Nutrition Phytochemicals Affecting Platelet Signaling and Responsiveness: Implications for Thrombosis and Hemostasis

Abstract

Cardiovascular disease, in particular due to arterial thrombosis, is a leading cause of mortality and morbidity, with crucial roles of platelets in thrombus formation. For multiple plant-derived phytochemicals found in common dietary components, claims have been made regarding cardiovascular health and antiplatelet activities. Here we present a systematic overview of the published effects of common phytochemicals, applied in vitro or in nutritional intervention studies, on agonist-induced platelet activation properties and platelet signaling pathways. Comparing the phytochemical effects per structural class, we included general phenols: curcuminoids (e.g., curcumin), lignans (honokiol, silybin), phenolic acids (caffeic and chlorogenic acid), derivatives of these (shikimic acid), and stilbenoids (isorhapontigenin, resveratrol). Furthermore, we evaluated the flavonoid polyphenols, including anthocyanidins (delphinidin, malvidin), flavan-3-ols (catechins), flavanones (hesperidin), flavones (apigenin, nobiletin), flavonols (kaempferol, myricetin, quercetin), and isoflavones (daidzein, genistein); and terpenoids including carotenes and limonene; and finally miscellaneous compounds like betalains, indoles, organosulfides (diallyl trisulfide), and phytosterols. We furthermore discuss the implications for selected phytochemicals to interfere in thrombosis and hemostasis, indicating their possible clinical relevance. Lastly, we provide guidance on which compounds are of interest for further platelet-related research.

Keywords

hemostasis - nutrition - platelet - signaling - thrombosis

Author Contributions

F.T., B.M.E.T., M.J.E.K., T.A.M.C., and J.W.M.H. performed research, analyzed data, drafted, and wrote the manuscript.

^* Equal contribution.

