Nutrition 7fl YEARS £j* Reviews # V19«-2012 W
Special Article
Anticoagulant activity of select dietary supplements
Michael J Stanger, Lauren A Thompson, Andrew J Young, and Harris R Lieberman
This review considers the potential of certain dietary supplements, including garlic, Ginkgo biloba, ginger, ginseng, fish oil, and vitamin E, to interfere with hemostasis. Dietary supplements are common components of the diet in the United States, with about half the US adult population taking some type of dietary supplement regularly. It has been suggested that some supplements could adversely affect coagulation when taken alone or in combination with antiplatelet medications. Supplements could alter hemostasis by a variety of mechanisms, such as reducing platelet aggregation or inhibiting arachidonic acid, a cellular signaling messenger and inflammatory intermediate. To conduct this review, multiple databases were searched using a variety of search terms to ensure relevant papers were located. Moderate to severe adverse events, such as spinal epidural hematoma, spontaneous intracerebral hemorrhage, retrobulbar hemorrhage, subarachnoid hemorrhage, spontaneous hyphema, and postoperative bleeding, have occasionally been anecdotally associated with consumption of dietary supplements. However, the number of controlled studies in the literature is too limited to demonstrate consistent anticoagulant effects of dietary supplements alone or in combination with drug therapy.
© 2012 International Life Sciences Institute
INTRODUCTION
More than half of the adult population in the United States regularly takes dietary supplements.1 Consequently, a concern is whether dietary supplements affect hemostasis, and if so, to what degree. Hemostasis is the process by which blood flow is halted by a complex chain of events, one of which is the coagulation cascade (Figure l).2 Some dietary supplements currently available in the United States alter hemostasis in vitro, but whether such effects are present in vivo is less certain.
Dietary supplements could alter coagulation at various points in the cascade, particularly via platelet aggregation (Table 1). Treatment with supplements with antiplatelet/anticoagulant activity could be beneficial for some individuals with cardiovascular illnesses or for preventing such diseases, hence their potential popularity. The effects of some dietary supplements on the coagulation cascade may be due to their putative ability to lower
arachidonic acid levels (Figure 2), providing an antiinflammatory effect of potential benefit to individuals suffering from arthritis, similar to the effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). However, if these products have anticoagulant activity, they may increase bleeding, especially if used in combination with other anticoagulants, for example, Coumadin, NSAIDs, or aspirin.
This review is focused on popular dietary supplements such as garlic, ginkgo biloba, ginger, ginseng, fish oil, and vitamin E, as well as other supplements that have been reported to alter hemostasis in humans. When appropriate, animal studies reporting relevant findings are discussed. The various points in the coagulation cascade at which dietary supplements may modify hemostasis and the potential consequences of such effects are discussed. Descriptions of the databases that were searched to prepare this review can be found in Table 2.
Affiliations: MJ Stanger, LA Thompson, AJ Young, and HR Lieberman are with the Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, Massachusetts, USA.
Correspondence: HR Lieberman, Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA 01760-5007, USA. E-mail: harris.lieberman@us.army.mil
Key words: adverse events, antiplatelet, hemorrhage, hemostasis, supplements dohlO.1111/j.l 753-4887.2011.00444.x
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Contact tystam (intrinsic)
Tissue factor pathway (extrinsic)
PKa		PK
	^-	
Tissue factor
Activation Of facto XI!
Figure 1 Coagulation cascade. Reproduced from Raghavan and Dikshit2 with permission. Copyright © Prous Science, S.A.U. or its licensors. All rights reserved.
It should be noted that intravenous administration of a supplement can have a greater effect on coagulation at smaller doses than oral supplementation due to the greater bioavailability of the supplement. Therefore, data from such studies should be interpreted with caution.
Garlic
Garlic (Allium sativum) is reported to be the third most popular herbal supplement in the United States, with sales exceeding 19 million US dollars per year.3 It is used raw as a seasoning or condiment, and as an extract in dietary supplements. Fresh garlic and garlic in dietary supplement form may have different physiological effects and properties, with both forms purported to have antibacterial and cholesterol-lowering properties. Dosages generally recommended in the literature for adults are 4 g (one to two cloves) of raw garlic per day, one 300 mg dried
garlic powder tablet (standardized to 1.3% allicin or 0.6% allicin yield) two to three times per day, or 7.2 g of aged garlic extract per day.4
Two types of compounds in garlic may be bioactive. S-allylcysteine is a water-soluble compound found in garlic that is excreted in the urine in the form of the metabolite N-acetyl-S-allycysteine. Oil-soluble compounds also present in garlic, mainly allicin, sulfides, ajoenes, and vinyldithins, are quickly metabolized by the body after consumption and are not found in the urine and blood.5
Three compounds of garlic, allicin, adenosine, and paraffinic sulfide, are hypothesized to have antiplatelet properties.6 Adenosine and allicin both inhibit platelet aggregation without affecting cyclooxygenase and lipoxygenase metabolism of arachidonic acid.7 In vivo human studies have documented garlic's effect on hemostatic parameters such as adenosine diphosphate (ADP)-
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Table 1 Mechanism(s) of anticoagulant activity of select dietary supplements.
