The influence of diet and nutrients on platelet function.

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The Influence of Diet and Nutrients on Platelet Function Bradley J. McEwen, PhD, MHlthSc1

Campbelltown, New South Wales, Australia Semin Thromb Hemost 2014;40:214–226.

Abstract

Keywords

► ► ► ►

cardiovascular disease platelet function nutrients diet

Address for correspondence Bradley J. McEwen, PhD, MHlthSc, Department of Nutrition, National Centre for Clinical Nutrition, PO Box 534, Campbelltown, NSW 2560, Australia (e-mail: [email protected]).

Cardiovascular disease (CVD) is the leading cause of death worldwide. Platelet activation and aggregation play an integral role in hemostasis and thrombosis. Diets and nutrients play a potential role in modifying CVD progression, particularly in platelet function, and have the potential of altering platelet function tests. Diets such as Mediterranean diet, high in omega-3 polyunsaturated fatty acids (PUFA), and vegetarian diets have inverse relationships with CVD. Dark chocolate, foods with low glycemic index, garlic, ginger, omega-3 PUFA, onion, purple grape juice, tomato, and wine all reduce platelet aggregation. Dark chocolate and omega-3 PUFA also reduce P-selectin expression. In addition, dark chocolate reduces PAC-1 binding and platelet microparticle formation. Berries inhibit platelet function (PFA-100). Energy drinks have been shown to increase platelet aggregation and caffeine increases platelet microparticle formation. Therefore, repeat testing of platelet function may be required, not only after exclusion of known antiplatelet medications but also potentially after exclusion of dietary substances/ nutrients that could have plausibly affected initial test data.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, especially in developed countries such as Australia,1 Europe,2 New Zealand,3 and the United States.4 Risk factors for CVD include platelet hyperaggregation,5 increased coagulation factor activity, decreased fibrinolytic capacity,6 diabetes, dyslipidemia (including hypercholesterolemia and hypertriglyceridemia), smoking, physical inactivity,7 overweight/obesity,7,8 and a family history of CVD.4,7 Platelets play a pivotal role in both health and disease, through their central involvement in hemostasis and thrombosis. The process of primary hemostasis is initiated through platelet adhesion at sites of vascular injury. The next step is platelet activation, which is initiated by several stimuli, such as adenosine diphosphate (ADP). This is followed by secretion of aggregatory substances and finally platelet aggregation.9 Platelets have long been implicated in the pathogenesis of atherosclerosis as constituents of atheroma.10 Platelet aggregates can be formed with leukocytes. Monocytes actively bind to platelets, forming prothrombotic platelet–monocyte aggregates. Platelet–monocyte aggregates are sensitive

markers of platelet activation and contribute to the initiation and progression of atherosclerosis.11 There are several tests commonly used to measure platelet function. These include bleeding time, platelet aggregometry, flow cytometry, Plateletworks, VerifyNow, Impact cone and plate(let) analyzer, and the platelet function analyzer (PFA100) assay.12,13 Bleeding time is the classical “functional” screening test for assessing primary hemostasis, but it is no longer performed in most developed countries.14 Light transmittance aggregometry (LTA) is traditionally regarded as the gold standard for evaluating platelet function.15,16 LTA measures light transmission through a test sample containing platelets typically platelet rich plasma that increases when platelets are aggregated by the addition of an agonist, for example, ADP or collagen.14 Flow cytometry rapidly measures the specific characteristics of a large number of individual cells and can be used as an assay of platelet function, for example, platelet activation markers and platelet–leukocyte aggregates, in specific clinical settings.17 The PFA-100 is a global test for primary hemostasis.18 The principle of the

published online February 4, 2014

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Issue Theme Quality in Hemostasis and Thrombosis, Part III; Guest Editors, Emmanuel J. Favaloro, PhD, FFSc (RCPA), Giuseppe Lippi, MD, and Mario Plebani, MD.

DOI http://dx.doi.org/ 10.1055/s-0034-1365839. ISSN 0094-6176.

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1 Department of Nutrition, National Centre for Clinical Nutrition,

PFA-100 is to aspirate citrated whole blood under high shear (5,000–6,000/s) through a capillary tube onto a collagencoated membrane, additionally coated with either ADP (CADP) or epinephrine (CEPI), containing a central aperture of 150 µm in diameter. These agonists trigger the primary hemostasis phases of platelet adhesion, activation, release, and aggregation, leading to rapid occlusion of the aperture and the cessation of blood flow. The time taken for the platelet plug to occlude the aperture reflects the assay end point, known as the “closure time.”14 Normal samples provide closure time within a given reference range; in contrast, samples from patients with platelet dysfunction, or on antiplatelet medication, will give longer closure times, or even no closure time in some cases. There is growing interest in the possible beneficial effects of specific dietary components on cardiovascular health, particularly in the area of thrombosis and hemostasis,19 dyslipidemia, inflammatory diseases, obesity, insulin sensitivity, oxidative stress, and endothelial function.20 The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to decrease blood pressure.21,22 Greater adherence to the traditional Mediterranean diet was associated with a significant reduction in mortality among individuals with coronary heart disease (CHD).23 The Diet and Reinfarction Trial (DART) found that men recovering from a myocardial infarction (MI) who were advised to eat fatty fish had a 29% reduction in 2-year all-cause mortality compared with those who were not advised.24 An inverse association has been associated with consumption of fruits and vegetables, particularly green leafy vegetables and vitamin C–rich fruits and vegetables, and CVD risk.25 In contrast, higher intakes of some types of red (e.g., beef, pork, lamb, hamburger) and processed meats, potatoes, French fries, refined grains, sweets, and desserts were associated with a higher risk of CVD.26,27 Diets with a high glycemic index have also been associated with significant increased risk of CVD.28 The impact of these dietary components on platelet function tests needs to be determined. Therefore this review focuses on diet and nutrients that have the potential to affect platelet function tests, particularly platelet aggregometry, flow cytometry, and the PFA-100 assay. As a quick reference guide, ►Table 1 shows the effect of diets and nutrients on platelet function parameters and, conversely, ►Table 2 shows the platelet function parameters affected by diets and nutrients.

