Topic of the Month

The effect of water-soluble tomato concentrate and marine omega-3 fatty acids on platelet activation

September 1, 2015

Platelet activation and aggregation play an integral role in hemostasis and thrombosis. Overactivation can lead to the formation of large thrombi and the blockage of essential blood vessels. Certain micronutrients are able to actively intervene in the biochemical clotting cascade, including the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and water-soluble tomato concentrate, and may therefore be beneficial to cardiovascular health.

Cardiovascular disease is the leading cause of death worldwide. Platelet activation and aggregation play an integral role in hemostasis and thrombosis. Platelets are lens-shaped structures measuring 2–3 µm in diameter that do not have a nucleus and are formed from fragments of cytoplasm derived from the megakaryocytes of bone marrow. Platelet aggregation is a key process in blood clotting. However, excess aggregation can result in the formation of thrombi, which in turn can block the blood vessels and lead to necrosis of local tissues. Platelet hyperactivity can compromise circulation, accelerate atherosclerotic plaque development, and further increase the risk of cardiovascular disease (CVD).

It is currently thought that diets and nutrients may play a role in preventing and/or ameliorating cardiovascular disease (CVD), particularly due to their effects on platelet function. Diets such as the Mediterranean diet and vegetarian diet have inverse relationships with incidence of CVD. Dark chocolate, garlic, ginger, marine omega-3 fatty acids, onion, purple grape juice, tomatoes, and wine all reduce platelet aggregation (1).

Damage to the endothelium of the blood vessels leads to the exposure of collagen. Platelets will stick to the collagen and then become activated, releasing thromboxane A2 (TX A2), an eicosanoid derived from membrane arachidonic acid, which in turn attracts more platelets. Subsequently, fibrous strands of a protein called fibrin develop on top of those platelets. A thrombus (clot) is formed when red blood cells become trapped within fibrin mesh and are then themselves covered in further fibers. This process repeats itself many times, causing a thrombus to form (2).

The first stage in platelet aggregation is a change in the shape of the platelets, which allows them to become sticky and adhere to one another. Second, the platelets express proteins on their cell surface such as P-selectin, which enable the platelets to stick to the blood vessel, and G proteins, which allow the platelets to bind fibrin.

Thromboxane A2 (TXA2) is a product of arachidonic acid (ARA) created through the actions of the enzyme cyclooxygenase (COX). Subsequently, TXA2 mediates the production of ADP and collagen – these molecules further amplify the platelet aggregation process. In addition, TXA2 also stimulates the production of thrombospondin, which is converted to thrombin. Thrombin then converts fibrinogen into fibrin. Clotting factors, including vitamin K-dependent clotting factors, play a role in both of these latter two stages.

Water-soluble tomato concentrate (WTSC) affects platelet aggregation by decreasing the expression of P-selectin and GPIIb/IIIa and the production of TXA2, and inhibiting ADP- and collagen-mediated platelet aggregation. Importantly, these actions are reversible (please see the diagram for further clarity).

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In contrast, aspirin prevents the formation of platelet thromboxane A2 by irreversibly inhibiting the COX enzyme and thus impeding further platelet aggregation. As platelets have no nuclei, they are unable to generate new cyclooxygenase themselves. Enzyme inhibition lasts for the lifetime of the cell (around 10 days) (3). Marine omega 3 fatty acids have long been known to decrease platelet aggregation and moderately prolong bleeding time (3, 4, 5, 6).

A meta-analysis of 15 RCTs by Gao et al (7) in 2013 showed that supplementation with omega-3 polyunsaturated fatty acid significantly reduced adenosine diphosphate-induced platelet aggregation. They also found trends for collagen and arachidonic acid-induced platelet aggregation, but these did not achieve clinical significance.

The European Cardiovascular Society promotes the consumption of marine omega 3 fatty acids in the secondary prevention of cardiovascular disease. It recommends an intake of 1 g fish oil per day in patients who have already suffered a heart attack (8). The European Food Safety Authority (EFSA) recommends a daily intake of at least 250 mg per day of EPA and DHA to help maintain heart health in the general population.

