Flavonoids as potential anti-platelet aggregation agents: from biochemistry to health promoting abilities

Abstract Cardiovascular ailments are the number one cause of mortalities throughout the globe with 17.9 million deaths per year. Platelet activation and aggregation play a crucial role in the pathogenesis of arterial diseases, including acute coronary syndrome, acute myocardial infarction, cerebrovascular transient ischemia, unstable angina, among others. Flavonoids-rich plant extracts are gaining interest for treating the heart-related problems due to safe nature of these herbal extracts. Consumption of plant-food-derived bioactives, particularly flavonoids, has shown antithrombotic, and cardiovascular protective effects due to its anti-platelet activity. Preclinical and clinical trials have proven that flavonoid-rich plant extracts are protective against the cardiac ailments through anti-platelet aggregation activity. This review aims to highlight the anti-platelet aggregation potential of flavonoids with a key emphasis on the therapeutic efficacy in humans. The mechanism of flavonoids in preventing and treating cardiovascular diseases is also highlighted based on preclinical and clinical experimental trials. Further studies are the need of time for exploring the exact molecular mechanism of flavonoids as anti-platelet aggregation agents for treating heart-related problems.

[1]  C. Tonelli,et al.  The Therapeutic Potential of Anthocyanins: Current Approaches Based on Their Molecular Mechanism of Action , 2020, Frontiers in Pharmacology.

[2]  Huayi Suo,et al.  Comparison of In Vitro and In Vivo Antioxidant Activities of Six Flavonoids with Similar Structures , 2020, Antioxidants.

[3]  M. Sharifi-Rad,et al.  Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases , 2020, Frontiers in Physiology.

[4]  I. Zabetakis,et al.  Platelet activation and prothrombotic mediators at the nexus of inflammation and atherosclerosis: Potential role of antiplatelet agents. , 2020, Blood reviews.

[5]  M. Sharifi-Rad,et al.  Diet, Lifestyle and Cardiovascular Diseases: Linking Pathophysiology to Cardioprotective Effects of Natural Bioactive Compounds , 2020, International journal of environmental research and public health.

[6]  J. Sharifi‐Rad,et al.  A Mechanistic and Pathophysiological Approach for Stroke Associated with Drugs of Abuse , 2019, Journal of clinical medicine.

[7]  B. Salehi,et al.  Veronica Plants—Drifting from Farm to Traditional Healing, Food Application, and Phytopharmacology , 2019, Molecules.

[8]  M. Mazighi,et al.  Management of antiplatelet therapy for non elective invasive procedures of bleeding complications: proposals from the French working group on perioperative haemostasis (GIHP), in collaboration with the French Society of Anaesthesia and Intensive Care Medicine (SFAR). , 2019, Anaesthesia, critical care & pain medicine.

[9]  Z. Selamoğlu,et al.  Cucurbits Plants: A Key Emphasis to Its Pharmacological Potential , 2019, Molecules.

[10]  I. Palomo,et al.  Chemical Characterization and Antiplatelet Potential of Bioactive Extract from Tomato Pomace (Byproduct of Tomato Paste) , 2019, Nutrients.

[11]  E. Grishina,et al.  The ABCB1, CYP2C19, CYP3A5 and CYP4F2 genetic polymorphisms and platelet reactivity in the early phases of acute coronary syndromes , 2018, Drug metabolism and personalized therapy.

[12]  Qiang Zhou,et al.  Aspirin plus clopidogrel may reduce the risk of early neurologic deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles , 2018, Journal of Neurology.

[13]  A. Ogawa,et al.  Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel , 2018, Journal of Thrombosis and Thrombolysis.

[14]  F. Greco,et al.  Impact of specific functional groups in flavonoids on the modulation of platelet activation , 2018, Scientific Reports.

[15]  M. L. La Rovere,et al.  Consensus Document ANMCO/ANCE/ARCA/GICR-IACPR/GISE/SICOA: Long-term Antiplatelet Therapy in Patients with Coronary Artery Disease , 2018, European heart journal supplements : journal of the European Society of Cardiology.