The Effect of Diet on Platelet Function and Coagulation There are numerous diets that have been found to impact on cardiovascular health. These include the Mediterranean diet, vegetarian diets, glycemic index, and diets high in saturated fat.

Mediterranean Diet The Mediterranean diet is characterized by abundant fruit, vegetables, breads, and other forms of cereals, beans, nuts, seeds, and fish. Olive oil is the principal source of fat. Dairy products (principally cheese and yogurt) and poultry are consumed in low

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to moderate amounts. Red meat is consumed in low amounts and (especially red) wine is consumed in low to moderate amounts, normally with meals. Fresh fruit is the typical daily dessert.29 Greater adherence to the traditional Mediterranean diet is associated with a significant reduction in total mortality with an inverse association for death due to CHD.30 After the first MI, patients were randomly assigned to an experimental “Mediterranean-style diet” (n ¼ 302) or control group (n ¼ 303).31 Patients in the experimental group were advised by the research cardiologist and dietitian to follow a Mediterranean-type diet (more bread, more root vegetables and green vegetables, more fish, less meat [beef, lamb, and pork to be replaced with poultry], no day without fruit, and butter and cream to be replaced with margarine supplied by the study). The control patients received no specific dietary advice. Patients were seen 8 weeks after randomization and then each year for 5 years. The experimental group consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and α-linolenic acids. In the experimental group, plasma levels of vitamins E and C were increased. After a mean follow-up of 27 months, there were 3 cardiac deaths in the experimental group and 16 in the control group (p ¼ 0.02) with 5 nonfatal MIs in the experimental group and 17 in the control group (p ¼ 0.001). The Lyon Diet Heart Study is a randomized, single-blind secondary prevention trial that investigated whether a Mediterranean-type diet, compared with a prudent Western-type diet (control), would reduce recurrence after a first MI.32 The Mediterranean diet, rich in fruits and vegetables and α-linolenic acid, substantially reduced the number of cardiac deaths and nonfatal MI (14 vs. 44 events, p ¼ 0.0001) for up to 4 years after the first MI compared with a regular low-fat diet.

Vegetarian Diet Vegetarian diets do not contain meat, poultry, or fish.29,33 Plant foods can provide α-linolenic acid but are devoid of the long-chain omega-3 fatty acids—eicosapentenoic acid (EPA) and docosahexenoic acid (DHA). Studies report lower total cholesterol, low-density lipoprotein (LDL) cholesterol, and blood pressure in vegetarians than in nonvegetarians. In addition, mortality from ischemic heart disease have been reported to be lower in vegetarians compared with nonvegetarians.33 A diet high in vegetables, legumes, and fruit was associated with a reduced risk of all-cause mortality in European diabetic population. A cohort of 10,449 participants with self-reported diabetes within the European Prospective Investigation into Cancer and Nutrition study were followed for a mean of 9 years. An increment in intake of total vegetables, legumes, and fruit of 80 g/day was associated with a relative risk (RR) of death from all causes of 0.94 (95% confidence interval [CI], 0.90–0.98). Vegetables, legumes, and fruit seemed to have impact especially on CVD mortality (RR, 0.88 [95% CI, 0.81– 0.95]).34 A significant rise in platelet linoleic acid concentration and a decline in platelet arachidonic acid (AA) concentration was observed in vegetarians.35 Intake of green leafy vegetables and vitamin C–rich fruits and vegetables was inversely related to risk for Seminars in Thrombosis & Hemostasis

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Table 1 Effect of diets and nutrients on platelet function parameters Diet/Nutrient

Parameter

References

Berries

Inhibits platelet function (PFA-100 assay CADP)

44

Caffeine

Increased platelet microparticle formation

46

Cocoa and dark chocolate

Reduced adrenaline-induced aggregation

46

Coffee

Energy drink

Garlic

Reduced collagen-induced aggregation

120

Reduced ADP-induced P-selectin expression

46

Reduced platelet PAC-1 binding

46

Reduced platelet microparticle formation

46

Reduced shear stress–dependent platelet adhesion

48

Vasodilatory effect (increased coronary artery diameter)

48

Reduction in ADP-stimulated expression of active IIb/IIIa receptors

50

Reduction in arachidonic acid–stimulated expression of active IIb/IIIa receptors

50

Increased closure time of PFA-100 assay (CADP and CEPI)

51

Reduced arachidonic-induced aggregation

53


53

Reduced collagen-induced thromboxane B2 formation

53

Increase in ADP-induced platelet aggregation

55

Increased mean arterial pressure

55

Increased blood pressure

54

Reduced ADP-induced aggregation

58, 59


58, 60


59

Reduction in thromboxane B2 levels

62

Ginger


65


65

Glycemic index

Reduction in ADP-induced platelet aggregation

42

Kiwi fruit

Reduced ADP-induced platelet aggregation

66

Reduced collagen-induced platelet aggregation

66


83, 90

Reduced adrenaline-induced platelet aggregation

83

Reduced collagen-induced platelet aggregation

86–88, 91–94

Reduced platelet P-selectin expression

83, 84

Reduced platelet CD63 expression

84

Reduced ADP-induced platelet–monocyte aggregates

73, 83

Omega-3 polyunsaturated fatty acids

Onion

Purple grape juice

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Reduction in platelet-derived thromboxane B2

87, 88, 91

Decreased arachidonic acid content of platelet phospholipids

93

Significantly longer bleeding time

82, 90, 94


96, 97


63

Improved postprandial flow-mediated vasodilation

98


106


106, 107

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Table 1 (Continued)

Red wine

Tomato Turmeric/Curcumin

Vegetarian diet White wine

Parameter

References

Reduced thrombin-induced aggregation

104

Reduction in plasma thromboxane B2

104

Reduction in plasma fibrinogen

100


111–114


111–114

Reduced ADP-induced aggregation (in vitro)

118

Reduced adrenaline-induced aggregation (in vitro)

118, 119

Reduced arachidonic-induced aggregation (in vitro)

118, 119

Reduced collagen-induced aggregation (in vitro)

118, 119

Reduced platelet-activating factor-induced aggregation (in vitro)

118

Inversely related to risk for CHD

25

Decrease in platelet arachidonic acid concentration

35


104


104


Diet/Nutrient

Abbreviations: ADP, adenosine diphosphate; CHD, coronary heart disease.