Publikationsverlauf

Eingereicht: 04. Juni 2021

Angenommen: 27. Oktober 2021

Accepted Manuscript online:
29. Oktober 2021

Artikel online veröffentlicht:
29. Dezember 2021

• References

• 1 Piepoli MF, Hoes AW, Agewall S. et al; ESC Scientific Document Group. 2016 European guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37 (29) 2315-2381
• 2 van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and clinical perspectives. Nat Rev Cardiol 2019; 16 (03) 166-179
• 3 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (01) 327-358
• 4 Fernández DI, Kuijpers MJE, Heemskerk JWM. Platelet calcium signaling by G-protein coupled and ITAM-linked receptors regulating anoctamin-6 and procoagulant activity. Platelets 2021; 32 (07) 863-871
• 5 Swieringa F, Kuijpers MJ, Heemskerk JW, van der Meijden PE. Targeting platelet receptor function in thrombus formation: the risk of bleeding. Blood Rev 2014; 28 (01) 9-21
• 6 Baaten CCFMJ, Ten Cate H, van der Meijden PEJ, Heemskerk JWM. Platelet populations and priming in hematological diseases. Blood Rev 2017; 31 (06) 389-399
• 7 Satoh K, Satoh T, Yaoita N, Shimokawa H. Recent advances in the understanding of thrombosis. Arterioscler Thromb Vasc Biol 2019; 39 (06) e159-e165
• 8 Mertens E, Markey O, Geleijnse JM, Givens DI, Lovegrove JA. Dietary patterns in relation to cardiovascular disease incidence and risk markers in a middle-aged British male population: data from the Caerphilly prospective study. Nutrients 2017; 9 (01) 75
• 9 Molyneux RJ, Lee ST, Gardner DR, Panter KE, James LF. Phytochemicals: the good, the bad and the ugly?. Phytochemistry 2007; 68 (22–24): 2973-2985
• 10 U.S. Food and Drug Administration. Health claims: fiber-containing grain products, fruits, and vegetables and cancer. Title 21: Food and Drugs. Subpart E 2017;10176. Accessed January 8, 2017 at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.76
• 11 European Food Safety Authority. Scientific opinion on the substantiation of health claims related to various food(s)/food constituent(s) and protection of cells from premature aging, antioxidant activity, antioxidant content and antioxidant properties, and protection of DNA, proteins and lipids from oxidative damage pursuant to Article 13(1) of Regulation (EC) No 1924/20061. EFSA J 2010; 8: 1489
• 12 U.S. Food and Drug Administration. Food labeling, subpart D, specific requirements for nutrient content claims, section 101.54. Code of Federal Regulations 2016;21(Part 101):2017
• 13 Shaw D. Toxicological risks of Chinese herbs. Planta Med 2010; 76 (17) 2012-2018
• 14 Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004; 79 (05) 727-747
• 15 Barbieri R, Coppo E, Marchese A. et al. Phytochemicals for human disease: an update on plant-derived compounds antibacterial activity. Microbiol Res 2017; 196: 44-68
• 16 Lewandowska H, Kalinowska M, Lewandowski W, Stępkowski TM, Brzóska K. The role of natural polyphenols in cell signaling and cytoprotection against cancer development. J Nutr Biochem 2016; 32: 1-19
• 17 Keihanian F, Saeidinia A, Bagheri RK, Johnston TP, Sahebkar A. Curcumin, hemostasis, thrombosis, and coagulation. J Cell Physiol 2018; 233 (06) 4497-4511
• 18 Rauf A, Patel S, Imran M. et al. Honokiol: an anticancer lignan. Biomed Pharmacother 2018; 107: 555-562
• 19 Calado A, Neves PM, Santos T, Ravasco P. The effect of flaxseed in breast cancer: a literature review. Front Nutr 2018; 5: 4
• 20 Grassi D, Desideri G, Di Giosia P. et al. Tea, flavonoids, and cardiovascular health: endothelial protection. Am J Clin Nutr 2013; 98 (6, Suppl): 1660S-1666S
• 21 Ali SS, Ahmad WANW, Budin SB, Zainalabidin S. Implication of dietary phenolic acids on inflammation in cardiovascular disease. Rev Cardiovasc Med 2020; 21 (02) 225-240