A lycopene- and fat-free WSTC has been developed containing a total of 37 identified ingredients (including nucleosides, nucleotides, glycosides and flavonoids) that have been shown to inhibit aggregation in vitro to varying degrees (9). The EFSA has issued an opinion (10, 11) on this benefit (published in article 13.5 of the current EC Regulation on health claims) which informs readers that a daily intake of 3 g of the liquid WTSC preparation or 150 mg of the powdered equivalent “helps maintain normal platelet aggregation”.

O’Kennedy et al. (12) conducted a randomized, double-blind, placebo-controlled, cross-over study of an intervention of WSTC in 90 healthy patients with normal platelet function. There was a large decrease in both collagen and ADP platelet aggregation three hours after consumption of the WSTC. The effects were greater among men (approx. 22–25%) than women (15–18%), and were dose dependent. Importantly, bleeding time was not affected. Proteomic studies have revealed that WSTC regulates around 50 proteins that have been shown to affect coagulation, structure, oxidative stress and ATP/ADP metabolism.

For comparative purposes, a dose of 162 mg aspirin – a dose often recommended for people thought to be at risk of a heart attack – will inactivate 95% of platelet cyclooxgenase but is also associated with an increased risk of bleeding in the stomach, and hemorrhagic stroke. All these data indicate that tomato contains very potent antiplatelet ingredients, and that consuming tomatoes may be beneficial both as a preventive and therapeutic regime for cardiovascular disease.

References

  1. McEwen BJ, “The influence of diet and nutrients on platelet function”, Semin Thromb Hemost. 2014 Mar;40(2):214-26.
  2. Handwrittentutorials.com, “Hemostasis 1 – Clots, Thrombi and Antiplatelets”, https://www.youtube.com/watch?v=f9Ojq9f2qaM , accessed 14th July 2015.
  3. Harrison N and Abhyankar B, “The Mechanism of Action of Omega-3 Fatty Acids in Secondary Prevention Post-Myocardial Infarction”, Curr Med Res Opin. 2005;21(1):95-100
  4. Agren JJ, Vaisanen S, Hanninen O, et al. Hemostatic factors and platelet Aggregation after a fish-enriched diet or fish oil or docosahexaenoic acid supplementation. Prostaglandins Leukot Essent Fatty Acids 1997;57:419-21
  5. Mori TA, Beilin LJ, Burke V, et al., “ Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease”. Arterioscler Thromb Vasc Biol 1997;17:279-86
  6. Guichardant M, Calzada C, Bernoud-Hubac N et al., “Omega-3 polyunsaturated fatty acids and oxygenated metabolism in atherothrombosis, Biochim Biophys Acta”. 2015 Apr;1851(4):485-495
  7. Gao LG, Cao J, Mao QX et al., “Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials”, Atherosclerosis. 2013 Feb;226(2):328-34
  8. Van de Werf F, Bax J, Betriu A et al, “Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation”, European Heart Journal 20108, 29(23): 2909-2945.
  9. Dutta-Roy AK, Lynn Crosbie L, & Gordon MJ, “Effects of tomato extract on human platelet aggregation in vitro”, Platelets 2001, 12 (4): 218-227
  10. European Food Safety Authority (EFSA), Scientific Opinion of the Panel on Dietetic Priducts, Nutrition and Allergies ona request from Provexis Natural Products Limited on Water-soluble tomato concentrate (WSTC I and II) and platelet aggregation. EFSA Journal 2009, 1101, 1-15.
  11. European Food Safety Authority (EFSA), “Scientific Opinion on the modification of the authorisation of a health claim related to water-soluble tomato concentrate and helps to maintain a healthy blood flow and benefits circulation pursuant to Article 13(5) of Regulation (EC) No 1924/2006 following a request in accordance with Article 19 of the Regulation (EC) No 1924/2006, EFSA Journal 2010; 8(7) 1689
  12. O'Kennedy N, Crosbie, L, Whelan, S et al..”Effects of tomato extract on platelet function: A double-blinded crossover study in healthy humans”, American Journal of Clinical Nutrition 2006, 84(3): 561-569.