Table 2 Platelet function parameters affected by diets and nutrients Parameter

Diet/Nutrient

References

Increase in ADP-induced platelet aggregation

Energy drink

55


Coffee

53

Garlic

58, 59

Ginger

65

Glycemic index

42, 43


83, 90


Kiwi fruit

66

Purple grape juice

106

Tomato

111–114

White wine

40


46, 47

Ginger

65


83

Reduced arachidonic-induced aggregation

Coffee

53



120

Garlic

59

Kiwi fruit

66


86–88, 92–94

Onion

96, 97


Purple grape juice

106, 107

Tomato

111–114

Red wine

104

White wine

104 (Continued)


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Table 2 (Continued) Parameter Reduced ADP-induced P-selectin expression

Diet/Nutrient

References


46


83, 84

Reduced platelet CD63 expression


84

Reduced ADP-induced platelet–monocyte aggregates


73, 83

Reduced platelet PAC-1 binding


46

Reduction in ADP-stimulated expression of active IIb/IIIa receptors


50

Reduction in arachidonic acid–stimulated expression of active IIb/IIIa receptors


50

Increased closure time of PFA-100 assay (CADP)

Berries

44


51

Increased closure time of PFA-100 assay (CEPI)


51

Reduced shear stress–dependent platelet adhesion


48

Increased platelet microparticle formation

Caffeine

46

Decreased arachidonic acid content of platelet phospholipids


93

Vegetarian diet

35

Reduction in thromboxane B2 levels

Coffee

53

Garlic

62

Red wine

104

White wine

104



87, 88, 91

Onion

63

Significantly longer bleeding time


82, 90, 94

Abbreviation: ADP, adenosine diphosphate.

CHD in both males and females.25 The possible beneficial constituents in fruits and vegetables include antioxidant vitamins, folate, fiber, and minerals such as potassium.25 Flavonoids, including quercetin, constitute a large class of natural polyphenolic compounds that are found in various fruits and vegetables. Epidemiologic studies suggest that diets rich in flavonoids can reduce the risk of arterial thrombosis.36 Proposed effects of flavonoids on platelet function include inhibition of signal transduction pathways in platelets,37,38 inhibition of TXA2 synthesis, and antagonism of TXA2 receptors.39 An in vitro study of quercetin on platelet aggregation inhibited both thrombin-induced and ADP-induced aggregation.40

Glycemic Index Postprandial hyperglycemia is increasingly recognized as a risk factor for CVD. Hyperglycemia may adversely affect the structure and function of the vascular system via multiple mechanisms, including procoagulant activity, oxidative stress, inflammation, LDL oxidation, and protein glycation.41 Seminars in Thrombosis & Hemostasis

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Diets with high glycemic loads have been associated with elevations of PAI-1.19 A randomized crossover design study investigated the effects of three different meals of varying glycemic index on postprandial platelet aggregation in 32 individuals. The test meals were a low GI, high carbohydrate (LGI-HC) meal; a high GI, high carbohydrate (HGI-HC) meal; and a low GI, moderate protein/fat meal (LGI-MPF). A washout period of 1 week was provided between test meals.42 Compared with baseline (time 0), all meals led to statistically significant (all p < 0.02) reductions in postprandial maximum platelet aggregation for 2.5 and 5 μM ADP over the 2-hour testing period after consumption of the test meal. In addition, the LGI-HC and LGI-MPF meals also showed significant (p < 0.04) reductions with 10 μM ADP. The acute effect of a high-carbohydrate low-fat meal on platelet aggregation was investigated in 16 healthy individuals.43 Compared with fasting baseline, significant reductions in the maximum aggregation and area under the aggregation curve (AUC) were found for each concentration of ADP (2.5, 5, 10 µM)


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120 minutes postmeal (overall p < 0.001). The reductions in platelet aggregation were larger in response to 2.5 (25%) than 5 (14%) or 10 µM ADP (9%). Similar results were observed for AUC at each ADP concentration. Although the rate of aggregation was reduced at 120 minutes postmeal, this was not statistically significant.

The Effect of Nutrients on Platelet Function and Coagulation There are numerous nutrients that have been found to impact on cardiovascular health. These include berries, caffeine, chocolate, garlic, ginger, the omega-3 polyunsaturated fatty acids (PUFA), onion, and tomato.

Berries A single-blind, randomized, placebo-controlled, 8-week dietary intervention trial was conducted with two treatment groups. The berry group consumed 100 g berries plus a berry juice daily. To control for the energy intake, the control group consumed 2 dL sugar–water and a 100-g porridge meal daily.44 Berry consumption significantly inhibited platelet function, as measured by the closure time of the PFA-100 assay CADP (76.3 vs. 84.7 seconds, p ¼ 0.018). At the end of the 8-week intervention period, closure times were prolonged by 11.0% in the berry group, whereas in the control group, closure times were shortened by 1.4%. The intervention had no significant effect on CEPI closure time or plasma biomarkers of platelet activation, coagulation, or fibrinolysis.

