Clinical Rheumatology

, Volume 38, Issue 9, pp 2443–2450 | Cite as

Influence of different supplementation on platelet aggregation in patients with rheumatoid arthritis

  • Marijana Tomic-Smiljanic
  • Dragan Vasiljevic
  • Aleksandra Lucic-Tomic
  • Nebojsa Andjelkovic
  • Vladimir Jakovljevic
  • Sergey Bolovich
  • Mirjana VeselinovicEmail author
Original Article



Long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) have been reported to reduce platelet aggregation. Our aim was to prospectively assess the potential influence of different supplementation omega-3 PUFA on the antiplatelet effects in rheumatoid arthritis (RA) patients.


The study included 60 patients with RA at the Department of Rheumatology, Clinical Center Kragujevac. Patients were divided into three groups depending on who used concentrated fish oil only or concentrated fish oil in combination with evening primrose oil or control group without supplementation in a period of 3 months. Platelet aggregation was measured using the multiplate analyzer and expressed through the value of adenosine diphosphate (ADP) test, aranchidonic acid–induced aggregation (ASPI) test, thrombin receptor–activating peptide (TRAP) test (to assess baseline platelet aggregation), and the ratio of ADP/TRAP and ASPI/TRAP representing the degree of inhibition of platelet aggregation compared to the basal value. The platelet function analysis in whole blood was performed 18–24 h before starting supplementation and after 90 days. Considerations were taken in the representation of demographic, clinical characteristics, and laboratory parameters between the groups.


Patients who used concentrated fish oil only had a significantly lower value of the ratio of ADP/TRAP (0.68 ± 0.20) compared to patients without supplementation (0.83 ± 0.12; p = 0.008), while there was no statistically significant difference in values of other laboratory parameters of platelet function between other groups.


Co-administration of supplementation-concentrated fish oil may reduce platelet aggregation in adults with RA.

Key Points

• Omega-3 PUFAs are essential for health and are known to possess anti-inflammatory properties, improving cardiovascular health as well as benefiting inflammatory diseases..

• In this paper, we report on anti-aggregation effects n-3 PUFAs and ɤ-linolenic acid in RA.

• The risk of cardiovascular morbidity and mortality is increased in RA, and dietary supplementation of n-3 PUFA may have preventive potential for the cardiovascular management in rheumatoid arthritis.