• 22 Anantharaju PG, Gowda PC, Vimalambike MG, Madhunapantula SV. An overview on the role of dietary phenolics for the treatment of cancers. Nutr J 2016; 15 (01) 99
• 23 Signorelli P, Ghidoni R. Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 2005; 16 (08) 449-466
• 24 Ramprasath VR, Jones PJ. Anti-atherogenic effects of resveratrol. Eur J Clin Nutr 2010; 64 (07) 660-668
• 25 Wang TY, Li Q, Bi KS. Bioactive flavonoids in medicinal plants: structure, activity and biological fate. Asian J Pharm Sci 2018; 13 (01) 12-23
• 26 Guo H, Ling W. The update of anthocyanins on obesity and type 2 diabetes: experimental evidence and clinical perspectives. Rev Endocr Metab Disord 2015; 16 (01) 1-13
• 27 The devil in the dark chocolate. Lancet 2007; 370: 2070
• 28 Mulvihill EE, Burke AC, Huff MW. Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis. Annu Rev Nutr 2016; 36: 275-299
• 29 López-Lázaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 2009; 9 (01) 31-59
• 30 Boots AW, Li H, Schins RP. et al. The quercetin paradox. Toxicol Appl Pharmacol 2007; 222 (01) 89-96
• 31 Rangel-Huerta OD, Pastor-Villaescusa B, Aguilera CM, Gil A. A systematic review of the efficacy of bioactive compounds in cardiovascular disease: phenolic compounds. Nutrients 2015; 7 (07) 5177-5216
• 32 Ørgaard A, Jensen L. The effects of soy isoflavones on obesity. Exp Biol Med (Maywood) 2008; 233 (09) 1066-1080
• 33 Eggersdorfer M, Wyss A. Carotenoids in human nutrition and health. Arch Biochem Biophys 2018; 652: 18-26
• 34 Katz E, Nisani S, Chamovitz DA. Indole-3-carbinol: a plant hormone combatting cancer. F1000 Res 2018; 7: 1
• 35 Butt MS, Sultan MT, Butt MS, Iqbal J. Garlic: nature's protection against physiological threats. Crit Rev Food Sci Nutr 2009; 49 (06) 538-551
• 36 Lissiman E, Bhasale AL, Cohen M. Garlic for the common cold. Cochrane Database Syst Rev 2014; 11 (11) CD006206
• 37 Köhler J, Teupser D, Elsässer A, Weingärtner O. Plant sterol enriched functional food and atherosclerosis. Br J Pharmacol 2017; 174 (11) 1281-1289
• 38 Mayanglambam A, Dangelmaier CA, Thomas D, Damodar Reddy C, Daniel JL, Kunapuli SP. Curcumin inhibits GPVI-mediated platelet activation by interfering with the kinase activity of Syk and the subsequent activation of PLCgamma2. Platelets 2010; 21 (03) 211-220
• 39 Shah BH, Nawaz Z, Pertani SA. et al. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol 1999; 58 (07) 1167-1172
• 40 Prakash P, Misra A, Surin WR. et al. Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis. Thromb Res 2011; 127 (02) 111-118
• 41 Onselaer MB, Nagy M, Pallini C. et al. Comparison of the GPVI inhibitors losartan and honokiol. Platelets 2020; 31 (02) 187-197
• 42 Bijak M, Szelenberger R, Dziedzic A, Saluk-Bijak J. Inhibitory effect of flavonolignans on the P2Y₁₂ pathway in blood platelets. Molecules 2018; 23 (02) 374
• 43 Bijak M, Szelenberger R, Saluk J, Nowak P. Flavonolignans inhibit ADP induced blood platelets activation and aggregation in whole blood. Int J Biol Macromol 2017; 95: 682-688
• 44 Parveen R, Baboota S, Ali J, Ahuja A, Vasudev SS, Ahmad S. Oil based nanocarrier for improved oral delivery of silymarin: in vitro and in vivo studies. Int J Pharm 2011; 413 (1–2): 245-253
• 45 Olthof MR, Hollman PC, Katan MB. Chlorogenic acid and caffeic acid are absorbed in humans. J Nutr 2001; 131 (01) 66-71
• 46 Park JB. 5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets. J Nutr Biochem 2009; 20 (10) 800-805
• 47 Ostertag LM, O'Kennedy N, Horgan GW, Kroon PA, Duthie GG, de Roos B. In vitro anti-platelet effects of simple plant-derived phenolic compounds are only found at high, non-physiological concentrations. Mol Nutr Food Res 2011; 55 (11) 1624-1636