[16]  P. Damman,et al.  Optimal duration of dual antiplatelet therapy for coronary artery disease , 2018, Netherlands Heart Journal.

[17]  M. Kamal,et al.  Evidence and prospective of plant derived flavonoids as antiplatelet agents: Strong candidates to be drugs of future. , 2018, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[18]  Sherry‐Ann Brown,et al.  Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine , 2018, Journal of personalized medicine.

[19]  J. Cho,et al.  Anti-platelet effects of epigallocatechin-3-gallate in addition to the concomitant aspirin, clopidogrel or ticagrelor treatment , 2017, The Korean journal of internal medicine.

[20]  Yun-Xiang Zhang,et al.  Inhibitory Effect of Propolis on Platelet Aggregation In Vitro , 2017, Journal of healthcare engineering.

[21]  T. Pilgrim,et al.  Dual antiplatelet therapy for secondary prevention of coronary artery disease , 2017, Open Heart.

[22]  A. Sureda,et al.  Flavonoids and platelet aggregation: A brief review , 2017, European journal of pharmacology.

[23]  H. Mekhfi,et al.  Anti-platelet aggregation effects of extracts from Arbutus unedo leaves , 2017 .

[24]  D. Calina,et al.  A guide to acquired vitamin K coagulophathy diagnosis and treatment: the Russian perspective , 2017, DARU Journal of Pharmaceutical Sciences.

[25]  Joo-In Park,et al.  Platelet Activation: The Mechanisms and Potential Biomarkers , 2016, BioMed research international.

[26]  Alexander C. Fanaroff,et al.  Antiplatelet Therapy in Percutaneous Coronary Intervention. , 2016, Interventional cardiology clinics.

[27]  E. Schuetz,et al.  Interindividual Variability in Cytochrome P450–Mediated Drug Metabolism , 2016, Drug Metabolism and Disposition.

[28]  Shih-Yi Huang,et al.  Prevention of arterial thrombosis by nobiletin: in vitro and in vivo studies. , 2016, The Journal of nutritional biochemistry.

[29]  C. Kwik-Uribe,et al.  Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. , 2015, The American journal of clinical nutrition.

[30]  F. Kobarfard,et al.  Evaluation of Anti-Platelet Aggregation Effect of Some Allium Species , 2015, Iranian journal of pharmaceutical research : IJPR.

[31]  Daniela Schuster,et al.  Discovery and resupply of pharmacologically active plant-derived natural products: A review , 2015, Biotechnology advances.

[32]  T. Warner,et al.  Effects of high flavanol dark chocolate on cardiovascular function and platelet aggregation. , 2015, Vascular pharmacology.

[33]  M. Palmery,et al.  Effect of cocoa products and flavanols on platelet aggregation in humans: a systematic review. , 2015, Food & function.

[34]  Ángel García,et al.  Platelet proteomics in cardiovascular diseases , 2015 .

[35]  J. Y. Baek,et al.  Kaempferol suppresses collagen-induced platelet activation by inhibiting NADPH oxidase and protecting SHP-2 from oxidative inactivation. , 2015, Free radical biology & medicine.

[36]  F. Da Settimo,et al.  Synthetic analogues of flavonoids with improved activity against platelet activation and aggregation as novel prototypes of food supplements. , 2015, Food chemistry.

[37]  G. Williamson,et al.  Consumption of both low and high (-)-epicatechin apple puree attenuates platelet reactivity and increases plasma concentrations of nitric oxide metabolites: a randomized controlled trial. , 2014, Archives of biochemistry and biophysics.

[38]  C. Hamm,et al.  Optimum Utilisation of Novel Antiplatelet Agents in Clinical Practice. , 2014, Interventional cardiology.

[39]  D. Jackson,et al.  The flavonols quercetin and 3′,4′-dihydroxyflavonol reduce platelet function and delay thrombus formation in a model of type 1 diabetes , 2014, Diabetes & vascular disease research.