Supplement	Action	Reference
Garlic	Reduces ADP-induced platelet aggregation;	Makheja and Bailey (1990)6; Rahman and
	thromboxane reduction; reduces clotting time	Billingham (2000)8; Steinerand Li (2001)9;
		Gadkari etal. (1991)10; Srivastava (1986)12
Gingko biloba	Inhibits binding of platelet activation factor to	Koch (2006)35
	receptors	
Ginseng	Inhibits thromboxane function	Teng etal. (1989)44
Ginger	Alters thromboxane synthesis; inhibits	Verma etal. (1993)46; Srivastava etal. (1984)47;
	arachidonic acid-induced platelet activation	Koo etal. (2001 )48
Fish oil	Increases bleeding time; reduction in platelet	Agren etal. (1997)54; Cobiac etal. (1991)55
	aggregation	
Vitamin E	Reduces platelet adhesion to endothelial cells;	Steiner etal. (1995)74; Szuwart etal. (2000)75;
	increases bleeding time; prevents platelet	Freedman etal. (1996)77
	aggregation	
Policosanol	Inhibits arachidonic acid production; reduces	Valdes etal. (1996)83; Carbajal etal. (1998)84;
	collagen- and ADP-induced platelet activation	Castano et al. (1999)85; Arruzazabala et al.
		(2002)86
Magnesium	Reduces platelet aggregation; increases bleeding tl IT1G	Gawaz etal. (1994)89; Ravn etal. (1996)91
Feverfew	Inhibits cyclo-oxygenase production and	Makheja and Bailey (1982)95; Heptinstall etal.
	arachidonic acid; reduces serotonin release by	(1985,1987)96'97
	collagen- and ADP- induced platelet	
	aggregating agents	
Dong quai	Inhibits thromboxane and prostacyclin	Norredand Brinker (2001 )100
	synthetase	
Coenzyme Q10	Reduction in platelet receptors and size	Serebruany et al. (1997)103
Glucosamine	Inhibition of ADP-induced platelet aggregation	Hua etal. (2004)105
Lycopene	Inhibits platelet aggregation	Hsiao etal. (2005)108
L-arginine	Inhibits platelet response	Anfossi etal. (1999)109
Taurine	Reduces platelet aggregation	Hayes et al. (1989)110; Miglis et al. (2002)111
Selenium	Inhibits thromboxane synthesis	Perona etal. (1990)112
Passion flower	Contains coumarin, an anticoagulant	Aoyagi etal. (1974)114
Chamomile	Contains coumarin, an anticoagulant	Segal and Pilote (2006)115
induced platelet aggregation8-10 (5 mL extract/day), thromboxane reduction11 (5.46g/day), and clotting time (10 g/day).12 In vitro studies have shown a reduction in ADP-induced platelet aggregation,8 thromboxane reduction,13 Ca+ mobilization (doses not provided),14 and inhibition of the synthesis of thromboxane B2.7
Ingestion of garlic at amounts much greater than the recommended dose is anecdotally linked in case reports to spinal epidural hematoma15'16 as well as spontaneous bilateral and postoperative bleeding.17 Furthermore, the results of two studies indicate that garlic increases the anticoagulant properties of NSAIDs or blood-thinning medications.18'19 Other studies have not shown any statistically significant effect of garlic on ADP- or collagen-induced aggregation ex vivo20 and in vivo21'22 when given in a 305 mg/L garlic-oil extract.
Overall, it appears that garlic supplements when taken at recommended doses by individuals who are not taking anticoagulant medication do not have anticoagulant properties. However, consuming higher than recommended doses or using garlic in combination with
anticoagulants cannot be ruled out as a risk factor for increased bleeding.
Ginkgo biloba
Ginkgo (Ginkgo biloba) is among the top ten best-selling herbs in the United States, with sales exceeding $17 million per year.3 Several manufacturers have added ginkgo to their multivitamin and other multi-component products in amounts that vary from 40 mg to 240 mg a day23 Gingko can also be found in energy drinks in varying amounts. For example, Original Rockstar*" energy drink contains 150 mg of gingko, which exceeds the doses present in many of the studies discussed below which found excessive bleeding to be associated with gingko consumption.
Of the 33 known flavone glycosides in ginkgo, the main bioavailable components are the terpenoides, i.e., gingkolides A, B, C and bilobalide.24 Purported benefits of taking ginkgo include prevention of the onset of Alzheimer's disease and dementia, increased mental
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Diacylglycerol or phospholipid
Phosphorylase C
Phospbo-lipase A2
Arachidonic acid
PGH2 synthase (cox-1 or -2 and peroxidase)
PGD
synthase
Lipooxyganasa (FLAP, AtoxS)
HPETE (hydroperoxy-aicosatetraenoic acid)
LTB4
HP J
Leukotriene A.
Glutathione
PGD,
r
Prostaglandin Hj{PGH2)
PGE synthase
PGE,
PGF-
J
% \
S3 3
Glutamic acid
i
trie
V
4
Glulalhione-(ransferase
Leukotriene Ca
Leukotriene D.
Leukotriene Et
6-keto-__ Prostacyclin
PGFin endotne|iurT1 (PGI2)
Thromboxane
platelets
Thromboxane (TXA2)
Figure 2 The influence of arachidonic acid on platelet function. Reproduced with permission under the terms of the GNU Free Documentation License, Version 1.2 or any later version published by the Free Software Foundation.
concentration, prevention of vertigo, and improved blood flow through platelet inhibition. Terpene ginkgolide B is believed to be the active component in ginkgo responsible for its purported platelet-inhibiting qualities.25
There are several case reports of potential associations between ginkgo use and hemorrhage, including spontaneous intracerebral hemorrhage,26 retrobulbar hemorrhage,27  subarachnoid  hemorrhage,28 subdural
Table 2 Description of the databases searched for the present literature review.