• 48 Nam GS, Park HJ, Nam KS. The antithrombotic effect of caffeic acid is associated with a cAMP-dependent pathway and clot retraction in human platelets. Thromb Res 2020; 195: 87-94
• 49 Lee DH, Kim HH, Cho HJ, Bae JS, Yu YB, Park HJ. Antiplatelet effects of caffeic acid due to Ca(2+) mobilizationinhibition via cAMP-dependent inositol-1, 4, 5-trisphosphate receptor phosphorylation. J Atheroscler Thromb 2014; 21 (01) 23-37
• 50 Lu Y, Li Q, Liu YY. et al. Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases. Sci Rep 2015; 5: 13824
• 51 Fuentes E, Caballero J, Alarcón M, Rojas A, Palomo I. Chlorogenic acid inhibits human platelet activation and thrombus formation. PLoS One 2014; 9 (03) e90699
• 52 Ok WJ, Cho HJ, Kim HH. et al. Epigallocatechin-3-gallate has an anti-platelet effect in a cyclic AMP-dependent manner. J Atheroscler Thromb 2012; 19 (04) 337-348
• 53 Crescente M, Jessen G, Momi S. et al. Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level. Functional and modelling studies. Thromb Haemost 2009; 102 (02) 336-346
• 54 Lill G, Voit S, Schrör K, Weber AA. Complex effects of different green tea catechins on human platelets. FEBS Lett 2003; 546 (2–3): 265-270
• 55 Veach D, Hosking H, Thompson K, Santhakumar AB. Anti-platelet and anti-thrombogenic effects of shikimic acid in sedentary population. Food Funct 2016; 7 (08) 3609-3616
• 56 Ravishankar D, Albadawi DAI, Chaggar V. et al. Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation. Eur J Pharmacol 2019; 862: 172627
• 57 Wang Z, Huang Y, Zou J, Cao K, Xu Y, Wu JM. Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med 2002; 9 (01) 77-79
• 58 Kirk RI, Deitch JA, Wu JM, Lerea KM. Resveratrol decreases early signaling events in washed platelets but has little effect on platelet in whole blood. Blood Cells Mol Dis 2000; 26 (02) 144-150
• 59 Rechner AR, Kroner C. Anthocyanins and colonic metabolites of dietary polyphenols inhibit platelet function. Thromb Res 2005; 116 (04) 327-334
• 60 Krga I, Vidovic N, Milenkovic D. et al. Effects of anthocyanins and their gut metabolites on adenosine diphosphate-induced platelet activation and their aggregation with monocytes and neutrophils. Arch Biochem Biophys 2018; 645: 34-41
• 61 Yao Y, Chen Y, Adili R. et al. Plant-based food cyanidin-3-glucoside modulates human platelet glycoprotein VI signaling and inhibits platelet activation and thrombus formation. J Nutr 2017; 147 (10) 1917-1925
• 62 Czank C, Cassidy A, Zhang Q. et al. Human metabolism and elimination of the anthocyanin, cyanidin-3-glucoside: a (13)C-tracer study. Am J Clin Nutr 2013; 97 (05) 995-1003
• 63 Yang Y, Shi Z, Reheman A. et al. Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: novel protective roles against cardiovascular diseases. PLoS One 2012; 7 (05) e37323
• 64 Pignatelli P, Pulcinelli FM, Celestini A. et al. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Am J Clin Nutr 2000; 72 (05) 1150-1155
• 65 Wright B, Moraes LA, Kemp CF. et al. A structural basis for the inhibition of collagen-stimulated platelet function by quercetin and structurally related flavonoids. Br J Pharmacol 2010; 159 (06) 1312-1325
• 66 Kang WS, Chung KH, Chung JH. et al. Antiplatelet activity of green tea catechins is mediated by inhibition of cytoplasmic calcium increase. J Cardiovasc Pharmacol 2001; 38 (06) 875-884
• 67 Iida Y, Doi T, Matsushima-Nishiwaki R. et al. (-)-Epigallocatechin gallate selectively inhibits adenosine diphosphate–stimulated human platelet activation: suppression of heat shock protein 27 phosphorylation via p38 mitogen–activated protein kinase. Mol Med Rep 2014; 10 (03) 1383-1388
• 68 Guerrero JA, Navarro-Nuñez L, Lozano ML. et al. Flavonoids inhibit the platelet TxA(2) signalling pathway and antagonize TxA(2) receptors (TP) in platelets and smooth muscle cells. Br J Clin Pharmacol 2007; 64 (02) 133-144
