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Thromb Haemost
DOI: 10.1055/a-2746-4552
Original Article: Cellular Haemostasis and Platelets

Free Fatty Acids Link Residual Lipid and Thrombotic Risk via Impairment of Aspirin Antiplatelet Effects

Authors

  • Philipp Mourikis‡   ‡

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Saif Zako‡   ‡

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Carolin Helten

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Laura Wildeis

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • David Beenken

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Marcel Benkhoff

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
    2   Institute of Analytical Chemistry, University of Vienna, Vienna, Austria

  • Christoph Dücker

    3   Institute for Clinical Pharmacology, University Medical Center, Georg-August University, Göttingen, Germany

  • Lisa Dannenberg

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Norbert Gerdes

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Tobias Zeus

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany

  • Malte Kelm

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
    4   Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany

  • Thomas Hohlfeld

    5   Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Dusseldorf, Germany

  • Amin Polzin

    1   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany
    4   Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany
    6   National Heart and Lung Institute, Imperial College London, London, United Kingdom

Funding Information This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No. 46-2016 and 29-2019 to L.D., No. 16-2014 and 18-2019 to A.P., No. 2020-51 to C.H., No. 2021-01 to P.M.), funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – grant no. 493659010 to P.M., grant no. 530690968 to M.B., grant no. 236177352- SFB 1116 (PO 2247/1-1) to A.P. and SFB1116 to A.P. (subproject B11), grant no. 493400536 to A.P., 413659045 to A.P, and 510844896 to A.P.
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Graphical Abstract

Abstract

Background

Insufficient lipid-lowering therapy is associated with residual cardiovascular risk. Low-density lipoprotein (LDL) is well known to promote atherosclerosis and cardiovascular disease (CVD) and during lipoprotein metabolism, free fatty acids (FFA) are generated. Besides this, residual thrombotic risk occurs in patients with impaired pharmacodynamic response to aspirin—so-called high on-treatment platelet reactivity (HTPR). Until now, it is not known if there is a mutual link.

Methods

For in vitro analyses, blood from healthy donors was used and incubated with different concentrations of LDL, FFA, and acetylsalicylic acid. Arachidonic acid (AA)-induced light transmittance aggregometry (LTA), thromboxane (TX) formation, and cyclooxygenase (COX)-1 activity were measured. In a cross-sectional analysis, aspirin antiplatelet effects, and LDL and FFA concentrations were measured in 612 aspirin-treated CVD patients.

Results

In vitro administration of LDL and FFA impaired aspirin antiplatelet effects. In patients, FFA levels were associated with HTPR to aspirin. FFA levels and plasma LDL correlated with AA-induced platelet aggregation. Statin medication improved aspirin antiplatelet effects. AA-induced platelet aggregation was decreased in patients with statin medication.

Conclusion

In this study, we were able to demonstrate a link between residual lipid and thrombotic risk in patients with cardiovascular disease. We could show that LDL and FFA impair pharmacodynamic response to aspirin at the level of COX. Statin therapy improved aspirin antiplatelet effects.

Keywords

aggregation - aspirin - platelet activation - platelet inhibition - statins

Ethical Approval

The study conformed to the Declaration of Helsinki and was approved by the University of Düsseldorf Ethics Committee.


‡ These authors contributed equally to this article.


Supplementary Material



Publication History

Received: 20 June 2025

Accepted after revision: 12 November 2025

Article published online:
04 December 2025

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