Cocoa and Chocolate Cocoa and chocolate products have been delicacies for hundreds of years.45 The consumption of a cocoa drink resulted in the inhibition of epinephrine-induced platelet activation. Cocoa also suppressed platelet PAC-1 binding on nonstimulated and stimulated platelets and suppressed ADP-induced P-selectin expression.46 Cocoa consumption suppressed ADPand adrenaline-stimulated platelet activation in healthy volunteers who had either cocoa, a caffeine-containing control beverage, or water.46 Platelet microparticle formation was decreased 2 and 6 hours after cocoa consumption, but increased after caffeine and water consumption. Sixteen healthy adults consumed aspirin (81 mg) alone, 300 mL cocoa beverage (18.75 g of flavonol-rich cocoa powder) alone, or aspirin plus cocoa.47 The cocoa beverage provided 897 mg of total epicatechin and procyanidins. Plasma epicatechin concentrations peaked approximately 2 hours after consumption of either cocoa beverage or aspirin plus cocoa beverage. After 6 hours, cocoa inhibited adrenaline-induced platelet function. Adrenaline-induced platelet function was inhibited 2 and 6 hours after aspirin, and after aspirin plus cocoa. Adrenaline-stimulated P-selectin expression was inhibited by aspirin at 6 hours, and after 2 and 6 hours by aspirin plus cocoa. ADP-stimulated P-selectin expression was not affected by the treatments. Cocoa and aspirin, given separately, reduced epinephrine-stimulated GPIIb/IIIa-act expression at 2 and 6 hours, respectively, and at 2 and 6 hours when given together, suggesting an additive

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effective. Acetylsalicylic acid (ASA) plus cocoa inhibited ADPstimulated GPIIb/IIIa-act expression at 6 hours. Flammer et al48 assessed the effect of 40 g flavonoid-rich dark chocolate (70% cocoa and 624 mg epicatechins) compared with cocoa-free flavonoid-free chocolate as a control on coronary vascular and platelet function in 22 heart transplant recipients in a double-blind, randomized study. Two hours after consumption, dark chocolate reduced shear stress–dependent platelet adhesion, whereas it remained unchanged after ingestion of control chocolate. Two hours after ingestion of dark chocolate, coronary artery diameter increased significantly (p < 0.01), while there was no change with the control chocolate. Concentrations of 8-iso-PGF2α, a specific marker of oxidative stress with vasoconstrictor potential, were significantly reduced 2 hours after dark chocolate consumption (p ¼ 0.029), whereas there was no change after control chocolate. Twenty healthy individuals and 20 smokers were randomly allocated to receive 40 g of dark (cocoa > 85%) or milk chocolate (cocoa < 35%) in a crossover, single-blind study.49 After dark chocolate intake, platelet oxidative stress changed in smokers but not in healthy individuals. Smokers showed lower platelet reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate oxidase activation and enhanced platelet nitric oxide 2 hours after chocolate consumption. Furthermore, collagen-induced in vitro platelet recruitment was measured. Briefly, platelet-rich plasma samples were incubated for 30 minutes at 37°C with or without scalar doses of epicatechin (0.1–10 μm), catechin (0.1–10 μm), or combination of epicatechin and catechin (0.1–10 μm), before activation with collagen (6 μg/mL). Solvents were used as controls. Collagen-induced platelet aggregation was measured for 10 minutes. Then, an equal portion of untreated platelets was added to each cuvette, which increased the density of the solution leading to a reduction in light transmission. Aggregation of the newly added platelet portion in the presence of an existing aggregate was then measured for 5 minutes and expressed as a percentage of the aggregation that had been initially reached. Dark chocolate consumption reduced platelet recruitment in smokers but not in healthy individuals. In another study, healthy individuals consumed 100 g of dark chocolate (70% cocoa and provided 700 mg of flavonoids) daily for 1 week.50 Platelet surface receptor expression was determined by flow cytometry before and after dark chocolate consumption. Both AA- and ADP-stimulated expression of active IIb/IIIa receptors were significantly reduced after 7 days of dark chocolate treatment by 33% (p < 0.005) and 37% (p < 0.006), respectively. A nonsignificant reduction in AA- and ADP-induced P-selectin expression was also observed after dark chocolate ingestion. Platelet function was assessed with the PFA-100 assay in 18 adult healthy individuals at baseline and at 2 and 6 hours after consuming 25 g of semisweet chocolate chips containing 220 mg of flavonols and procyanidins.51 Significant increases in closure time were observed in both CADP-induced (p ¼ 0.006) and CEPI-induced (p < 0.05) primary hemostasis 2 hours after chocolate consumption. Six hours after Seminars in Thrombosis & Hemostasis

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consuming chocolate, the closure times remained significantly increased for CADP (p ¼ 0.01), but not CEPI.

Coffee, Caffeine, and Energy Drinks Caffeinated beverages, such as coffee, are some of the most popular beverages consumed worldwide. Epidemiological studies suggest the existence of a U-shaped relationship between coffee consumption and cardiovascular events. A lower risk of CVD seems to be associated with a low consumption of coffee (less than one cup per day) or with a high consumption (more than or equal to four cups of coffee per day).52 A crossover study investigated the effect of coffee on platelet aggregation.53 In two different sessions, 10 healthy individuals drank 200 mL coffee, containing 180 mg caffeine, or a capsule of caffeine (180 mg) with 200 mL water as a control. Platelet aggregation was measured at baseline and 30 and 60 minutes after consumption of coffee or the caffeine control. Platelet aggregation induced by collagen and AA (30 minutes [p < 0.05] and 60 minutes [p < 0.05] is significantly inhibited after coffee consumption, respectively), while no statistically significant differences were observed in platelet aggregation induced by ADP. The caffeine control did not affect platelet aggregation induced by the three different agonists. Drinking coffee also inhibited collagen-induced thromboxane B2 formation. Caffeinated energy shots significantly increased systolic and diastolic blood pressure over a 3-hour period compared with decaffeinated energy shots in healthy, nonhypertensive individuals.54 A significant increase in ADP-induced (1 µmol/L) platelet aggregation was found 1 hour after consumption of 250 mL of a sugar-free energy drink.55 There was no change observed with the control group. Mean arterial pressure significantly increased following energy drink consumption, compared with controls (p < 0.05).