Database
Description
PubMed/NCBI
International Bibliographic Information on Dietary Supplements
Cat.inist
The Cochrane Library
Google Scholar
Defense Technical Information Center
Defence Research Reports_
PubMed comprises more than 20 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher websites
I BIDS provides access to bibliographic citations and abstracts from published, international, and scientific literature on dietary supplements. IBIDS is a collaboration between two US government agencies: the Office of Dietary Supplements of the National Institutes of Health, and the Food and Nutrition Information Center of the United States Department of Agriculture's National Agricultural Library
This database of The Institute for Scientific and Technical Information of the French Center for Scientific Research contains 15 million bibliographic references in science, technology, medicine, humanities, and social sciences
The Cochrane Library contains high-quality, independent evidence to inform healthcare decision-making. It includes reliable evidence from Cochrane and other systematic reviews, clinical trials, and more. Cochrane reviews bring you the combined results of the world's best medical research studies, and are recognized as the gold standard in evidence-based health care
Provides a search of scholarly literature across many disciplines and sources, including theses, books, abstracts, and articles
Serves the Department of Defense community as the largest central resource for Department of Defense and government-funded scientific, technical, engineering, and business related information available
A database of scientific and technical research produced by and for Defence Research & Development Canada (DRDC) over the past 60 years_
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hematoma,29 and spontaneous hyphema.30 In these case reports, ginkgo was used in combination with warfarin or with NSAIDs such as aspirin, so the independent and/or interactive effects of these latter drugs cannot be isolated from the effects attributable solely to ginkgo.
A few case reports document bleeding with Ginkgo biloba supplementation, at 120 mg, 80 mg, and 75 mg, respectively.31-33 A study of 12 healthy males showed no excessive bleeding when 125 mg extract of ginkgo was taken in combination with warfarin for 7 consecutive days.34 Other studies with healthy male volunteers also did not show any significant effect of ginkgo on platelet activating factor (at 1,200-2,400 mg/day)35 or platelet function in vivo (at 120 mg/day).22
A study to determine the effects of taking ginkgo in combination with cilostazol (a drug used to alleviate symptoms of claudication in peripheral vascular disease) reported lower sheer-induced platelet aggregation, but no effects on bleeding time.36 A 52-week study conducted to determine the efficacy of ginkgo for dementia found no adverse events in the ginkgo-treated subjects who received 120 mg/day, but one hemorrhage in the placebo group.37
In conclusion, controlled studies have shown that short-term, low doses of ginkgo below 120 mg/day appear to alter platelet aggregation, especially when taken with certain medications such as cilostazol, but they may or may not increase bleeding time. Nevertheless, due to the large number of case reports describing bleeding with ginko supplementation, caution is warranted.
Ginseng
Ginseng (Panax ginseng) is a perennial herb found in Korea and China. It has been used in eastern Asian herbal remedies for thousands of years as a stimulant and aphrodisiac and is presently marketed in the United States and many other countries to increase alertness and energy.38 Globally, sales of ginseng exceeded 1.5 billion US dollars in 2008.2 Various beverages contain ginseng, including energy drinks. For example, Original Rockstar™ contains 25 mg of ginseng and SoBe® Green Tea contains 50 mg of ginseng.
Ginsenosides are reportedly the bioactive components in ginseng.39 Saponin complexes within the ginsenosides are metabolized in various parts of the body, mainly the hypothalamus-pituitary-adrenal axis and immune system, and are responsible for ginseng's purported benefits.40 Saponin may act on the immune system by inhibiting platelet-activating factor, thereby potentially reducing platelet volume.
There are a few case reports in the literature stating that ginseng consumption, in doses ranging from 120 to 200 mg daily, is associated with vaginal bleeding41 and increased blood-clotting time.42 One article reported that
ginseng alters the efficacy of anticoagulant therapy.43 Ginseng at a concentration of 0.1 mg/mL has been reported to inhibit in vitro thromboxane formation.44 In another study, no effect on platelet function in vivo was found (dose not provided).45
Ginseng appears to be safe when taken alone. Its interaction with NSAIDs does not appear to have been examined; therefore, caution should be exercised when taking ginseng with these drugs.
Ginger
Ginger is the rhizome of the plant Zingeber officinale. Medicinally, it has been used to alleviate nausea. The recommended daily dose of ginger is 1 g daily. Amounts exceeding 4 g may cause stomach discomfort and nausea.
Recently, ginger has been reported to lower cholesterol levels and to have blood-thinning properties.46 One of its active components, gingerol, is reported to inhibit platelet aggregation in vitro by acting on prostaglandin and thromboxane synthesis47 and inhibiting arachidonic acid-induced platelet aggregation.48 Ginger's effect on in vitro platelet aggregation has led to research on its potential adverse effects if used with blood thinners such as NSAIDs and warfarin. One study showed a single dose of 2 g of ginger had no significant effect on platelet aggregation49 within a 24-h period and another showed that a single dose of 25 mg of ginger did not affect clotting status in individuals taking warfarin.50 No case reports of ginger interacting with warfarin or NSAIDs were located. Therefore, ginger supplements do not have confirmed anticoagulant properties.
Fish oil
In 1970, Danish researchers discovered that the Inuit in Greenland had a low incidence of heart disease despite their high-fat diets.51 They also found that the Inuit bruised easily, had long bleeding times, and low levels of triglyceride, lipoprotein, and total cholesterol compared to individuals consuming standard Western diets. Furthermore, when platelets from Inuits were compared to those of Caucasians, they appeared to be less adhesive and did not clump together as easily.52 In 1985, it was suggested that consumption of fish oil lowered levels of certain plasma lipids, lipoproteins, and apoproteins.53 Later, researchers found that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the bioactive ingredients in fish oil, were responsible for its purported antiplatelet properties through absorption by platelets and leukocytes.54 Most commercially available fish oil supplements contain, on average, 1,000 mg of fish oil.
