See article vol. 24: 1016–1022
In recent years, there have been sporadic reports suggesting the involvement of serum polyunsaturated fatty acid (PUFA) levels in the development and/or suppression of ischemic heart diseases1–3); however, no consensus has been reached from the results of published clinical studies investigating the suppressive effect of intervention, namely, therapy with PUFAs [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], on the risk of atherosclerotic cardiovascular disease (ASCVD)4, 5). On the other hand, there are only a few reports until date on the relationship of the serum levels of PUFAs and plasma EPA/arachidonic acid (AA) ratio with the risk of development of venous thromboembolism (VTE).
Previous basic research has demonstrated a prophylactic effect of oral EPA administration against venous thrombosis6), whereas a small-scale cross-sectional study has shown an increased incidence of pulmonary embolism in patients with low plasma EPA/AA ratios7). In a case-control study, known to yield a high level of evidence among observational researches, the authors found that depression of the serum EPA/AA ratio may contribute to the development of VTE in young individuals8). Although further investigation is needed because of the small size of the study population in the aforementioned study, the results of the study are expected to provide the basis for prevention and treatment of VTE, which poses a serious problem in the clinical practice setting.
The pathogenetic mechanism underlying the association between VTE and low serum EPA/AA ratios, which is the subject of the present study, involves imbalanced bioactivities of PUFAs (n-3 series, n-6 series) in vivo, based on the evidence accumulated through extensive basic and clinical studies9). Localized intravascular inflammation, vascular endothelial dysfunction, and blood coagulation abnormalities have been reported as being involved in the development of VTE, and depression of the serum EPA/AA ratio likely enhances vascular inflammatory reactions, giving rise to vascular endothelial dysfunction and platelet aggregation (Fig. 1 and 2).
Fig. 1.
Physiological Activities of Arachidonic Acid and Eicosapentaenoic Acid
It is well-known that proinflammatory lipid mediators, such as TXA2, PGE2, LTC4, and LTB4, are synthesized from arachidonic acid. On the other hand, eicosanoids biosynthesized from EPA, such as each of the 3-series prostaglandins and the 5-series leukotrienes, act to suppress the inflammation induced by the proinflammatory eicosanoids. Since the action of a metabolite of EPA antagonizes that of arachidonic acid, an inflammation-suppressing physiological environment is formed.
TX = thromboxane; PG = prostaglandin; LT = leukotriene; EPA = eicosapentaenoic acid
Fig. 2.
Anti-thrombotic and Anti-inflammatory Effects of EPA versus AA, and the Effect of an Unbalanced EPA/AA Ratio on the Risk of Development of VTE
AA = arachidonic acid; EPA = eicosapentaenoic acid; PLA = phospholipase; X = thromboxane; PG = prostaglandin; LT = leukotriene; VTE = venous Thromboembolism
A large-scale clinical study to verify whether the serum EPA/AA ratio, which is a marker of the risk of ASCVD development, as suggested by the Japan EPA Lipid Intervention Study (JELIS) in Japanese subjects10), can serve as a predictor of the risk of VTE, or a multicenter randomized controlled clinical trial to verify the prophylactic effect of oral PUFA administration on the risk of VTE is warranted to clarify the association between the serum EPA/AA ratio and the risk of VTE.
Disclosure of Conflict of Interest
S. Tani has received scholarship fund and lecture fee from Mochida Pharmaceutical Company Ltd. and Takeda Pharmaceutical Company Ltd.
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