Garlic Garlic has been used medicinally for centuries, in particular for reducing cardiovascular risk factors, for hypertension, hypercholesterolemia,56 and for the inhibition of platelet aggregation.57 Epidemiologic studies show an inverse correlation between garlic consumption and progression of CVD.57 Platelet aggregation was tested before and after the consumption of garlic.58 Each capsule contained oil equivalent to 1 g of raw garlic. Platelet aggregation was induced using the agonists ADP, collagen, and epinephrine. Several doses of garlic were tested 4 hours after consumption with wash out periods of 5 days. These doses included 6, 8, 10, and 14 g. The inhibitory effect of garlic was observed only in epinephrineinduced aggregation at 8, 10, and 14 g doses. In the long-term study, 5 healthy males and 10 patients (40–60 years) with coronary artery disease (CAD) were administered 2 g of garlic three times a day for a period of 1 month. At the end of this period, platelet aggregation was again performed as triggered using the same agonists as the 4-hour study. Garlic significantly reduced the platelet aggregation induced by ADP and epinephrine in the healthy individuals and only in epinephrine-induced aggregation in patients with CAD. Seminars in Thrombosis & Hemostasis

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Platelet aggregation induced by ADP and collagen was significantly inhibited 2 and 4 hours after garlic ingestion.59 When platelet aggregation was tested after 7 and 14 days of garlic treatment, values were also significantly lower. In another study,60 blood was collected from healthy individuals who then consumed a capsule containing the equivalent of 9.9 g of garlic or an identical looking placebo. The individuals then consumed a set breakfast consisting of two pieces of toast with strawberry jam. Four hours later, blood was collected to assess the effect of garlic on platelet aggregation. Adrenaline-induced platelet aggregation was found to be significantly reduced (p < 0.05), whereas platelet aggregation in response to ADP or collagen showed no change. In contrast, in healthy volunteers tested before and 5 hours after single consumption of fresh garlic of approximately 4.2 g (1–2 garlic cloves),61 no inhibitory effect on platelet function was found using either the PFA-100 assay or impedance aggregometry (Multiplate; Verum Diagnostica GmbH, Munich, Germany). The effects of continuous ingestion of 4.2 g garlic daily for a week also showed no effect on platelet inhibition. The effect of garlic on thromboxane B2 levels was investigated at 4 and 12 weeks.62 The ingestion of one clove of garlic per day for 26 weeks showed a significant decrease (90%; p < 0.001) in TXB2 levels, with results showing a reduction in TXB2 levels of approximately 23% (p < 0.02) at 4 weeks from baseline. Garlic extracts were found to be weak inhibitors of platelet thromboxane synthesis.63 In vitro studies have demonstrated that garlic inhibits platelet aggregation.64 Platelet inhibition was examined in the presence of aqueous garlic extract. Garlic was shown to reduce the formation of thromboxane and lipoxygenase, and also inhibited phospholipase activity. The effect of garlic on inhibition of platelet function is varied. Some studies show significant reductions of platelet aggregation, while others show little to no effect, especially at dietary doses.61 Further research is indicated to evaluate the dosages required to inhibit platelet function that are both clinically and socially acceptable. Garlic has been noted for its inhibitory effects of cytochrome P45056 and its concurrent use with antiplatelet and anticoagulant medication needs to be investigated.

Ginger Ginger was administered in two different doses, 4 g daily for 3 months and 10 g as a single dose.65 Ginger given in a dose of 4 g daily did not affect ADP- and adrenaline-induced platelet aggregation measured at 1.5 and 3 months of administration. There was also no change in fibrinolytic activity and fibrinogen levels. However, a single dose of 10 g powdered ginger after 4 hours produced a significant reduction in platelet aggregation induced by the ADP (p < 0.05) and adrenaline (p < 0.05) agonists.

Kiwi Fruit Kiwi fruit contains high amounts of vitamin C, vitamin E, folic acid, anthocyanidins, and flavonols. Consuming two or three


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kiwi fruit per day for 28 days significantly reduced platelet aggregation in response to ADP and collagen (p < 0.05).66

Omega-3 Polyunsaturated Fatty Acids Omega-3 PUFA are long chain fatty acids with two or more double bonds.67 The two main long-chain PUFA (LC-PUFA) components of omega-3 are EPA (20:5n-3) and DHA (22:6n-3).68 The food sources of omega-3 are mainly from fish.69 However, plant-based omega-3 PUFA may be used as a source when seafood-based omega-3 PUFA intake is low, which may be useful for populations with low consumption or availability of fatty fish.70 The omega-3 PUFA has a multitude of functions relating to the cardiovascular system. These include eicosanoid metabolism, cell membrane phospholipid composition,71,72 and cell membrane function.72 Omega-3 fatty acids can influence many aspects of the pathogenesis of CVD, including lipid profile,71,72 platelet aggregation,72 platelet–monocyte aggregation,73 vascular relaxation, inflammation,72 and arrhythmias.74 The antiinflammatory effects of omega-3 PUFA include their partial replacement of AA, the precursor of proinflammatory eicosanoids.75 Dietary omega-3 fatty acids are incorporated into cellular membranes of all tissues,76 with fatty acid composition of diet having a major impact on fatty acid compositions in plasma lipids, platelets, and erythrocyte membranes.77 DHA is the main PUFA incorporated.78,79 The extent of this incorporation into tissue membranes is dependent on dietary intake.76 Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths,80 and is also associated with a lower CHD incidence and total mortality among diabetic women.81 Modest dietary intake of long-chain omega-3 PUFAs (250 mg/day) was associated with a 40 to 50% lower risk of sudden death in men.70 One of the early studies by Dyerberg and Bang82 found significantly longer bleeding time in Inuits. This was attributed to a reduction in platelet aggregation and significantly lower platelet counts than the Danish controls. The Inuits typically had a high consumption of omega-3 LC-PUFA. Forty healthy individuals and 16 patients with a history of CVD completed 4 weeks of omega-3 (DHA 520 mg and EPA 120 mg) supplementation.83 In healthy individuals, omega-3 PUFA significantly reduced ADP-induced and adrenalineinduced platelet aggregation. Omega-3 PUFA reduced Pselectin expression on platelets and formation of platelet– monocyte aggregates after activation with 0.5 μM ADP. There were fewer changes in platelet aggregation and activation found in patients with CVD. Nevertheless, there was a reduction in the slope of AA-induced platelet aggregation, and lag time was increased for U46619-induced platelet aggregation. Nomura et al84 found that after the administration of EPA (1.8 g/day) to hyperlipidemic patients with type 2 diabetes, there was a significant decrease of P-selectin positive and CD63-positive platelets along with decreased levels of monocytes, microparticles, and soluble E-selectin. After supplementing with EPA 1.4 g and DHA 0.6 g per day for 4 weeks, platelet aggregation induced by collagen was significantly