Numerous studies have investigated the effects of fish oil on hemostasis. Results of several studies provide
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evidence of fish oil's reported antiplatelet effect. The hemostatic properties observed have varied, with some studies reporting a hypocoagulant effect,55 reduction in in vitro platelet aggregation,56 and moderate effects on extending bleeding time in humans.57 However, nine studies of fish oil found no significant effects on hemostatic parameters such as bleeding time,58'59 abnormal bleeding during surgery,60'61 platelet aggregation,62 prothrombin formation,63 or platelet activating factor.64 The dosages employed in these studies ranged from 1 to 5 g per day.
Given fish oil's popularity, concern has arisen regarding its effects on hemostasis when it is taken daily in combination with NSAIDs or warfarin. A few studies have shown that fish oil supplementation in combination with aspirin at doses of 10 g of fish oil and 325 mg of aspirin,65 5 g of fish oil and 325 mg of aspirin,66 and 4.5 g of fish oil and 480 mg of aspirin67 increases bleeding time. In addition, a study with non-human primates reported that fish oil supplementation increased bleeding time and interrupted vascular thrombus formation.68
Thus, fish oil taken alone appears to have a marginal effect on coagulation; however, when taken with NSAIDs or other anticoagulants, such as warfarin, bleeding time may increase; therefore, caution is warranted.
Vitamin E
Vitamin E is a generic name used for a group of fat-soluble vitamins with certain antioxidant properties. It occurs naturally in eight chemical forms: alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol. Of the eight, alpha-tocopherol has the highest bioavailability in humans.69 For US adults, the recommended dietary allowance of vitamin E is 22.4 IU (15 mg) per day, and the tolerable upper intake level is 1500 IU (1000 mg) per day.68'70 Through a search of common commercially available dietary supplements, the range of vitamin E supplementation doses was found to be 200 IU (134 mg) to 1,000 IU (670 mg), with 400 IU (268 mg) being the most common. Although one study found that a dose of only 50 mg/day of vitamin E resulted in an increase in subarachnoid hemorrhage,71 most other studies did not observe such an association, even at higher doses.
For example, two studies, one with 20 healthy adults receiving vitamin E supplementation at doses of 530 mg/ day for 5 consecutive weeks72 and another with 42 healthy adults receiving 530 mg/day for 2 consecutive weeks,73 failed to show any reduction in in vivo platelet aggregation. Another study found no significant effect of 45 mg/ day of vitamin E on platelet aggregation when it was taken for 8 consecutive weeks.74
Other human studies do suggest that vitamin E possesses platelet antiaggregation properties. For example,
two studies reported a reduction in in vitro platelet adhesion to endothelial cells.75'76 Furthermore, a randomized, double-blind study of 100 volunteers found a significant decrease in platelet adhesion in volunteers that took 265 mg/day of vitamin E with 325 mg aspirin for 2 years compared with 48 volunteers that took 325 mg of aspirin alone for the same length of time.77 Another study with 15 volunteers measured the ability of vitamin E at various doses (400, 800, and 1,200 IU/day) to inhibit platelet aggregation. All three dose levels inhibited platelet aggregation, and the 1,200 IU/day dosage was found to inhibit platelet aggregation by altering arachidonic acid production.78 Another study reported that alpha-tocopherol inhibited platelet aggregation in vitro in a dose dependent manner.79 Furthermore, gamma-tocopherol was reported to ameliorate effects of exercise-induced platelet aggregation, while alpha-tocopherol did not.80
Therefore, overall, it appears vitamin E may have dose-dependent anticoagulant properties. Doses lower than 400 IU/day have inconsistent antiplatelet activity. However, doses closer to the tolerable upper intake level may inhibit platelet aggregation when taken in the form of either alpha- or gamma-tocopherol.
Policosanol
Although policosanol is not a popular dietary supplement according to published surveys,81'82 it has been investigated for beneficial effects on cardiovascular health, such as reducing low-density lipoprotein (LDL) levels and increasing high-density lipoprotein (HDL).83 Policosanol is a natural extract of waxes derived from plants like sugar cane and yams and from beeswax. It is composed of several fatty alcohols, including octocosanol and tricontanol.
Policosanol at a dose of 10 mg/day is reported to reduce arachidonic acid production and collagen- and ADP-induced platelet aggregation.8486 When policosanol is taken in conjunction with aspirin, it has been reported to decrease ADP-induced platelet aggregation by 10% and collagen-induced platelet aggregation by 35% compared to aspirin alone.87 No studies have demonstrated that policosanol causes excessive bleeding. Moreover, no case reports of bleeding due to policosanol supplementation were located. Policosanol may cause bleeding when taken with aspirin or other NSAIDs, but this has not been established definitely,
Magnesium
Magnesium is the fourth most abundant mineral in the human body88 and is essential for adenosine triphosphate (ATP) metabolism. In commercially available oral supplements, magnesium is found in doses ranging from 250 to 500 mg.
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One study of magnesium supplementation found that an intravenous infusion of 192 mg/dL at a dose of 3 mL/h for 24 hours (for a total dose of 138 mg) increased bleeding time by roughly 40% in vivo and ex vivo in eight healthy volunteers.89 Another study administered the same concentration of magnesium for the same duration intravenously to 14 volunteers and reported that it increased bleeding time by 48% and decreased platelet aggregation in vitro.90 A third study administered the same concentration and duration of intravenous magnesium with 100 mg of aspirin in 12 volunteers and found the combination inhibited platelet adhesion ex vivo.91 Daily doses of magnesium (800-1,200 mg tablets) in combination with a daily dose of 81 mg aspirin in 42 volunteers for 3 months decreased platelet-dependent thrombosis 35% more than aspirin alone (there was no magnesium-only supplement group in this study).92 Intravenous infusion of magnesium in combination with aspirin does appear to alter hemostasis; however, the oral dietary supplement formulation and dosage of magnesium has not been extensively studied.