• 69 Navarro-Núñez L, Rivera J, Guerrero JA, Martínez C, Vicente V, Lozano ML. Differential effects of quercetin, apigenin and genistein on signalling pathways of protease-activated receptors PAR(1) and PAR(4) in platelets. Br J Pharmacol 2009; 158 (06) 1548-1556
• 70 Nam GS, Lee KS, Nam KS. Morin hydrate inhibits platelet activation and clot retraction by regulating integrin α_IIbβ₃, TXA₂, and cAMP levels. Eur J Pharmacol 2019; 865: 172734
• 71 Choi JH, Park SE, Kim SJ, Kim S. Kaempferol inhibits thrombosis and platelet activation. Biochimie 2015; 115: 177-186
• 72 Gaspar RS, da Silva SA, Stapleton J. et al. Myricetin, the main flavonoid in Syzygium cumini leaf, is a novel inhibitor of platelet thiol isomerases PDI and ERp5. Front Pharmacol 2020; 10: 1678
• 73 Dang Y, Lin G, Xie Y. et al. Quantitative determination of myricetin in rat plasma by ultra performance liquid chromatography tandem mass spectrometry and its absolute bioavailability. Drug Res (Stuttg) 2014; 64 (10) 516-522
• 74 Lescano CH, Freitas de Lima F, Mendes-Silvério CB. et al. Effect of polyphenols from Campomanesia adamantium on platelet aggregation and inhibition of cyclooxygenases: molecular docking and in vitro analysis. Front Pharmacol 2018; 9: 617
• 75 Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans. J Thromb Haemost 2004; 2 (12) 2138-2145
• 76 Pignatelli P, Di Santo S, Buchetti B, Sanguigni V, Brunelli A, Violi F. Polyphenols enhance platelet nitric oxide by inhibiting protein kinase C-dependent NADPH oxidase activation: effect on platelet recruitment. FASEB J 2006; 20 (08) 1082-1089
• 77 Beretz A, Stierle A, Anton R, Cazenave JP. Role of cyclic AMP in the inhibition of human platelet aggregation by quercetin, a flavonoid that potentiates the effect of prostacyclin. Biochem Pharmacol 1982; 31 (22) 3597-3600
• 78 Lanza F, Beretz A, Stierlé A, Corre G, Cazenave JP. Cyclic nucleotide phosphodiesterase inhibitors prevent aggregation of human platelets by raising cyclic AMP and reducing cytoplasmic free calcium mobilization. Thromb Res 1987; 45 (05) 477-484
• 79 Shanmuganayagam D, Beahm MR, Osman HE, Krueger CG, Reed JD, Folts JD. Grape seed and grape skin extracts elicit a greater antiplatelet effect when used in combination than when used individually in dogs and humans. J Nutr 2002; 132 (12) 3592-3598
• 80 Gottstein N, Ewins BA, Eccleston C. et al. Effect of genistein and daidzein on platelet aggregation and monocyte and endothelial function. Br J Nutr 2003; 89 (05) 607-616
• 81 Kondo K, Suzuki Y, Ikeda Y, Umemura K. Genistein, an isoflavone included in soy, inhibits thrombotic vessel occlusion in the mouse femoral artery and in vitro platelet aggregation. Eur J Pharmacol 2002; 455 (01) 53-57
• 82 Kansra SV, Reddy MA, Weng YI, Shukla SD. Activation of mitogen activated protein kinase in human platelets by genistein. Pharmacol Res 1999; 39 (01) 21-31
• 83 Ozaki Y, Yatomi Y, Jinnai Y, Kume S. Effects of genistein, a tyrosine kinase inhibitor, on platelet functions. Genistein attenuates thrombin-induced Ca2+ mobilization in human platelets by affecting polyphosphoinositide turnover. Biochem Pharmacol 1993; 46 (03) 395-403
• 84 Nakashima S, Koike T, Nozawa Y. Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses. Mol Pharmacol 1991; 39 (04) 475-480
• 85 Kim K, Lim KM, Kim CW. et al. Black soybean extract can attenuate thrombosis through inhibition of collagen-induced platelet activation. J Nutr Biochem 2011; 22 (10) 964-970
• 86 Hosono T, Sato A, Nakaguchi N, Ozaki-Masuzawa Y, Seki T. Diallyl trisulfide inhibits platelet aggregation through the modification of sulfhydryl groups. J Agric Food Chem 2020; 68 (06) 1571-1578