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decreased at 2 weeks (p < 0.01) and at 4 weeks (p < 0.005) and ADP was also reduced, although not significantly.85 A randomized, double-blind, controlled study86 found that a 2.5 g/day dose of omega-3 PUFA significantly reduced the slope of dose–response curves for collagen-induced platelet aggregation to one-third the value observed with safflower oil. Patients with high initial collagen-induced platelet thromboxane A2 production showed a significantly larger drop in production after fish oil than safflower oil. The study patients ingested five 1 g fish oil capsules each containing 0.5 g omega-3 fatty acids or five 1 g safflower oil capsules per day for 6 weeks. After 12 weeks, collagen-stimulated platelet aggregation was reduced significantly to all doses of fish and fish oil on both the high- and low-fat diets. Platelet aggregation in response to platelet activating factor was significantly reduced in all groups consuming omega-3 fatty acids. Platelet-derived thromboxane B2 from collagen-induced aggregation was significantly reduced in all groups taking omega-3 fatty acids. It was noted that groups consuming omega-3 fatty acids from fish or fish oil capsules showed a significant increase (p < 0.00001) in total omega-3 fatty acids with a significant reduction (p < 0.00001) in total omega-6 fatty acids.87 Hypertensive patients with type 2 diabetes were randomly assigned to take 4 g/day of EPA, DHA, or olive oil for 6 weeks.88 Relative to placebo (olive oil), DHA but not EPA supplementation significantly reduced collagen aggregation (16.9%, p ¼ 0.05) and platelet-derived thromboxane B2 (18.8%, p ¼ 0.03). There was also an increase in DHA in platelet phospholipids following the intervention. Vanschoonbeek et al89 found that an intake of omega-3 LCPUFA at 3.0 g/day for 4 weeks reduced platelet αIIbβ3 integrin activation. This was accompanied by reduced thrombin generation, reduction in plasma levels of fibrinogen, factor V (p < 0.05), and an insignificant decrease in factor VII. A prospective, controlled trial90 in which healthy individuals were fed with diets containing omega-3 fatty acids in the form of Pacific Northwest Chinook salmon and salmon oil found that platelet aggregation to low-dose (final concentration of 1.4 or 2 µM) ADP decreased significantly. Bleeding time tests were prolonged, both platelet EPA and DHA rose, and the omega-6 fatty acids C20:4 and C18:2 fell during the experimental period. A placebo-controlled, double-blind study with 26 hypercholesterolemic patients were supplemented with either EPA 216 mg, DHA 140 mg, gamma-linolenic acid 390 mg, and linoleic acid 3,480 mg or placebo (olive oil) for 6 weeks.91 In ex vivo platelet function testing, thromboxane B2 decreased from a mean of 225 16 to 212 21 ng/mL (p ¼ 0.003) in patients taking fish oil, but it did not change in the placebo group. Malondialdehyde formation was also lowered by omega-3 fatty acid supplementation. Fifty-five individuals were randomly allocated into control, fish diet, fish oil, and DHA-oil groups for 15 weeks.92 The individuals in the fish diet group ate 4.3 fish containing meals per week and this provided 0.38 g EPA and 0.67 g DHA per day. Supplemental fish oil group consumed EPA 1.33 g and DHA 0.95 g daily and the supplemental DHA group consumed Seminars in Thrombosis & Hemostasis

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1.68 g of DHA per day. Compared with controls, collageninduced maximum platelet aggregation decreased in the fish diet and the fish oil groups, while ADP platelet aggregation did not change. Additionally, compared with controls, the fish diet and supplemental groups had no change in hemostatic factors, such as factor VII, factor X, and fibrinogen after 15 weeks. In addition, EPA-free DHA oil was not effective in decreasing in vitro platelet aggregability. Thirty-two patients with symptomatic and angiographically demonstrated peripheral vascular disease were randomly allocated to take either 15 g/day of fish oil or olive oil for 4 weeks.93 Compared with baseline, platelet aggregation in response to collagen or platelet-activating factor was significantly reduced after fish oil, but was increased by olive oil. Following fish oil supplementation, there was a significant increase in EPA and DHA levels and a decrease in AA content of platelet phospholipids. The platelet fatty acid composition after olive oil was unchanged. Fourteen volunteers consumed 500 g of mackerel per week for 4 weeks (equivalent to 1 g/day of EPA þ DHA).73 Platelet–monocyte aggregation was reduced by 35% following 4 weeks dietary intervention with oil-rich fish. Platelet– monocyte aggregates are sensitive markers of platelet activation and contribute to the initiation and progression of atherosclerosis. The proportion of plasma phospholipid fatty acid composition of EPA and DHA increased during the fish diet with a corresponding reduction in the percentage of AA, linolenic acid, and oleic acid at 4 weeks compared with baseline measurements. A study was conducted on healthy men whose usual diet was partly replaced by fish, predominantly mackerel and salmon, for 11 weeks.94 This diet provided 2 to 3 g EPA per day. Two doses (3.5 and 10 mg/kg body weight) of ASA were given before and during the diet. Bleeding time increased by an average of 31% (p < 0.01) 3 weeks after the start of the diet; the maximum increase (42%, p < 0.01) was reached after 6 weeks; and after 11 weeks the bleeding time was still prolonged (by 33%, p < 0.05). Aggregation induced by collagen was depressed after 3 weeks of the fish diet. The decrease in platelet aggregation was observed 6 weeks after the start of the diet (p < 0.01), and lasted until after the dietary period; the significance of the decrease was (p < 0.05) at 11 weeks of the dietary period, and at 6 weeks (p < 0.05) and 11 weeks (p < 0.01) after the end of the diet. The changes in platelet phospholipid fatty acid composition consisted of increases in the omega-3 series (EPA and DHA) and decreases in omega-6 PUFA. The flexibility of the PUFA chain in membranes accounts for the high fluidity, permeability, elasticity, fusion, and enhanced flip-flop associated with DHA in the membrane.79 DHA-rich regions in membranes are thin, have looser lipid packing, and are found to be more dynamic than the regions of membranes composed of other fatty acids.79

