Inhibition of platelet aggregation and thromboxane synthesis after intake of small amount of icosapentaenoic acid

doi:10.1016/0049-3848(84)90295-0

Thrombosis Research

Volume 36, Issue 5, 1 December 1984, Pages 389-396

https://doi.org/10.1016/0049-3848(84)90295-0 Get rights and content

Abstract

Elderly people ingested 150 mg/day of icosapentaenoic acid (20:5n-3) or a placebo for one month. Platelet aggregation, platelet arachidonate metabolism and the fatty acid composition of both plasma and platelet lipids were investigated before and after the intake. Platelet aggregation induced by collagen, epinephrine or low concentrations of ADP was significantly reduced after 20:5n-3 intake. Besides, the main oxygenated product formation from endogenous platelet arachidonate under thrombin stimulation was markedly decreased after the 20:5n-3 supplementation. Such a decrease was absent after placebo. Moreover, no modification in the fatty acid composition of both plasma lipids and platelet phosphatidylcholine could be observed. We conclude that intake of low amounts of 20:5n-3 by elderly people, is able to lower their platelet sensitivity to aggregating agents, probably by decreasing the endogenous formation of platelet thromboxane A₂, although no modification in the fatty acid composition was detected.

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On the opposite of increased platelet activation, moderate concentrations of long-chain omega-3 PUFA (EPA and DHA) may lower such activation, although these PUFA are usually considered as highly sensitive to peroxidation [74]. Indeed, low intake of EPA by elderly people, who show elevated oxidative stress, including in platelets, significantly decreased platelet aggregation and thromboxane production [75], likely through platelet vitamin E protection, resulting in its elevation [76]. This could be reproduced with normal platelets in vitro [77].
The oxygenation metabolism of arachidonic acid (ArA) has been early described in blood platelets, in particular with its conversion into the potent labile thromboxane A₂ that induces platelet aggregation and vascular smooth muscle cells contraction. In addition, the primary prostaglandins D₂ and E₂ have been mainly reported as inhibitors of platelet function. The platelet 12-lipoxygenase (12-LOX) product, i.e. the hydroperoxide 12-HpETE, appears to stimulate platelet ArA metabolism at the level of its release from membrane phospholipids through phospholipase A₂ (cPLA₂) and cyclooxygenase (COX-1) activities, the first enzymes in prostanoid production cascade. Also, 12-HpETE may regulate the oxygenation of other polyunsaturated fatty acids (PUFA) by platelets, especially that of eicosapentaenoic acid (EPA). On the other hand, the reduced product of 12-HpETE, 12-HETE, is able to antagonize TxA₂ action. This is even more obvious for the 12-LOX end-products from docosahexaenoic acid (DHA), 11- and 14-HDoHE. In addition, 12-HpETE plays a key role in platelet oxidative stress as observed in pathophysiological conditions, but may be regulated by DHA with a bimodal way according to its concentration. Other oxygenated products of PUFA, especially omega-3 PUFA, produced outside platelets may affect platelet functions as well.
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Omega-3 fatty acids are widely used. This article reviews the coagulopathic effects of fish oil.
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After supplementation with EPA, von Schacky and Weber [7] found a decreased platelet reactivity and an increased docosapentaenoic acid (DPA; 22:5ω3), an intermediate between EPA and DHA (Fig. 1). In addition, low intake of EPA may reduce platelet aggregation, without changing the fatty acid platelet composition [64,65]. In the same way, following supplementation with DHA [7], platelet function was reduced and a retroconversion of DHA into DPA and EPA was evidenced.
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Of note, this antioxidant effect was also observed in pregnancy [20]. Finally, the Lagarde and Calzada group proposed a threshold below which PUFA supplementation results in antioxidant actions and above which pro-oxidant activities take place [24–26]. Very recently, EPA and DHA supplementation was shown to lower plasma lipoperoxide concentrations in mild cognitive impairment patients [27].
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However, our meta-analysis showed that decreases were usually shorter term (less than 8 weeks) and/or when using lower dosage of n-3 PUFAs. Small doses of n-3 PUFAs have documented inhibitory effects on platelet function while causing no changes in plasma lipids or lipoproteins [26]. The data obtained from a recent study strongly indicate that not only total concentrations of n-3 PUFAs in the platelet compartment but also distribution of EPA or DHA in selected phospholipid pools may be responsible for the different platelet responses to collagen [25].
Increased platelet activity predicts adverse cardiovascular events. The objective was to assess the effects of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA)-supplementation on platelet aggregation.
We conducted a meta-analysis of randomized controlled trials identified using PubMed, Embase and the Cochrane Library. Fifteen studies were included. In comparison to placebo using the random-effect model, n-3 PUFA-supplementation significantly reduced adenosine diphosphate-induced platelet aggregation (standard mean difference [SMD] = −1.23 with 95% confidence interval [CI] −2.24 to −0.23, p = 0.02) and platelet aggregation units, determined using the VerifyNow^® rapid platelet-function assay system (SMD = −6.78 with 95% CI −12.58 to −0.98, p = 0.02). There was a trend toward decreased collagen-induced (SMD = −0.70 with 95% CI −0.72 to 0.33, p = 0.18) and arachidonic acid-induced platelet aggregation (SMD = −0.43 with 95% CI −2.26 to 1.40, p = 0.64) compared with controls; however, statistical significance was not reached.
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PaperInhibition of platelet aggregation and thromboxane synthesis after intake of small amount of icosapentaenoic acid

Abstract

The Lancet

The Lancet

Blood

The Lancet

Thrombos. Res.

Thrombos. Res.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Selective release of arachidonic acid from the ohospholipids of human platelets in response to thrombin

J. Clin. Invest.

Thromboxanes : a new group of biologically active compounds derived from prostaglandin endoperoxide

Paper
Inhibition of platelet aggregation and thromboxane synthesis after intake of small amount of icosapentaenoic acid