• 87 Chan KC, Hsu CC, Yin MC. Protective effect of three diallyl sulphides against glucose-induced erythrocyte and platelet oxidation, and ADP-induced platelet aggregation. Thromb Res 2002; 108 (5–6): 317-322
• 88 Qi R, Liao F, Inoue K, Yatomi Y, Sato K, Ozaki Y. Inhibition by diallyl trisulfide, a garlic component, of intracellular Ca(2+) mobilization without affecting inositol-1,4, 5-trisphosphate (IP(3)) formation in activated platelets. Biochem Pharmacol 2000; 60 (10) 1475-1483
• 89 Badol P, David-Dufilho M, Auger J, Whiteheart SW, Rendu F. Thiosulfinates modulate platelet activation by reaction with surface free sulfhydryls and internal thiol-containing proteins. Platelets 2007; 18 (07) 481-490
• 90 Thushara RM, Hemshekhar M, Santhosh MS. et al. Crocin, a dietary additive protects platelets from oxidative stress-induced apoptosis and inhibits platelet aggregation. Mol Cell Biochem 2013; 373 (1–2): 73-83
• 91 Keen CL, Holt RR, Polagruto JA, Wang JF, Schmitz HH. Cocoa flavanols and cardiovascular health. Phytochem Rev 2002; 1: 231-240
• 92 Pellegrini N, Pareti FI, Stabile F, Brusamolino A, Simonetti P. Effects of moderate consumption of red wine on platelet aggregation and haemostatic variables in healthy volunteers. Eur J Clin Nutr 1996; 50 (04) 209-213
• 93 Kikura M, Levy JH, Safon RA, Lee MK, Szlam F. The influence of red wine or white wine intake on platelet function and viscoelastic property of blood in volunteers. Platelets 2004; 15 (01) 37-41
• 94 Erlund I, Koli R, Alfthan G. et al. Favorable effects of berry consumption on platelet function, blood pressure, and HDL cholesterol. Am J Clin Nutr 2008; 87 (02) 323-331
• 95 Ras RT, Zock PL, Zebregs YE, Johnston NR, Webb DJ, Draijer R. Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension. Br J Nutr 2013; 110 (12) 2234-2241
• 96 Duttaroy AK, Jørgensen A. Effects of kiwi fruit consumption on platelet aggregation and plasma lipids in healthy human volunteers. Platelets 2004; 15 (05) 287-292
• 97 Keevil JG, Osman HE, Reed JD, Folts JD. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr 2000; 130 (01) 53-56
• 98 Thompson K, Hosking H, Pederick W, Singh I, Santhakumar AB. The effect of anthocyanin supplementation in modulating platelet function in sedentary population: a randomised, double-blind, placebo-controlled, cross-over trial. Br J Nutr 2017; 118 (05) 368-374
• 99 Thompson K, Pederick W, Singh I, Santhakumar AB. Anthocyanin supplementation in alleviating thrombogenesis in overweight and obese population: a randomized, double-blind, placebo-controlled study. J Funct Foods 2017; 32: 131-138
• 100 Song F, Zhu Y, Shi Z. et al. Plant food anthocyanins inhibit platelet granule secretion in hypercholesterolaemia: Involving the signalling pathway of PI3K-Akt. Thromb Haemost 2014; 112 (05) 981-991
• 101 Ostertag LM, Kroon PA, Wood S. et al. Flavan-3-ol-enriched dark chocolate and white chocolate improve acute measures of platelet function in a gender-specific way–a randomized-controlled human intervention trial. Mol Nutr Food Res 2013; 57 (02) 191-202
• 102 Bordeaux B, Yanek LR, Moy TF. et al. Casual chocolate consumption and inhibition of platelet function. Prev Cardiol 2007; 10 (04) 175-180
• 103 Polagruto JA, Gross HB, Kamangar F. et al. Platelet reactivity in male smokers following the acute consumption of a flavanol-rich grapeseed extract. J Med Food 2007; 10 (04) 725-730
• 104 Conquer JA, Maiani G, Azzini E, Raguzzini A, Holub BJ. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J Nutr 1998; 128 (03) 593-597
• 105 Janssen K, Mensink RP, Cox FJ. et al. Effects of the flavonoids quercetin and apigenin on hemostasis in healthy volunteers: results from an in vitro and a dietary supplement study. Am J Clin Nutr 1998; 67 (02) 255-262