Onion Onion is a member of the garlic family. Onions are versatile and are often used as an ingredient in many dishes and are accepted by almost all traditions and cultures.95 Quercetin is a Seminars in Thrombosis & Hemostasis

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bioflavonoid found in high levels in onions. In a twotreatment, randomized, double-blind, crossover study, six individuals ingested a soup containing either a high or a low amount of quercetin.96 Collagen-stimulated (0.5 µg/mL) platelet aggregation was inhibited after ingestion of the high quercetin soup at 1 and 3 hours after ingestion compared with baseline. The inhibitory effect was greater 3 hours after ingestion of the high quercetin soup, when platelets were stimulated with 0.5, 1, and 2 µg/mL collagen. Collagenstimulated tyrosine phosphorylation of a key component of the collagen-signaling pathway via glycoprotein VI was significantly inhibited by ingestion of the high-quercetin soup at 1 and 3 hours after ingestion compared with baseline. The effect of 150 or 300 mg of quercetin was investigated on collagen-stimulated platelet aggregation and cell signaling in six healthy individuals.97 Ingestion of 150 or 300 mg of quercetin inhibited platelet aggregation 30 minutes after ingestion. The inhibitory effect was greater 120 minutes after ingestion. The inhibition of platelet aggregation with 300 mg of quercetin was twofold greater than for 150 mg. Collagenstimulated tyrosine phosphorylation of whole platelet protein was also inhibited. Forty-four healthy men consumed 4.3 g of onion extract (containing 51 mg of quercetin) once a day for 30 days.98 Onion extract consumption improved postprandial flowmediated vasodilation, but did not alter the fasting flowmediated vasodilation. Chronic onion extract intake ameliorated postprandial endothelial dysfunction and may be beneficial for preventing cardiovascular outcomes. Onion extracts have been found to be weak inhibitors of platelet thromboxane synthesis.63 Onion and its effects on platelet inhibition are not as well established as garlic. Further studies are advisable to evaluate the effectiveness of onion on inhibition of platelet function.

Red Wine, Resveratrol, and Alcohol There are inverse associations between red wine consumption and prevalence of vascular risk factors in CVD.99,100 A meta-analysis found a 32% risk reduction in vascular disease in people drinking 150 mL wine daily.101 The components of red wine, principally alcohol, resveratrol, and other polyphenolic compounds, may decrease oxidative stress, inhibit the oxidation of lipoproteins, improve endothelial function, and counteract platelet hyperactivity.99 Conversely, chronic heavy alcohol consumption and binge drinking are associated with increased risk of cardiovascular events.99 Moderate red wine consumption was investigated in 15 healthy males.100 After 4 weeks, there was a reduction in plasma fibrinogen (p < 0.05). There was no change in ADP or collagen-induced platelet aggregation, CD40 ligand and Pselectin levels, activated partial thromboplastin time, or biomarkers of oxidative stress. Resveratrol is a common polyphenol found in grape skins and red wine.102,103 Studies were performed on 24 healthy males aged 26 to 45 years.104 Each consumed the following beverages for a period of 4 weeks: red wine, white wine, commercial grape juice, and the same grape juice enriched with trans-resveratrol. White wine (p < 0.05) but not red


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Tomato Tomatoes and their major antioxidant component lycopene have recently been focused as important antioxidant nutrients because of their ability to reduce to generation of ROS.110 In vitro studies have shown that tomato inhibits platelet aggregation.111,112 Platelet-rich plasma was prepared from human blood and incubated in the presence or absence of tomato extract before stimulating the platelets with the platelet agonists ADP, AA, and collagen.112 Platelet aggregation induced by either collagen or ADP was significantly inhibited by the tomato extract (p < 0.001). No effect was observed with AA-induced platelet aggregation.111 ADP-induced platelet aggregation was significantly lower than baseline values after supplementation with tomato extract, but not after supplementation with a control drink.113 A randomized, double-blinded, placebo-controlled crossover study was conducted in 90 healthy individuals selected for normal platelet function.114 Changes from baseline hemostatic function were measured 3 hours after consumption of tomato extract–enriched or placebo supplements. Significant reductions in platelet aggregation induced by ADP and collagen were observed 3 hours after consumption. No significant changes were found for the placebo supplement. Lazarus and colleagues115 found that consumption of tomato juice by individuals with type 2 diabetes significantly inhibited platelet aggregation after 3 weeks (p < 0.001). There was no change in the placebo group.

Turmeric Curcumin is the active ingredient in the spice turmeric (Curcuma longa).116,117 Curcumin has a wide range of beneficial properties with potential use in CVD including antiinflammatory and antioxidant actions.116,117 There are limited data on the effect of turmeric on platelet function. However, in vitro studies have found inhibited platelet aggregation induced by ADP,118 adrenaline, AA, collagen,118,119 and platelet-activating factor.118 The potential for turmeric in reducing platelet aggregation needs further investigations in human studies.