[40]  A. Bulmer,et al.  A review of the mechanisms and effectiveness of dietary polyphenols in reducing oxidative stress and thrombotic risk. , 2014, Journal of human nutrition and dietetics : the official journal of the British Dietetic Association.

[41]  Fang Huang,et al.  Metabonomic analysis of Allium macrostemon Bunge as a treatment for acute myocardial ischemia in rats. , 2014, Journal of pharmaceutical and biomedical analysis.

[42]  I. Palomo,et al.  Antiplatelet effects of natural bioactive compounds by multiple targets: Food and drug interactions , 2014 .

[43]  M. Asad,et al.  Effect of aged garlic extract and s-allyl cysteine and their interaction with atenolol during isoproterenol induced myocardial toxicity in rats , 2014, Indian journal of pharmacology.

[44]  D. Jackson,et al.  Inhibition of platelet-mediated arterial thrombosis and platelet granule exocytosis by 3′,4′-dihydroxyflavonol and quercetin , 2013, Platelets.

[45]  G. Vilahur,et al.  Antiplatelet properties of natural products. , 2013, Vascular pharmacology.

[46]  D. Dikshit,et al.  Platelets and atherothrombosis: causes, targets and treatments for thrombosis. , 2013, Current medicinal chemistry.

[47]  D. Webb,et al.  Effect of polyphenol-rich grape seed extract on ambulatory blood pressure in subjects with pre- and stage I hypertension , 2013, British Journal of Nutrition.

[48]  G. Horgan,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. , 2013, Molecular nutrition & food research.

[49]  D. Jackson,et al.  Treatment with quercetin and 3′,4′-dihydroxyflavonol inhibits platelet function and reduces thrombus formation in vivo , 2013, Journal of Thrombosis and Thrombolysis.

[50]  W. Oleszek,et al.  The polyphenol-rich extracts from black chokeberry and grape seeds impair changes in the platelet adhesion and aggregation induced by a model of hyperhomocysteinemia , 2013, European Journal of Nutrition.

[51]  M. Rhee,et al.  Dual Roles of Quercetin in Platelets: Phosphoinositide-3-Kinase and MAP Kinases Inhibition, and cAMP-Dependent Vasodilator-Stimulated Phosphoprotein Stimulation , 2012, Evidence-based complementary and alternative medicine : eCAM.

[52]  A. Shatoor,et al.  Effect of Hawthorn (Crataegus aronia syn. Azarolus (L)) on platelet function in albino Wistar rats. , 2012, Thrombosis research.

[53]  A. Bast,et al.  Pleiotropic Benefit of Monomeric and Oligomeric Flavanols on Vascular Health - A Randomized Controlled Clinical Pilot Study , 2011, PloS one.

[54]  A. Ferro,et al.  Current concepts of platelet activation: possibilities for therapeutic modulation of heterotypic vs. homotypic aggregation. , 2011, British journal of clinical pharmacology.

[55]  B. Wachowicz,et al.  Changes of platelet antioxidative enzymes during oxidative stress: The protective effect of polyphenol-rich extract from berries of Aronia melanocarpa and grape seeds , 2011, Platelets.

[56]  S. Matetzky,et al.  The genetic basis of platelet responsiveness to clopidogrel , 2011, Thrombosis and Haemostasis.

[57]  S. Tomic,et al.  Evaluation of antiaggregatory activity of flavonoid aglycone series , 2011, Nutrition journal.

[58]  É. Vigh,et al.  Thrombosis Preventive Potential of Chicory Coffee Consumption: A Clinical Study , 2011, Phytotherapy research : PTR.

[59]  M. Zubair,et al.  Augmentation of anti-platelet effects of aspirin. , 2011, JPMA. The Journal of the Pakistan Medical Association.

[60]  F. Perez-Vizcaino,et al.  Flavonols and cardiovascular disease. , 2010, Molecular aspects of medicine.

[61]  A. Orekhov,et al.  The effects of time-released garlic powder tablets on multifunctional cardiovascular risk in patients with coronary artery disease , 2010, Lipids in Health and Disease.

