The use of herbal or natural medicines is increasing among patients and many of these products share pharmacologic properties with medications that require a prescription.1  It is also well known that oral antiplatelet medications (such as aspirin, clopidogrel, prasugrel, ticlopidine, dipyridamole/aspirin) for the prevention and/or treatment of cardiovascular diseases (CVD) and oral anticoagulants, such as warfarin, for the prevention and/or treatment of thrombotic related disorders are common across the world.  This risk for bleeding due to antiplatelet effects can also be increased with the use of non-steroidal anti-inflammatory drugs (NSAIDs).  Their use may be initiated by a healthcare provider or by patients themselves since they can purchase them over-the-counter (OTC) for any pain related problems.  In fact, the use of self-initiated NSAIDs is fairly common.  According to a survey of 4,263 people in 2002 by the National Consumer League, ibuprofen was the most common OTC medication at 38% of consumers followed by acetaminophen at 33%, aspirin at 16% and naproxen at 9%.2 While in some cases the coadministration of two or more antiplatelet drugs may be medically necessary, use of any of these drugs incurs risk and this risk is compounded when multiple agents are employed.  Therefore, whether intentional or not, the concomitant use of medications that are known to have antiplatelet effects can could put the patient at additional risk for bleeding, especially if they are already taking an anticoagulant. 

Unfortunately, the use of herbal or natural medicines may contribute to these effects without the knowledge of the healthcare provider caring for that patient.  As such, a thorough medication use evaluation should be performed for the purposes of identifying herbal products that may have been initiated by the patient without the knowledge of the clinician.  The table below provides a summary of commonly used herbal and natural medicines that are known to have either antiplatelet properties or to increase the risk of bleeding through other mechanisms known to influence hemostasis.3-26  

It is also important for clinicians to recognize that while many of these herbal products can inhibit platelet aggregation or hemostasis, some of them can also increase the international normalized ratio (INR) in patients taking warfarin.   This could obviously put the patient at even greater risk for clinically relevant bleeding.  Of note, there is wide spread belief that fish oil supplements (omega-3 fatty acids) put the patient at increased risk for bleeding.  The National Lipid Association did a thorough evaluation of the available data and did not find any significant evidence that fish oil supplements confer this effect.12  However, in patients with active or uncontrolled bleeding it would still be prudent to hold the fish oil supplement just in case.12

Based on the table, it is evident that there are many common herbal products that have been shown to have antiplatelet properties and/or influence hemostasis.  EBM Consult hopes that this table provides a user friendly summary of those herbal and natural medicines that may be encountered in clinical practice.

References:

1. National Center for Complementary and Alternative Medicine: National Institutes of Health.  The Use of complementary and alternative medicine in the United States: 2007 National Health Interview Survey Report.  Last accessed on 1-17-2009.
2. Wilcox CM, Cryer B, Triadafilopoulos G.  Patterns of use and public perception of over-the-counter pain relievers: focus on nonsteroidal anti-inflammatory drugs.  J Rheumatol  2005;32:2218-24.
3. Lam AY, Elmer GW, Mohutsky MA.  Possible interaction between warfarin and Lycium barbarum L.  Ann Pharmacother  2001;35:1199-201.
4. Leung H, Hung A, Hui AC et al.  Warfarin overdose due to the possible effects of Lycium barbarum L.  Food Chem Toxicol  2008;46:1860-2.
5. Suvarna R, Pirmohamed M, Henderson L.  Possible interaction between warfarin and cranberry juice.  BMJ  2003;327:1454.
6. Rindone JP, Murphy TW.  Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding.  Am J Ther  2006;13:283-4.
7. Aston JL, Lodoice AE, Shapiro NL.  Interaction between warfarin and cranberry juice.  Pharmacotherapy  2006;26:1314-9.
8. Duthie GG, Kyle JA, Jenkinson AM et al.  Increased salicylate concentrations in urine of human volunteers after consumption of cranberry juice.  J Agric Food Chem  2005;53:2897-900.
9. Chan K, Lo AC, Yeung JH et al.  The effects of Danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats.  J Pharm Pharmacol  1995;47:402-6.
10. Chan TY.  Interaction between warfarin and danshen (Salvia miltiorrhiza).  Ann Pharmacother  2001;35:501-4.
11. Page RL 2^nd, Lawrence JD.  Potentiation of warfarin by dong quai.  Pharmacotherapy  1999;19:870-6.
12. Bays HE.  Safety considerations with omega-3 fatty acid therapy.  Am J Cardiol  2007;99[suppl]:35C-43C.
13. Hendler SS, Rorvik DM.  Flaxseed oil.  In: PDR for Nutritional Supplements.  2^nd Ed.  Physicians' Desk Reference Inc.  Montvale, NJ.  2008:218-221.
14. Cassileth BR, Lucarelli C.  Garlic.  In: Herb-Drug Interactions in Oncology. BC Decker Inc.  Hamilton, Ontario.  2003:163-164.
15. Foster BC, Foster MS, Vandenhoek S et al.  An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic.  J Pharm Pharm Sci  2001;4:176-84. 
    
16. Lesho EP, Saullo L, Udvari-Nagy S.  A 76 year-old woman with erratic anticoagulation.  Cleve Clin J Med  2004;71:651-6. 
    
17. Vale S.  Subarachnoid haemorrhage associated with Ginkgo biloba.  Lancet  1998;352:36.
18. Engelsen J, Nielsen JD, Hansen KF.  [Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in patients on long-term warfarin treatment.  A randomized, double-blind, placebo-controlled cross-over trial].  Ugeskr Laeger  2003;165:1868-71.  
    
19. Mohutsky MA, Anderson GD, Miller JW et al.  Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo.  Am J Ther  2006;13:24-31. 
    
20. Fujita M, Nomura K, Hong K et al.  Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the vegetable cheese natto, a popular soybean fermented food in Japan.  Biochem Biophys Res Commun  1993;197:1340-7. 
    
21. Chang YY, Liu JS, Lai SL et al.  Cerebellar hemorrhage proviked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds.  Intern Med  2008;47:467-9. 
    
22. Suzuki Y, Kondo K, Matsumoto Y et al.  Dietary supplementation of fermented soybean, natto, suppresses intimal thickening and modulates the lysis of mural thrombi after endothelial injury in rat femoral artery.  Life Sci  2003;73:1289-98. 
    
23. Urano T, Ihara H, Umemura K et al.  The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis cleaves and inactivates plasminogen activator inhibitor type 1.  J Biol Chem  2001;276:24690-6. 
    
24. Johansson JO, Egberg N, Asplund-Carlson A et al.  Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridemic men.  J Cardiovasc Risk 1997;4:165-71.
    
25. Saareks V, Mucha I, Sievi E et al.  Nicotinic acid and pyridoxine modulate arachidonic acid metabolism in vitro and ex vivo in man.  Pharmacol Toxicol 1999;84:274-80. 
    
26. Wong AL, Chan TY.  Interaction between warfarin and the herbal product quilinggao.  Ann Pharmacother  2003;37:836-8.