Feverfew
Feverfew (Tanacetum parthenium) has been used as an herbal remedy for migraine headaches since medieval times.93 Sesquiterpene lactones in feverfew are reported to be responsible for its purported effects on platelets.94 Feverfew reduces in vitro serotonin release by ADP- and collagen-induced platelet aggregating agents.95 It also prevents thromboxane synthesis in vitro by inhibiting cyclo-oxygenase production96 and arachidonic acid production.97 No clinical evidence that feverfew is an anticoagulant was located and feverfew does not appear to interact with NSAIDs. However, due to its possible antiplatelet properties, caution should be exercised when taking feverfew with NSAIDs.
Dong quai
Dong quai (Radix Angelicae sinensis) is a fragrant perennial herb that grows at high altitudes in China, Korea, and Japan. It has been used in Eastern medicine to treat migraine headache, irregular menstruation, and menstrual pain.98
Six biochemical constituents related to the anticoagulant coumarin have been identified in dong quai. These are osthole, ferulic acid, bergapten, imperatorin, oxypeucedonin, and psoralin." There is no predominant component, and the concentration of each component in dong quai varies considerably in different lots. Osthole and ferulic acid are the primary components that appear to affect platelet aggregation through inhibition of in vitro thromboxane A2 and prostacyclin synthetase.100
There are anecdotal accounts implicating dong quai in hemorrhage and suggesting it interacts with warfarin,101 but no studies were found that examined the effects of dong quai on coagulation. Because dong quai contains coumarin derivatives, it should be used with caution, especially by patients being treated with warfarin or NSAIDs.
Coenzyme Q™
Coenzyme Qio is increasing in popularity as a dietary supplement. It is found in mitochondria and is involved in aerobic cellular respiration. Coenzyme Qio is necessary for cell function.102 When administered as a dietary supplement in doses of 400 mg/day, it appears to affect platelet size, but it does not alter platelet aggregation in vitro.103 Coenzyme Qio does not appear to interact with warfarin104 or have any harmful effects on coagulation. Insufficient evidence currently exists in the literature to recommend against coenzyme Qio supplementation for individuals receiving Coumadin-containing drugs.
Glucosamine
Glucosamine is naturally present in shellfish shells, animal bone, and bone marrow. It is also present in some fungi, such as Aspergillus niger. It is used to treat arthritis, typically in doses of 1,500 mg/day. It suppresses ADP-mediated platelet activation in humans105 and appears to reduce platelet aggregation in guinea pigs.106 A recent review noted 21 case reports describing a glucosamine and warfarin interaction resulting in an increased international normalized ratio.107 No studies were found that showed an interaction between glucosamine and NSAIDs. Glucosamine appears to exhibit antiplatelet properties and may interact with NSAIDs. Although glucosamine appears to interact with warfarin, it does not appear to cause excessive bleeding itself.
Other supplements
Several dietary supplements have occasionally been reported to possess anti-platelet/anti-coagulation properties.
Lycopene. Lycopene is a bioactive ingredient in tomatoes reported to inhibit platelet aggregation.108
L-arginine. The amino acid L-arginine may also inhibit platelet response.109
Taurine. Taurine is an amino acid added to energy drinks and two studies indicate it may reduce platelet aggregation.110'111
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Selenium. The essential mineral selenium appears to inhibit thromboxane synthesis in vitro112 and has been shown to interact with warfarin.113
Passionflower. Passion flower (Passiflora incarnata) contains small amounts of coumarin114 and, theoretically, may increase bleeding; however, no documented cases of excessive bleeding have been reported with its use.
Chamomile. Chamomile (Matricaria recutita) also contains small amounts of coumarin.115 Theoretically, it may potentiate the effect of warfarin and NSAIDs, but no reports have documented this.
CONCLUSION
Although there has been considerable research examining potential adverse or beneficial effects of various dietary supplements on hemostasis, there is no definitive clinical data demonstrating that any unadulterated dietary supplement adversely affects hemostasis when taken alone or in combination with blood-thinning medications in the doses typically provided by reliable manufacturers. However, there are numerous reports in the literature suggesting several supplements may affect coagulation; therefore, future research is necessary.
Acknowledgment
The views, opinions and/or findings in this report are those of the authors, and should not be construed as an official Department of the Army position, policy, or decision, unless so designated by other official documentation. Citation of commercial organization and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.
Funding. This work was supported by the US Army Medical Research and Materiel Command (USAMRMC) and the Department of Defense Center Alliance for Dietary Supplements Research.
Declaration of interest. The authors have no relevant interests to declare.
REFERENCES
1. Radimer K, Bindewald B, Hughes J, etal. Dietary supplement use by adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epid. 2004; 160:339-349.
2. Raghavan SAV, Dikshit M. Recent advances in the status and targets of antithrombotic agents. Drugs Future. 2002;27: 669-683.
3. Cavaliere C, Rea P, Blumenthal M. Herbal supplement sales in the United States show growth in all channels. Herbal Gram. 2008;78:60-63.
4. Tattelman E. Health effects of garlic. Am Fam Physician. 2005;72:13-106.
5. Amagase H, Petesch BL, Matsuura H, etal. Intake of garlic and its bioactive components. J Nutr. 2001 ;131 (Suppl): S955-9S962.
