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The Mechanism for How Omega-3 Fatty Acids (Fish Oil) Could Increase the Risk of Bleeding

Summary:

  • Fish oil has been used to treat a number of conditions which include asthma, diabetes mellitus, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, hyperlipidemia and cardiovascular disease.
  • Omega-3 fatty acids include docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 22:5n-3) and for the most part, neither DHA nor EPA cause any major side effects or clinically relevant drug interactions, but are known to influence platelet function.
  • In patients who take fish oil supplements, the omega-3 fatty acids compete with AA (20:4n-6) for incorporation into the platelet cell membranes, thereby increasing the ratio of omega-3 fatty acids:AA.
  • As such, when DHA and EPA are utilized the balance or preference is shifted towards a greater degree of prostaglandin I2 production (also called PGI2 or prostacyclin) which has local vasodilatory and antiplatelet effects.  In addition, there is less formation of TXA2 and platelet activating factor which are both known to activate platelets.
  • All of these effects translate to increases in bleeding time and a reduction in ADP, collagen and epinephrine induced platelet aggregation in patients taking omega-3 fatty acid supplements.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewer:
Donald S.Nuzum, PharmD, BCACP, CDE
Last Reviewed:
October 2015

Explanation

  • Fish oil has been used to treat a number of conditions, which include asthma, diabetes mellitus, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, hyperlipidemia and cardiovascular disease (CVD).1-6 As it relates to CVD, fish oil is most commonly used to treat high triglycerides (hypertriglyceridemia).  When clinicians refer to the use of "fish oil", they are generally referring to omega-3 fatty acids (also known as polyunsaturated fatty acids (PUFA)).  These specific omega-3 fatty acids include docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 22:5n-3).7  For the most part, neither DHA nor EPA cause any major side effects or clinically relevant drug interactions, but they are known to influence platelet function.  As such, some clinicians perceive that this can put the patient at greater risk of bleeding, especially during surgical procedures or while on other medications that are known to affect coagulation and platelet aggregation.  

           

    How do omega-3 fatty acids affect platelet function and possibly increase the risk for bleeding in certain situations?
    After a platelet has been activated, a number of intracellular reactions and changes take place to prepare the platelet for binding during the formation of a primary hemostatic plug, and to help recruit or activate other nearby platelets.  One of these intracellular reactions is the metabolism/utilization of cell membrane fatty acids to form various eicosanoids, in particular thromboxane A2 (TXA2).   It is well known that TXA2 is a platelet activator and is used to facilitate platelet aggregation.  However, the type of membrane fatty acid utilized can influence which metabolic pathway(s) within eicosanoid biochemical synthesis predominates.  In humans, one of the essential fatty acids required and used in cell membranes is the omega-6 fatty acid, arachidonic acid (AA).  However, in patients who take fish oil supplements, the omega-3 fatty acids compete with AA for incorporation into the platelet cell membranes, thereby increasing the ratio of omega-3 fatty acids:AA.8-10  This is important because phospholipase A2 will then cleave more omega-3 fatty acids from the cell membrane when needing to activate the ecosanoid intracellular pathway.  The omega-3 fatty acids (DHA and EPA) differ from AA in the number of double bonds present and the location of the first double bond in relation to the omega end of the fatty acid.7  Docosahexanoic acid has 6 double bonds and EPA has 5 double bonds, both with the first double bond starting at carbon 3; whereas, AA has only 4 double bonds which start at carbon 6.7  Furthermore, both DHA and EPA are 22 carbons long whereas AA is 20 carbons long.7  This is the rationale for their respective names DHA (22:6n-3), EPA (22:5n-3) and AA (20:4n-6).  

    Why do these structural differences in fatty acids matter? 
    The various enzymes within the ecosanoid pathway have differential binding affinities or preference for each of the types of fatty acids.  As such, when DHA and EPA are utilized the balance or preference is shifted towards a greater degree of prostaglandin I2 production (also called PGI2or prostacyclin) which has local vasodilatory and antiplatelet effects.11  In addition, there is less formation of TXA2 which is known to activate platelets.11  It is important to recognize that this process also occurs within the vascular endothelial lining thereby creating an imbalance towards the formation of antiplatelet ecosanoids (PGI2) versus TXA2.11  This shift in the balance of ecosanoids is also a product of omega-3 fatty acids being able to suppress platelet activating factor (PAF), a potent platelet activator.11,12  All of these effects translate to increases in bleeding time and a reduction in ADP, collagen and epinephrine induced platelet aggregation in patients taking omega-3 fatty acid supplements.9,10

    Therefore, it is biologically plausible that the use of fish oil supplements or prescription omega-3 fatty acids could put certain patients at unwanted or unnecessary risk for bleeding.  However, in patients with underlying cardiovascular disease and/or hypertriglyceridemia this biologic effect may be beneficial.  Part 2 of this series will answer the question of whether the use of omega-3 fatty acids actually does cause more bleeding, especially in surgical patients or patients taking an anticoagulant or antiplatelet agent.

    References:

    1. Woods RK, Thien FC, Abramson MJ.  Dietary marine fatty acids (fish oil) for asthma in adults and children.  Cochrane Database Syst Rev  2002;3:CD001283.
    2. Sirtori CR, Crepaldi G, Manzato E et al.  One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: reduced triglyceridemia, total cholesterol, and increased HDL-c without glycemic alterations.  Atherosclerosis  1998;137:419-27.
    3. Kremer JM, Bigauoette J, Michalek AV et al.  Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis.  Lancet  1985;1:184-7.
    4. Belluzzi A, Brignola C, Campieri M et al.  Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease.  N Engl J Med  1996;334:1557-60.
    5. He K, Song Y, Daviglus ML et al.  Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies.  Circulation  2004;109:2705-11.
    6. Bays HE.  Safety considerations with omega-3 fatty acid therapy.  Am J Cardiol 2007;99:35C-43C.
    7. Leiberman M, Marks AD, eds.  Mark's Basic Medical Biochemistry A Clinical Approach.  3rd Ed.  Philadelphia, PA: Lippincott Williams & Wilkins; 2009:479-566.
    8. Kim DN, Eastman A, Baker JE et al.  Fish oil, atherogenesis, and thrombogenesis.  Ann N Y Acad Sci  1995;748:474-80. 
    9. Goodnight SH Jr, Harris WS, Connor WE.  The effects of dietary omega 3 fatty acids on platelet composition and function in man: a prospective, controlled study.  Blood  1981;58:880-5. 
    10. Lorenz R, Spengler U, Fischer S et al. Platelet function, thromboxane formation and blood pressure during supplementation of the Western diet with cod liver oil.  Circulation  1983;67:504-11. 
    11. DeCaterina R, Giannessi D, Mazzone A et al.  Vascular prostacyclin is increased in patients ingesting omega-3 polyunsaturated fatty acids before coronary artery bypass graft surgery.  Circulation  1990;82:428-38. 
    12. Torrejon C, Jung UJ, Deckelbaum RJ.  N-3 fatty acids and cardiovascular disease:  actions and molecular mechanisms.  Prostaglandins Leukot Essent Fatty Acids  2007;77:319-26.

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MESH Terms & Keywords

  • Fish Oil, Omega-3 Fatty Acids, EPA, DHA, Fish Oil Mechanism for Bleeding