[62]  V. Karalis,et al.  Examining the role of metabolites in bioequivalence assessment. , 2010, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[63]  J. Lovegrove,et al.  A structural basis for the inhibition of collagen‐stimulated platelet function by quercetin and structurally related flavonoids , 2010, British journal of pharmacology.

[64]  M. Keltai,et al.  Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study , 2010, The Lancet.

[65]  R. Altman,et al.  Clopidogrel pathway. , 2010, Pharmacogenetics and genomics.

[66]  V. Vicente,et al.  Differential effects of quercetin, apigenin and genistein on signalling pathways of protease‐activated receptors PAR1 and PAR4 in platelets , 2009, British journal of pharmacology.

[67]  M. El Haouari,et al.  Platelet function in hypertension. , 2009, Blood cells, molecules & diseases.

[68]  K. Pandey,et al.  Plant polyphenols as dietary antioxidants in human health and disease , 2009, Oxidative medicine and cellular longevity.

[69]  P. Gurbel,et al.  Dark Chocolate Effect on Platelet Activity, C-Reactive Protein and Lipid Profile: A Pilot Study , 2008, Southern medical journal.

[70]  M. El Haouari,et al.  Platelet signalling abnormalities in patients with type 2 diabetes mellitus: a review. , 2008, Blood cells, molecules & diseases.

[71]  P. Nurden,et al.  Platelets and wound healing. , 2008, Frontiers in bioscience : a journal and virtual library.

[72]  M. Díaz-Ricart,et al.  Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway. , 2008, Journal of agricultural and food chemistry.

[73]  B. Wachowicz,et al.  Comparative anti-platelet and antioxidant properties of polyphenol-rich extracts from: berries of Aronia melanocarpa, seeds of grape and bark of Yucca schidigera in vitro , 2008, Platelets.

[74]  T. Okudera,et al.  A Randomized, Double-Blind Study Comparing the Safety and Efficacy of Clopidogrel versus Ticlopidine in Japanese Patients with Noncardioembolic Cerebral Infarction , 2007, Cerebrovascular Diseases.

[75]  P. Moore,et al.  S-allylcysteine mediates cardioprotection in an acute myocardial infarction rat model via a hydrogen sulfide-mediated pathway. , 2007, American journal of physiology. Heart and circulatory physiology.

[76]  G. Salido,et al.  Antiaggregant effects of Arbutus unedo extracts in human platelets. , 2007, Journal of ethnopharmacology.

[77]  V. Vicente,et al.  Flavonoids inhibit the platelet TxA(2) signalling pathway and antagonize TxA(2) receptors (TP) in platelets and smooth muscle cells. , 2007, British journal of clinical pharmacology.

[78]  G. Salido,et al.  Cinnamtannin B-1 from bay wood reduces abnormal intracellular Ca2+ homeostasis and platelet hyperaggregability in type 2 diabetes mellitus patients. , 2007, Archives of biochemistry and biophysics.

[79]  C. Scaccini,et al.  Role of dietary polyphenols in platelet aggregation. A review of the supplementation studies , 2007, Platelets.

[80]  J. Lovegrove,et al.  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. , 2006, The British journal of nutrition.

[81]  C. Scaccini,et al.  ROLE OF DIETARY POLYPHENOLS IN THE PLATELET AGGREGATION NETWORK - A REVIEW OF THE IN VITRO STUDIES , 2006 .

[82]  N. Samel,et al.  Effects of α-tocopherol, l-arginine, and quercetin on aggregation of human platelets , 2005 .

[83]  W. Tsai,et al.  Evaluation of caffeic acid amide analogues as anti-platelet aggregation and anti-oxidative agents. , 2005, Bioorganic & medicinal chemistry.

[84]  V. Vicente,et al.  Flavonoids inhibit platelet function through binding to the thromboxane A2 receptor , 2005, Journal of thrombosis and haemostasis : JTH.

[85]  Robert Anton,et al.  Inhibition of aggregation and secretion of human platelets by quercetin and other flavonoids: Structure-activity relationships , 1982, Agents and Actions.