6. Makheja AN, Bailey JM. Antiplatelet constituents of garlic and onion. Agents Actions. 1990;29:360-363.
7. El-Sabban F. Garlic as an antithrombotic and antiplatelet aggregation agent. J Chin Clin Med. 2009;4:288-294.
8. Rahman K, Billington D. Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr. 2000;130:2662-2665.
9. Steiner M, Li W. Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr. 2001,-131 (Suppl):S980-S984.
10. Gadkari JV, Joshi VD. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. Postgrad Med J. 1991 ;37:128-131.
11. Pierre S, Crosbie L, Duttaroy AK. Inhibitory effect of aqueous extracts of some herbs on human platelet aggregation in vitro. Platelets. 2005;16:469-473.
12. Srivastava KC. Evidence for the mechanism by which garlic inhibits platelet aggregation. Prostaglandins Leukot Med. 1986;22:313-321.
13. Allison GL, Lowe GM, Rahman K. Aged garlic extract may inhibit aggregation in human platelets by suppressing calcium mobilization. J Nutr. 2006;136(Suppl):S789-S792.
14. Rose KD, Croissant PD, Parliament CF, etal. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report. Neurosurgery. 1990;26:880-882.
15. Rose KD, Croissant PD, Parliament CF, etal. Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: a case report. Neurosurgery. 1990;26:880-882.
16. Rowin J, Lewis SL. Spontaneous bilateral subdural hematomas associated with chronic Ginkgo biloba ingestion. Neurology. 1996;46:1775-1776.
17. German K, Kumar U, Blackford HN. Garlic and the risk of TURP bleeding. Br J Urol. 1995,76:518.
18. Borrelli F, Capasso R, Izzo AA. Garlic [Allium satiuum L): adverse effects and drug interactions in humans. Mol Nutr Food Res. 2007;51:1386-1397.
19. Saw JT, Bahari MB, Ang HH, et al. Potential drug-herb interaction with antiplatelet/anticoagulant drugs. Complement Ther Clin Pract. 2006;12:236-241.
20. Wojcikowski K, Myers S, Brooks L. Effects of garlic oil on platelet aggregation: a double-blind placebo-controlled crossover study. Platelets. 2007;18:29-34.
21. Harenberg J, Giese C, Zimmermann R. Effect of dried garlic on blood coagulation, fibrinolysis, platelet aggregation and serum cholesterol levels in patients with hyperlipoproteinemia. Atherosclerosis. 1988;74:247-249.
22. Beckert BW, Concannon MJ, Henry SL, et al. The effect of herbal medicines on platelet function: an in vivo experiment and review of the literature. Plast Reconstr Surg. 2007;120:2044-2050.
23. Abebe W. Herbal medications: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. 2002;27:391-401.
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Nutrition Reviews" Vol. 70(2):107-117
24. Yoskikawa T, Naito Y, Kondo M. Ginkgo biloba leaf extract: review of biological actions and clinical application. Anti-oxid Redox Signal. 1999;1:469-480.
25. Sierpina VS, Wollschlager B, Blumenthal M. Ginkgo biloba. Am Fam Physician. 2003;68:923-926.
26. Benjamin J, Muir T, Briggs K, etal. A case of cerebral haemorrhage-can Ginkgo biloba be implicated? Postgrad Med J. 2001;77:112-113.
27. Fong KCS, Kinnear PE. Retrobulbar haemorrhage associated with chronic Ginkgo biloba ingestion. Postgrad Med J. 2003;79:531-532.
28. Friedman JA, Taylor SA, McDermott W, et al. Multifocal and recurrent subarachnoid hemorrhage due to an herbal supplement containing natural coumarins. Neurocrit Care. 2007;7:76-80.
29. Rosenblatt M, Mindel J. Spontaneous hyphema associated with ingestion of Ginkgo biloba extract. N Engl J Med. 1997;336:1108.
30. Vale S. Subarachnoid haemorrhage associated with Ginkgo biloba. Lancet. 1998;352:36.
31. Gilbert GJ. Ginkgo biloba. Neurology. 1997;48:1137.
32. Bent S, Goldberg H, Padula A, etal. Spontaneous bleeding associated with Ginkgo biloba: a case report and systematic review of the literature. J Gen Intern Med. 2005; 20:657-661.
33. Jiang X, Williams KM, Liauw WS, et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005;59: 425-432.
34. Koehler S, Funk P, Kieser M. Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers. Blood Coagul Fibrinolysis. 2004;15:303-309.
35. Koch E. Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications after oral intake of Ginkgo biloba extracts. Phytomedicine. 2005;12: 10-16.
36. Ryu KH, Han HY, Lee SY, etal. Ginkgo biloba extract enhances antiplatelet and antithrombotic effects of cilosta-zol without prolongation of bleeding time. Thromb Res. 2009;124:328-334.
37. Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997;278:1327-1332.
38. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25: 323-344.
39. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic review of randomized clinical trials. Eur J Clin Pharmacol. 1999;55:567-575.
40. Kiefer D, Pantuso T. Panax ginseng. Am Fam Physician. 2003;68:1539-1542.
41. Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol. 1988;159:1121-1122.
42. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm. 1997;54:692-693.
43. Paoletti A, Gallo E, Benemei S, etal. Interactions between natural health products and oral anticoagulants: spontaneous reports in the Italian Surveillance System of Natural
Nutrition Reviews" Vol. 70(2):107-117
Health Products. Evid Based Complement Alternat Med. 2011;2011:1-5.
44. Teng CM, Kuo SC, Ko FN, et al. Antiplatelet actions of pan-axynol and ginsenosides isolated from ginseng. Biochim Biophys Acta. 1989;990:315-320.
