Cardiovascular disease (CVD) is the leading cause of death globally, accounting for 1 in 4 deaths (Tsao et al., 2023). Cardiovascular events, such as myocardial infarction and stroke, occur as a result of hyperactive platelet clotting, leading to vessel-occluding thrombus formation. Therapies that are currently available attempt to decrease platelet reactivity by regulating one, or a combination of, five targets in the platelet: two enzymes cyclooxygenase-1 (COX-1) and phosphodiesterase (PDE), and three receptors protease-activated receptor-1 (PAR1), purinergic receptor (P2Y12), and integrin receptor αIIbβ3 (Yeung, Li, & Holinstat, 2018). While these therapeutic approaches have significantly decreased morbidity and mortality arising from cardiovascular events triggered by thrombosis, CVD remains a major cause of death. Furthermore, although current approaches modulate platelet activity, they may result in an increased risk of bleeding due to decreased hemostatic capabilities (Dawson et al., 2022). Therefore, there is continued need for novel anti-platelet therapeutics that effectively reduce the risk of a thrombotic event without affecting hemostatic potential.

The cardioprotective effects of polyunsaturated fatty acids (PUFAs) were first reported in observational studies involving supplementation with omega-3 fatty acids (Adkins & Kelley, 2010; Daviglus et al., 1997; von Schacky, 2003; Von Schacky & Harris, 2007). When incorporated into the phospholipid membrane of the cell, PUFAs can be metabolized into bioactive oxidized lipids (oxylipins). In platelets, activation increases intracellular levels of calcium to activate cytosolic phospholipase A2 (cPLA2) and translocate it to the platelet membrane, where cPLA2 can cleave the membrane PUFAs and release free fatty acids (Leslie, 1997). These free fatty acids are metabolized within the platelet by oxygenase enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s (CYP450s) to form oxylipins.

While there is evidence that both the omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPAn-3), and docosahexanoic acid (DHA) as well as the omega-6 PUFAs arachidonic acid (AA), linoleic acid (LA), docosapentaenoic acid (DPAn-6), and dihomo-γ-linolenic acid (DGLA) regulate platelet function through their oxylipins (Lagarde et al., 2013; Thorngren & Gustafson, 1981; Yamaguchi et al., 2021; Yeung et al., 2016; Yeung et al., 2020), a better understanding of the mechanisms by which PUFAs regulate platelet reactivity through the formation of oxylipins will help to uncover novel pathways within the platelet for targeting platelet reactivity in CVD. This review will cover the oxygenase pathways, effects of the oxylipins in the platelet and how we can utilize the mechanisms of the oxylipins to pharmacologically regulate platelet activity.