

AU - Zikeli, Dorothee

AU - Utz, Amelie

AU - Trojovsky, Kajetan

AU - Richter, Hannah

AU - Al Kassis, Gabrielle

AU - M'Pembele, René

AU - Zako, Saif

AU - Huckenbeck, Tim

AU - Bauer, Sofia

AU - Schmitz, Danny

AU - Pfeiler, Susanne

AU - Gerdes, Norbert

AU - Dücker, Christof

AU - Pircher, Joachim

AU - Zhe, Zhang

AU - Thienel, Manuela

AU - Ul Ain, Qurrat

AU - Keul, Petra

AU - Kirkby, Nicholas

AU - Sohn, Dennis

AU - Budach, Wilfried

AU - Hohlfeld, Thomas

AU - Schrör, Karsten

AU - Levkau, Bodo

AU - Zeus, Tobias

AU - Verhelst, Steven H L

AU - Ahrends, Robert

AU - Sickmann, Albert

AU - Mitchell, Jane

AU - Mora, Samia

AU - Manson, JoAnn E

AU - Bhatt, Deepak L

AU - Landmesser, Ulf

AU - Massberg, Steffen

AU - Kelm, Malte

AU - Petzold, Tobias

AU - Polzin, Amin

N1 - Accession Number WOS:001491858400002 PubMed ID 40397711

PY - 2025/5/21

Y1 - 2025/5/21

N2 - Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)-deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA's inhibitory effects was confirmed by platelet-specific COX-1-deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.

AB - Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)-deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA's inhibitory effects was confirmed by platelet-specific COX-1-deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.

KW - Animals

KW - Cyclooxygenase 1/metabolism

KW - Thrombosis/drug therapy

KW - Eicosapentaenoic Acid/pharmacology

KW - Humans

KW - Blood Platelets/drug effects

KW - Platelet Aggregation/drug effects

KW - Mice

KW - Male

KW - Platelet Adhesiveness/drug effects

KW - Mice, Inbred C57BL

KW - Arteries/pathology

UR - https://www.scopus.com/pages/publications/105006416469

U2 - 10.1126/scitranslmed.ado0610

DO - 10.1126/scitranslmed.ado0610

M3 - Article

C2 - 40397711

SN - 1946-6234

VL - 17

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 799

ER -

Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

Keywords

Access to Document

Other files and links

Fingerprint

Cite this