45. Thomson M, Al-Qattan KK, Al-Sawan SM, etal. The use of ginger {Zingiber officinale Rose.) as a potential antiinflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids. 2002;67:475-478.
46. Verma SK, Singh J, Khamesra R, etal. Effect of ginger on platelet aggregation in man. Indian J Med Res. 1993;98: 240-242.
47. Srivastava KC. Aqueous extracts of onion, garlic and ginger inhibit platelet aggregation and alter arachidonic acid metabolism. Biomed Biochim Acta. 1984;43(Suppl):S335-S346.
48. Koo KL, Ammit AJ, Tran VH, et al. Gingerols and related analogues inhibit arachidonic acid-induced human platelet serotonin release and aggregation. Thromb Res. 2001,-103: 387-397.
49. Lumb AB. Effect of dried ginger on human platelet function. Thromb Haemost. 1994;71:110-111.
50. Dyerberg J, Bang HO. Hemostatic function and platelet polyunsaturated fatty acids in Eskimos. Lancet. 1979;1:433-435.
51. Phillipson BE, Rothrock DW, Connor WE, et al. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N Engl J Med. 1985;312:1210-1216.
52. Mueller BA, Talbert RL. Biological mechanisms and cardiovascular effects of omega-3 fatty acids. Clin Pharm. 1988;7: 795-807.
53. Vanschoonbeek K, Feijge MA, Paquay M, etal. Variable hypocoagulant effect offish oil intake in humans: modulation of fibrinogen level and thrombin generation. Arterio-scler Thromb Vase Biol. 2004;24:1734-1740.
54. 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;57:419-421.
55. Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects offish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr. 1991 ;53:1210-1216.
56. Blonk MC, Bilo HJ, Nauta JJ, et al. Dose-response effects of fish-oil supplementation in healthy volunteers. Am J Clin Nutr. 1990;52:120-127.
57. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol. 2007;99:35C-43C.
58. Knapp HR. Dietary fatty acids in human thrombosis and hemostasis. Am J Clin Nutr. 1997;65(Suppl):S1687-S1698.
59. Leaf A, Jorgensen MB, Jacobs AK, et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation. 1994;90: 2248-2257.
60. Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation. 1992;85:950-956.
61. 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;82:428-438.
62. Rogers S, James KS, Butland BK, etal. Effects of a fish oil supplement on serum lipids, blood pressure, bleeding time, haemostatic and rheological variables. A double blind
randomised controlled trial in healthy volunteers. Atherosclerosis. 1987;63:137-143.
63. Kaul N, Kreml R, Austria JA, etal. A comparison offish oil, flaxseed oil and hempseed oil supplementation on selected parameters of cardiovascular health in healthy volunteers. J Am Coll Nutr. 2008;27:51-58.
64. Mueller BA, Talbert RL, Tegeler CH, et al. The bleeding time effects of a single dose of aspirin in subjects receiving omega-3 fatty acid dietary supplementation. J Clin Pharmacol. 1991;31:185-190.
65. Harris WS, Silveira S, Dujovne CA. The combined effects of N-3 fatty acids and aspirin on hemostatic parameters in man.Thromb Res. 1990;57:517-526.
66. Svaneborg N, Kristensen SD, Hansen LM, et al. The acute and short-time effect of supplementation with the combination of n-3 fatty acids and acetylsalicylic acid on platelet function and plasma lipids. Thromb Res. 2002;105:311-316.
67. Harker LA, Kelly AB, Hanson SR, et al. Interruption of vascu-lart thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates. Circulation. 1993;87:1017-1029.
68. Institute of Medicine. Dietary Reference Intakes: Vitamin Q Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academies Press; 2000:186-263.
69. Traber MG. Vitamin E regulatory mechanisms. Annu Rev Nutr. 2007;27:347-362.
70. Stampfer MJ, Jakubowski JA, Faigel D, etal. Vitamin E supplementation effect on human platelet function, arachi-donic acid metabolism, and plasma prostacyclin levels. Am J Clin Nutr. 1988;47:700-706.
71. Leppala JM, Virtamo J, Fogelholm R, etal. Vitamin E and beta carotene supplementation in high risk for stroke: a subgroup analysis of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Arch Neurol. 2000;57:1503-1509.
72. Dereska NH, McLemore EC, Tessier DJ, etal. Short-term, moderate dosage vitamin E supplementation may have no effect on platelet aggregation, coagulation profile, and bleeding time in healthy individuals. J Surg Res. 2006; 132:121-129.
73. Liu M, Wallmon A, Olsson-Mortlock C, etal. Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms. Am J Clin Nutr. 2003;77:700-706.
74. Steiner M. Influence of vitamin E on platelet function in humans. J Am Coll Nutr. 1991;10:466-473.
75. Szuwart T, Brzoska T, Luger TA, etal. Vitamin E reduces platelet adhesion to human endothelial cells in vitro. Am J Hematol. 2000;65:1-4.
76. Steiner M, Glantz M, Lekos A. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr. 1995;62(Suppl):S1381-S1384.
77. Freedman JE, Farhat JH, Loscalzo J, etal. a-Tocopherol inhibits aggregation of human platelets by a protein kinase c-dependent mechanism. Circulation. 1996;94:2434-2440.
78. Mabile L, Bruckdorfer KR, Rice-Evans C. Moderate supplementation with natural alpha-tocopherol decreases platelet aggregation and low-density lipoprotein oxidation. Atherosclerosis. 1999;147:177-185.
79. Bakaltcheva I, Gyimah D, Reid T. Effects of alpha-tocopherol on platelets and the coagulation system. Platelets. 2001; 12:389-394.
80. Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287:337-344.
