Background
Studies on the use of polyunsaturated omega-3 fatty acids (PUFAs) to reduce cardiovascular events have yielded inconsistent results. Varied dosages and PUFA combinations (eicosapentaenoic acid (EPA) alone vs. EPA + docosahexaenoic acid (DHA)) further complicate the interpretation of these findings. Moreover, the mechanisms contributing to a potential reduction in cardiovascular risk remain insufficiently investigated. Studies utilizing pure EPA preparations have demonstrated greater benefits compared to those involving EPA+DHA combinations. Concurrently, bleeding events were increased under EPA therapy. We therefore hypothesize that EPA inhibits platelet activity, thereby contributing to the reduction of cardiovascular events.
Methods
To analyze the impact of EPA on platelet function, we utilized a murine in vivo model of arterial thrombosis in wild-type and platelet cyclooxygenase-1 (COX-1)-deficient mice. In human platelets, we evaluated adhesion, degranulation, and aggregation in vitro, and performed binding assays. In a clinical cohort, we investigated the impact of switching from an EPA preparation to an EPA+DHA combination preparation.
Results
EPA inhibits arterial thrombus formation in mice in vivo. In human platelets, EPA inhibits adhesion, degranulation, and aggregation following arachidonic acid stimulation in vitro in a concentration-dependent manner. In a binding assay, we demonstrated that EPA competitively competes with arachidonic acid for the active site of COX-1. This mechanism of action was confirmed by the fact that EPA showed no effect on arterial thrombosis formation in vivo in COX-1-deficient mice. In a human cohort, we showed that the initiation of EPA medication (2 g per day) is associated with a reduction in arachidonic acid-induced platelet aggregation and degranulation, whereas switching from an EPA preparation to a low-dose EPA+DHA combination preparation (460 mg EPA and 380 mg DHA) abolished this effect.
Conclusion
Our analyses demonstrate that EPA inhibits platelet function in a concentration-dependent manner via a competitive interaction with arachidonic acid for the active site of COX-1. This results in stronger platelet inhibition by a high-dose EPA preparation compared to an EPA+DHA combination preparation in patients. This mechanism presumably contributes to the cardiovascular risk reduction observed with EPA and explains the discrepant findings in PUFA studies.