Fatty acids Platelet aggregation Rheumatoid arthritis 


Compliance with ethical standards




  1. 1.
    Souza PR, Norling LV (2015) Implications for eicosapentaenoic acid- and docosahexaenoic acid-derived resolvins as therapeutics for arthritis. Eur J Pharmacol 785:165–173. CrossRefPubMedGoogle Scholar
  2. 2.
    Hollan I, Dessein PH, Ronda N, Wasko MC, Svenungsson E, Agewall S, Cohen-Tervaert JW, Maki-Petaja K, Grundtvig M, Karpouzas GA, Meroni PL (2015) Prevention of cardiovascular disease in rheumatoid arthritis. Autoimmun Rev pii S1568-9972(15):00135–00134. CrossRefGoogle Scholar
  3. 3.
    Peters M, Symmons D, McCarey D, Dijkmans B, Nicola P, Kvien T et al (2010) EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 69:325–331CrossRefPubMedGoogle Scholar
  4. 4.
    Miles EA, Calder PC (2012) Influence of marine n-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr 107(Suppl 2):171–184CrossRefGoogle Scholar
  5. 5.
    Calder PC (2013) Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J ClinPharmacol 75(3):645–662Google Scholar
  6. 6.
    Mozaffarian D, Wu JH (2012) (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 142(3):614–625CrossRefGoogle Scholar
  7. 7.
    Bachmair EM, Ostertag LM, Zhang X, de Roos B (2014) Dietary manipulation of platelet function. PharmacolTher. 144(2):97–113Google Scholar
  8. 8.
    Byelashov OA, Sinclair AJ, Kaur G (2015) Dietary sources, current intakes, and nutritional role of omega-3 docosapentaenoic acid. Lipid Technol 27(4):79–82CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Larson MK, Shearer GC, Ashmore JH, Anderson-Daniels JM, Graslie EL, Tholen JT, Vogelaar JL, Korth AJ, Nareddy V, Sprehe M, Harris WS (2011) Omega-3 fatty acids modulate collagen signaling in human platelets. Prostaglandins Leukot Essent Fatty Acids 84:93–98CrossRefPubMedGoogle Scholar
  10. 10.
    Mozaffarian D, Marchiolo R, Gardner T et al (2011) The omega-3 fatty acids for prevention of post-operative atrial fibrillation (OPERA) trial—rationale and design. Am Heart J 162:56–63CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wachira JK, Larson MK, Harris WS (2014) n-3 Fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. Br J Nutr 111(9):1652–1662CrossRefPubMedGoogle Scholar
  12. 12.
    Ho KK, Abrams-Ogg AC, Wood RD, O'Sullivan ML, Kirby GM, Blois SL (2015) Assessment of platelet function in healthy sedated cats using three whole blood platelet function tests. J Vet DiagnInvest 27(3):352–360. CrossRefGoogle Scholar
  13. 13.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TWJ, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581CrossRefPubMedGoogle Scholar
  14. 14.
    Pullman-Mooar S, Laposata M, Lem D, Holman RT, Leventhal LJ, Demarco D, Zurier RB (1990) Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma-linolenic acid. Arthritis Rheum 33:1526–1533CrossRefPubMedGoogle Scholar
  15. 15.
    Mohebi-Nejad A, Bikdeli B (2014) Omega-3 supplements and cardiovascular diseases. Tanaffos 13(1):6–14PubMedPubMedCentralGoogle Scholar
  16. 16.
    Harris WS, Von Schacky C (2004) The omega-3 index: a new risk factor for death from coronary heart disease? Prev Med 39:212–220CrossRefPubMedGoogle Scholar
  17. 17.
    Jabbar R, Saldeen T (2006) A new predictor of risk for sudden cardiac death. Ups J Med Sci 111:169–177CrossRefPubMedGoogle Scholar
  18. 18.
    Dawczynski C, Hackermeier U, Viehweger M, Stange R, Springer M, Jahreis G (2011) Incorporation of n-3 PUFA and γ-linolenic acid in blood lipids and red blood cell lipids together with their influence on disease activity in patients with chronic inflammatory arthritis--a randomized controlled human intervention trial. Lipids Health Dis 10:130CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D (2008) Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 59:1690–1697CrossRefPubMedGoogle Scholar
  20. 20.
    Meune C, Touzé E, Trinquart L, Allanore Y (2009) Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford) 48:1309–1313CrossRefGoogle Scholar
  21. 21.
    Nomura S, Inami N, Shouzu A, Omoto S, Kimura Y, Takahashi N, Tanaka A, Urase F, Maeda Y, Ohtani H, Iwasaka T (2009) The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectinhyperlipidemic, diabetic patients. Platelets 20:16–22CrossRefPubMedGoogle Scholar
  22. 22.
    Gao LG, Cao J, Mao QX, Lu XC, Zhou XL, Fan L (2013) Influence of omega-3 polyunsaturated fatty acid-supplementation on platelet aggregation in humans: a meta-analysis of randomized controlled trials. Atherosclerosis 226(2):328–334CrossRefPubMedGoogle Scholar
  23. 23.
    Takada K, Ishikawa S, Yokoyama N, Hosogoe N, Isshiki T (2014) Effects of eicosapentaenoic acid on platelet function in patients taking long-term aspirin following coronary stent implantation. Int Heart J 55(3):228–233CrossRefPubMedGoogle Scholar
  24. 24.
    Wiktorowska-Owczarek A, Berezińska M, Nowak JZ (2015) PUFAs: structures, metabolism and functions. AdvClinExp Med 24(6):931–941. CrossRefGoogle Scholar
  25. 25.
    Gajos G, Zalewski J, Nessler J, Zmudka K, Undas A, Piwowarska W (2012) Polyunsaturated omega-3 fatty acids improve responsiveness to clopidogrel after percutaneous coronary intervention in patients with cytochrome P450 2C19 loss-of-function polymorphism. Kardiol Pol 70(5):439–445PubMedGoogle Scholar
  26. 26.
    Fer M, Corcos L, Dréano Y, Plée-Gautier E, Salaün JP, Berthou F, Amet Y (2008) Cyttochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J Lipid Res 49(11):2379–2389CrossRefPubMedGoogle Scholar
  27. 27.
    Arnold C, Konkel A, Fischer R, Schunck WH (2010) Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol Rep 62:536–547CrossRefPubMedGoogle Scholar
  28. 28.
    Larson MK, Tormoen GW, Weaver LJ, Luepke KJ, Patel IA, Hjelmen CE, Ensz NM, McComas LS, McCarty OJ (2013) Exogenous modification of platelet membranes with the omega-3 fatty acids EPA and DHA reduces platelet procoagulant activity and thrombus formation. Am J Physiol Cell Physiol 304(3):C273–C279CrossRefPubMedGoogle Scholar
  29. 29.
    Serebruany VL, Miller M, Pokov AN, Lynch D, Jensen JK, Hallén J, Atar D (2011) Early impact of prescription Omega-3 fatty acids on platelet biomarkers in patients with coronary artery disease and hypertriglyceridemia. Cardiology 118:187–194CrossRefPubMedGoogle Scholar
  30. 30.
    Phang M, Sinclair AJ, Lincz LF, Garg ML (2012) Gender-specific inhibition of platelet aggregation following omega-3 fatty acid supplementation. NutrMetabCardiovasc Dis 22(2):109–114Google Scholar
  31. 31.
    Phang M, Lincz LF, Garg ML (2013) Eicosapentaenoic and docosahexaenoic acid supplementations reduce platelet aggregation and hemostatic markers differentially in men and women. J Nutr 143(4):457–463CrossRefPubMedGoogle Scholar
  32. 32.
    Bagge A, Schött U, Kander T (2016) Effects of naturopathic medicines on multiplate and ROTEM: a prospective experimental pilot study in healthy volunteers. BMC Complement Altern Med 16:64CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  1. 1.Public Health CenterDZ RakovicaBelgradeSerbia
  2. 2.Faculty of Medical Sciences, Department of Hygiene and EcologyUniversity of KragujevacKragujevacSerbia
  3. 3.Faculty of Medical Sciences, Department of Internal medicineUniversity of KragujevacKragujevacSerbia
  4. 4.Faculty of Medical Sciences, Department of PhysiologyUniversity of KragujevacKragujevacSerbia
  5. 5.Department of Human Pathology, 1st Moscow State MedicalUniversity IM SechenovMoscowRussia

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