Conclusion Some diets and nutrients have been shown to affect platelet function. Dark chocolate, foods with low glycemic index, garlic, ginger, omega-3 PUFA, onion, purple grape juice, tomato, and wine reduce platelet aggregation. Dark chocolate also reduces P-selectin expression, PAC-1 binding, and platelet microparticle formation. Berries inhibit platelet function (PFA-100 assay). Energy drinks have been shown to increase platelet aggregation and caffeine increases platelet microparticle formation. Nutrients and foods that alter platelet function have the potential to lead to unexpected abnormal results in laboratory tests. Care should be placed when taking case histories to include dietary factors and nutritional supplements. Repeat laboratory testing may be required after exclusion of nutrients and foods that have been found to alter platelet function and Seminars in Thrombosis & Hemostasis

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wine increased the concentration of ADP required for 50% aggregation. Both wines increased the concentration of thrombin required for 50% aggregation (p < 0.02 and p < 0.001, respectively). Red wine and white wine significantly lowered plasma thromboxane B2 concentrations (p < 0.01 and p < 0.025, respectively). Twenty healthy volunteers were studied before and after 15 days of controlled white or red wine intake (300 mL/day).105 Plasma resveratrol and the release of nitric oxide by stimulated platelets increased significantly (p < 0.05) after 15 days of white or red wine consumption. Twenty healthy individuals consumed 7 mL/kg/day of purple grape juice for 14 days.106 Compared with baseline, maximum platelet aggregation was decreased by 18.2 7.4% (p ¼ 0.09) and 12.8 5.3% (p ¼ 0.08) for ADP and collagen, respectively. Supplementation with purple grape juice also led to an increase in platelet-derived nitric oxide release and a significant decrease in platelet superoxide production. In a randomized crossover design, Keevil et al107 investigated the effect of 5 to 7.5 mL/(kg/day) of purple grape juice, orange juice, or grapefruit juice in 10 healthy individuals for 7 to 10 days each. Drinking purple grape juice for 1 week reduced the whole blood platelet aggregation response to collagen (1.0 mg/L) by 77% (p ¼ 0.0002) compared with baseline. In addition, a higher concentration of collagen (12.5 mg/L), purple grape juice consumption for 7 days, also significantly inhibited platelet aggregation by 21% (p ¼ 0.003). Orange juice and grapefruit juice consumption had no effect on collagen-induced platelet aggregation. ADP- or thrombininduced platelet aggregation was not affected by drinking any of the three juices. Intake of alcohol and platelet aggregation was determined in 1,600 men (aged 49–66 years) in the Caerphilly Prospective Heart Disease Study.108 Participants gave a fasting blood sample and completed a detailed series of questions about the frequency, amount, and type of alcohol usually consumed. Platelet aggregation in response to ADP, collagen, and thrombin was measured. Significant trends of decreasing odds ratios with increasing frequency of alcohol consumption were found for primary ADP-, secondary ADP-, and collagen-induced platelet aggregation (p < 0.05, p < 0.001, and p < 0.02, respectively) compared with nondrinkers. Moderate intake of alcohol occurring only on weekends (mean 60 g alcohol/week; odds ratio 0.37, p < 0.01), most days of the week (odds ratio 0.34, p < 0.01), or every day (odds ratio 0.30, p < 0.001) had significantly decreased secondary aggregation to ADP compared with nondrinkers. An in vitro study109 tested the effects of resveratrol on platelet function. Pretreatment of platelets with resveratrol, at a concentration of 50 μg/mL, inhibited their adhesion to collagen by 32% in resting platelets and by 57% in thrombinactivated platelets after 1 hour of preincubation. Thrombininduced platelet aggregation was also inhibited by 59% after 30 minutes preincubation. In another study,40 resveratrol inhibited both thrombin-induced and ADP-induced aggregation. Red wine and resveratrol have been linked to reducing CVD. Further studies are suggested to test the short- and longterm effect of red wine on platelet function.

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that could have plausibly affected initial test data. It may be advisable to conduct platelet function studies with fasting morning blood samples to eliminate the effects of foods and beverages that have the potential of altering the results, although some of these may have long lasting effects.

19 Allman-Farinelli MA, Dawson B. Diet and aging: bearing on

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Funding No financial support was received for the article.

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Copyright of Seminars in Thrombosis & Hemostasis is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Influence of diet on tear function.

Influence of cephalosporin antibiotics on blood coagulation and platelet function.

Influence of thrombolytic agents on human platelet function.

Influence of diet intake on liver function test.

The influence of herbal medicine on platelet function and coagulation: a narrative review.

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces.

The effect of dexamethasone on platelet function.

Influence of diet and feed restriction on kidney function of aging male rats.

Phosphodiesterase-inhibitors enoximone and piroximone in cardiac surgery: influence on platelet count and function.

What are the effects of dietary fatty acid modification on platelet eicosanoid metabolism, platelet-activating factor, and platelet function? How might these metabolic alterations influence thrombosis?

The influence of metabolities on the assay of platelet serotonin.

Influence of diet on survival of mice.

Influence of mental stress on platelet bioactivity.

The effects of insects, nutrients, and plant invasion on community structure and function above-and belowground.

The effect of ethanol on platelet function and vascular prostanoids.

The influence of prostaglandin G2 on platelet ultrastructure and platelet secretion.

Influence of five different priming solutions on platelet function in patients undergoing cardiac surgery.

Influence of diet on digoxin dose requirements.

Effects of clofibrate on platelets and evidence of the involvement of platelet lipids in platelet function.

Nutrients as modulators of immune function.

Nutrients as modulators of immune function.

The influence of latitude on imipramine platelet binding sites.

The influence of plasma proteins on human platelet metabolism.

The influence of prostaglandin endoperoxides on platelet ultrastructure.