[86]  J. Lovegrove,et al.  Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen‐stimulated platelet activation pathway in humans , 2004, Journal of thrombosis and haemostasis : JTH.

[87]  N. Samel,et al.  Potentiation of antiaggregating effect of prostaglandins by α-tocopherol and quercetin , 2004 .

[88]  Y. Yun,et al.  Antiplatelet effect of green tea catechins: a possible mechanism through arachidonic acid pathway. , 2004, Prostaglandins, leukotrienes, and essential fatty acids.

[89]  N. Samel,et al.  Potentiation of antiaggregating effect of prostaglandins by alpha-tocopherol and quercetin. , 2004, Platelets.

[90]  M. Iinuma,et al.  Anti-platelet and membrane-rigidifying flavonoids in brownish scale of onion , 2003 .

[91]  P. Janmey,et al.  Flavonoid inhibition of platelet procoagulant activity and phosphoinositide synthesis , 2003, Journal of thrombosis and haemostasis : JTH.

[92]  J. Lovegrove,et al.  Quercetin inhibits collagen‐stimulated platelet activation through inhibition of multiple components of the glycoprotein VI signaling pathway , 2003, Journal of thrombosis and haemostasis : JTH.

[93]  S. Mehta.  Appropriate antiplatelet and antithrombotic therapy in patients with acute coronary syndromes: recent updates to the ACC/AHA guidelines. , 2002, The Journal of invasive cardiology.

[94]  Zaverio M. Ruggeri,et al.  Platelets in atherothrombosis , 2002, Nature Medicine.

[95]  C. Keen,et al.  The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function. , 2002, Thrombosis research.

[96]  A. Dutta-Roy.  Dietary components and human platelet activity , 2002, Platelets.

[97]  J. Chung,et al.  Antiplatelet Activity of Green Tea Catechins Is Mediated by Inhibition of Cytoplasmic Calcium Increase , 2001, Journal of cardiovascular pharmacology.

[98]  P. Gazzaniga,et al.  The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. , 2000, The American journal of clinical nutrition.

[99]  C. Keen,et al.  Cocoa inhibits platelet activation and function. , 2000, The American journal of clinical nutrition.

[100]  J. Folts,et al.  Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. , 2000, The Journal of nutrition.

[101]  B. Holub,et al.  Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. , 1998, The Journal of nutrition.

[102]  R. Mensink,et al.  Effects of the flavonoids quercetin and apigenin on hemostasis in healthy volunteers: results from an in vitro and a dietary supplement study. , 1998, The American journal of clinical nutrition.

[103]  R. Andriantsitohaina,et al.  Nitric oxide production and endothelium‐dependent vasorelaxation induced by wine polyphenols in rat aorta , 1997, British journal of pharmacology.

[104]  B. Halliwell,et al.  Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability. , 1991, Biochemical pharmacology.

[105]  C. Teng,et al.  Inhibition of platelet aggregation by some flavonoids. , 1991, Thrombosis research.

[106]  S. Nakashima,et al.  Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses. , 1991, Molecular pharmacology.

[107]  R. Korbut,et al.  On the mechanism of antiaggregatory effect of myricetin. , 1988, Polish journal of pharmacology and pharmacy.

[108]  J. Maclouf,et al.  Interference of some flavonoids and non-steroidal anti-inflammatory drugs with oxidative metabolism of arachidonic acid by human platelets and neutrophils. , 1985, Biochimica et biophysica acta.

[109]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[110]  M. Steiner,et al.  Modification of platelet function and arachidonic acid metabolism by bioflavonoids. Structure-activity relations. , 1984, Biochemical pharmacology.

[111]  J. Cazenave,et al.  Role of cyclic AMP in the inhibition of human platelet aggregation by quercetin, a flavonoid that potentiates the effect of prostacyclin. , 1982, Biochemical pharmacology.

[112]  M. Ruckstuhl,et al.  Flavonoids are selective cyclic GMP phosphodiesterase inhibitors. , 1979, Biochemical pharmacology.