• 106 Gooderham MH, Adlercreutz H, Ojala ST, Wähälä K, Holub BJ. A soy protein isolate rich in genistein and daidzein and its effects on plasma isoflavone concentrations, platelet aggregation, blood lipids and fatty acid composition of plasma phospholipid in normal men. J Nutr 1996; 126 (08) 2000-2006
• 107 Fakhar H, Hashemi Tayer A. Effect of the garlic pill in comparison with plavix on platelet aggregation and bleeding time. Iran J Ped Hematol Oncol 2012; 2 (04) 146-152
• 108 Legnani C, Frascaro M, Guazzaloca G, Ludovici S, Cesarano G, Coccheri S. Effects of a dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung 1993; 43 (02) 119-122
• 109 Rahman K, Lowe GM, Smith S. Aged garlic extract inhibits human platelet aggregation by altering intracellular signaling and platelet shape change. J Nutr 2016; 146 (02) 410S-415S
• 110 Wojcikowski K, Myers S, Brooks L. Effects of garlic oil on platelet aggregation: a double-blind placebo-controlled crossover study. Platelets 2007; 18 (01) 29-34
• 111 Morris J, Burke V, Mori TA, Vandongen R, Beilin LJ. Effects of garlic extract on platelet aggregation: a randomized placebo-controlled double-blind study. Clin Exp Pharmacol Physiol 1995; 22 (6–7): 414-417
• 112 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 (03) 247-249
• 113 Morihara N, Hino A, Yamaguchi T, Suzuki J. Aged garlic extract suppresses the development of atherosclerosis in apolipoprotein E-knockout mice. J Nutr 2016; 146 (02) 460S-463S
• 114 Clifford MN, van der Hooft JJ, Crozier A. Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols. Am J Clin Nutr 2013; 98 (6, Suppl): 1619S-1630S
• 115 Wright B, Spencer JP, Lovegrove JA, Gibbins JM. Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs. Cardiovasc Res 2013; 97 (01) 13-22
• 116 Hubbard GP, Wolffram S, de Vos R, Bovy A, Gibbins JM, Lovegrove JA. Ingestion of onion soup high in quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in man: a pilot study. Br J Nutr 2006; 96 (03) 482-488
• 117 Bucki R, Pastore JJ, Giraud F, Sulpice JC, Janmey PA. Flavonoid inhibition of platelet procoagulant activity and phosphoinositide synthesis. J Thromb Haemost 2003; 1 (08) 1820-1828
• 118 Guglielmone HA, Agnese AM, Núñez Montoya SC, Cabrera JL. Inhibitory effects of sulphated flavonoids isolated from Flaveria bidentis on platelet aggregation. Thromb Res 2005; 115 (06) 495-502
• 119 Bijak M, Sut A, Kosiorek A, Saluk-Bijak J, Golanski J. Dual anticoagulant/antiplatelet activity of polyphenolic grape seeds extract. Nutrients 2019; 11 (01) 93
• 120 Olas B, Wachowicz B, Stochmal A, Oleszek W. The polyphenol-rich extract from grape seeds inhibits platelet signaling pathways triggered by both proteolytic and non-proteolytic agonists. Platelets 2012; 23 (04) 282-289
• 121 Chan KC, Yin MC, Chao WJ. Effect of diallyl trisulfide-rich garlic oil on blood coagulation and plasma activity of anticoagulation factors in rats. Food Chem Toxicol 2007; 45 (03) 502-507
• 122 Li W, Ma Y, Zhang C. et al. Tetrahydrocurcumin downregulates MAPKs/cPLA2 signaling and attenuates platelet thromboxane A₂ generation, granule secretion, and thrombus growth. Thromb Haemost 2021; DOI: 10.1055/s-0041-1735192.
• 123 Chen XQ, Wang XB, Guan RF. et al. Blood anticoagulation and antiplatelet activity of green tea (-)-epigallocatechin (EGC) in mice. Food Funct 2013; 4 (10) 1521-1525
• 124 Vaiyapuri S, Roweth H, Ali MS. et al. Pharmacological actions of nobiletin in the modulation of platelet function. Br J Pharmacol 2015; 172 (16) 4133-4145
• 125 Oh TW, Do HJ, Jeon JH, Kim K. Quercitrin inhibits platelet activation in arterial thrombosis. Phytomedicine 2021; 80: 153363
• 126 Frank J, Fukagawa NK, Bilia AR. et al. Terms and nomenclature used for plant-derived components in nutrition and related research: efforts toward harmonization. Nutr Rev 2020; 78 (06) 451-458