116
81. Lieberman HR, Stavinoha TB, McGraw SM, etal. Use of dietary supplements among active-duty US Army soldiers. Am J Clin Nutr. 2010;92:985-995.
82. Singh DK, Li L, Porter TD. Policosanol inhibits cholesterol synthesis in hepatoma cells by activation of AMP-kinase. J Pharmacol ExpTher. 2006;318:1020-1026.
83. Valdes S, Arruzazabala ML, Fernandez L, etal. Effect of policosanol on platelet aggregation in healthy volunteers. Int J Clin Pharmacol Res. 1996;16:67-72.
84. Carbajal D, Arruzazabala ML, Valdes S, etal. Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids. 1998;58:61-64.
85. Castano G, Mas R, Arruzazabala ML, etal. Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients. Int J Clin Pharmacol Res. 1999;19:105-116.
86. Arruzazabala ML, Molina V, Mas R, et al. Antiplatelet effects of policosanol (20 and 40 mg/day) in healthy volunteers and dyslipidaemic patients. Clin Exp Pharmacol Physiol. 2002; 29:891-897.
87. Arruzazabala ML, Valdes S, Mas R, et al. Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Pharmacol Res. 1997;36:293-297.
88. Wester PO. Magnesium. Am J Clin Nutr. 1987;45:1305-1312.
89. Gawaz M, Ott I, Reininger AJ, et al. Effects of magnesium on platelet aggregation and adhesion. Magnesium modulates surface expression of glycoproteins on platelets in vitro and ex vivo. Thromb Haemost. 1994,72:912-918.
90. Ravn HB, Vissinger H, Kristensen SD, etal. Magnesium inhibits platelet activity—an infusion study in healthy volunteers. Thromb Haemost. 1996;75:939-944.
91. Ravn HB, Kristensen SD, Vissinger H, etal. Magnesium inhibits human platelets. Blood Coagul Fibrinolysis. 1996;7: 241-244.
92. Shechter M, Merz CN, Paul-Labrador M, etal. Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease. Am J Cardiol. 1999;84:152-156.
93. Loeshe W, Mazurov AV, Heptinstall S, etal. An extract of feverfew inhibits interactions of human platelets with collagen substrates. Throm Res. 1987;48:511-518.
94. Groenewegen WA, Heptinstall S. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J Pharm Pharmacol. 1990;42:553-557.
95. Makheja AN, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew [Tanacetum parthenium). Prostaglandins Leukot Med. 1982;8:653-660.
96. Heptinstall S, White A, Williamson L, etal. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet. 1985;1:1071-1074.
97. Heptinstall S, Groenewegen WA, Spangenberg P, etal. Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups. J Pharm Pharmacol. 1987;39:459-465.
98. Zhu DP. Dong quai. Am J Chin Med. 1987;15:117-125.
99. Page RL, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy. 1999;19:870-876.
100. Norred CL, Brinker F. Potential coagulation effects of preoperative complementary and alternative medicines. Altern Ther Health Med. 2001;7:58-67.
Nutrition Reviews" Vol. 70(2):107-117
101. Heck AM, DeWitt BA, Lukes AL Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000;57:1221 -1227.
102. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinone function. Biochim Biophys Acta. 1995;1271:195-204.
103. Serebruany VL, Ordonez JV, Herzog WR, et al. Dietary coenzyme Q10 supplementation alters platelet size and inhibits human vitronectin (CD51/CD61) receptor expression. J Car-diovasc Pharmacol. 1997;29:16-22.
104. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial. Thromb Haemost. 2002;87:1075-1076.
105. Hua J, Suguro S, Iwabuchi K, et al. Glucosamine, a naturally occurring amino monosaccharide, suppresses the ADP-mediated platelet activation in humans. Inflamm Res. 2004;53:680-688.
106. Lu-Suguro JF, Hua J, Sakamoto K, etal. Inhibitory action of glucosamine on platelet activation in guinea pigs. Inflamm Res. 2005;54:493-499.
107. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database. Pharmacotherapy. 2008;28:540-548.
108. Hsiao G, Wang Y, Tzu NH, et al. Inhibitory effects of lycopene on in vitro platelet activation and in vivo prevention of thrombus formation. J Lab Clin Med. 2005;146:216-226.
109. Anfossi G, Russo I, Massucco P, etal. L-arginine modulates aggregation and intracellular cyclic 3,5-guanosine monophosphate levels in human platelets: direct effect and interplay with antioxidative thiol agent. Thromb Res. 1999;94:307-316.
110. Hayes KC, Pronczuk A, Addesa AE, et al. Taurine modulates platelet aggregation in cats and humans. Am J Clin Nutr. 1989;49:1211-1216.
111. Miglis M, Wilder D, Reid T, et al. Effect of taurine on platelets and the plasma coagulation system. Platelets. 2002;13:5-10.
112. Perona G, Schiavon R, Guidi GC, et al. Selenium dependent glutathione peroxidase: a physiological regulatory system for platelet function. Throm Haem. 1990;64:312-318.
113. Davila JC, Edds GT, Osuna O, et al. Modification of the effects of aflatoxin B1 and warfarin in young pigs given selenium. Am J Vet Res. 1983;44:1877-1883.
114. Aoyagi N, Kimura R, Murata T. Studies on Passiflora incarnata dry extract. I. Isolation of maltol and pharmacological action of maltol and ethyl maltol. Chem Pharm Bull (Tokyo). 1974;22:1008-1013.
115. Segal R, Pilote L. Warfarin interaction with Matricaria cha-momilla. CMAJ. 2006;174:1281 -1282.
Nutrition Reviews" Vol. 70(2):107-117
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