Iranian Journal of Medical Sciences

Document Type : Review Article

Authors

Cardiac Primary Prevention Research Center, Cardiovascular Disease Research Institute, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Background: Platelet aggregation is a crucial mechanism in the progression of atherothrombotic events. This systematic review aims to introduce the plants studied in healthy people as the primary prevention to inhibit platelet aggregation. We also discuss possible mechanisms that are involved in the inhibition of platelet aggregation.
Methods: A systematic search on the electronic medical databases from 1970 to February 2020 was performed. The selected keywords were: “herb”, “plant”, “platelet aggregation”, “platelet activation”, “clinical trial”, “randomized” and “controlled”. 
Results: The result of the initial search was a pool of 136 articles. After initial abstract reviewing, there were 55 relevant articles. Finally, 28 eligible records fulfilled our inclusion criteria to enter the qualitative synthesis process. 
Conclusion: Out of the 10 plants evaluated in the clinical trials, nine had inhibitory effects on platelet aggregation. Most of the reviewed plants, including tomato (Solanum lycopersicum L), garlic (Allium sativum), kiwifruit (Actinidia deliciosa), cacao (Theobroma cacao), grape (Vitis vinifera), ginkgo (Ginkgo biloba), flaxseed (Linum usitatissimum), sea buckthorn berry (Hippophae), and argan (Argania spinose) could be potential sources for the primary prevention of atherothrombotic events at an appropriate dosage. Finally, we do not consider phytoceuticals as a replacement for the guideline-directed medical treatment. Large randomized double-blind clinical trials are required to evaluate the anti-platelet characteristics of these plants for the adjuvant primary prevention of cardiovascular disease. 

Keywords

What’s Known

Platelet aggregation plays an important role in atherothrombotic events, such as cerebrovascular and cardiovascular events. Potential adverse effects of established antiplatelet therapies encourage us to evaluate the possible role of medicinal herbs in the primary prevention of cardiovascular disease in the general population.

What’s New

Of the 10 plants evaluated in clinical trials, nine plants had inhibitory effects on platelet aggregation, including tomato, garlic, kiwifruit, cacao, grape, ginkgo, flaxseed, sea buckthorn berry, and argan. Phytoceuticals could have a potential effect on the primary prevention of atherothrombotic events at an appropriate dosage, but not as a replacement for the current treatment.

Introduction

Atherothrombotic events, such as strokes and coronary heart disease (CHD), cause high mortality and morbidity rates in the human population. 1 Platelet aggregation plays a substantial role in their pathogenesis. 2 The pathogenesis of atherothrombotic events encompasses the interactive processes of atherosclerotic lesions and the development of thrombi following platelet activation at the injured vascular site. 3 The concomitant increase in platelet activity is associated with a higher risk of atherothrombotic events. 4 Therefore, inhibiting platelet aggregation is the cornerstone of protection against CHD and strokes, and it would decrease the risk of atherothrombotic events. Antiplatelet drugs, such as aspirin, clopidogrel, and ticlopidine, are a part of the current clinical practice to treat and prevent CHD and strokes. 5

Plants have been the primary source of the discovery and development of the active ingredients of medicines. Plant-based treatments have resulted in numerous clinical trials. 6 Several in vitro, in vivo, and human studies have been conducted to assess the impact of medicinal herbs on the inhibition of platelet aggregation. In vitro studies demonstrated the reduction of platelet aggregation by andrographis, feverfew, garlic, ginger, ginkgo, ginseng, horse chestnut, and turmeric, 7 hawthorns, 8 cranberry, 9 strawberry, 10 green tea, 11 pomegranate juice. 12 In vivo studies found platelet aggregation inhibiting effects in herbs such as strawberry, 13 green tea, 11 onion, 14 wine, and grape juice. 15 Clinical trials reported antiplatelet effects for garlic, 16 ginkgo, 17 and tomato. 18

The potential adverse effects of standard antiplatelet therapies 19 encourage us to use medicinal herbs, particularly for the primary prevention of cardiovascular disease. Various mechanisms have been proposed for inhibiting platelet aggregation by medicinal herbs, including the inhibition of the collagen and adenosine diphosphate (ADP) pathway, 20 an increase in the basal levels of tyrosine phosphorylation, 21 the inhibition of cyclooxygenase activity, 22 the inhibition of thromboxane A2 production, 17 and the reduction of intracellular Ca2+ mobilization. 23 The current medical literature still lacks a systematic review on the antiplatelet activity of herbs. We conducted this systematic review to report the plants that can inhibit platelet aggregation. In other words, this review can answer whether plants can be used as the primary prevention of atherothrombotic events or not.

Materials and Methods

Identification of Studies

An electronic literature systematic search was conducted in PubMed (Medline, PubMed central), Scopus, Cochrane, Web of Science Core Collection, and Embase from the year 1970 to November 2020. We developed separate search strategies for each database, which can be seen in table 1 as an example for PubMed. The reference lists of eligible articles were manually searched to find additional relevant studies. The search terms in this study included “plant”, “herb”, “platelet aggregation”, and “platelet activation”. There was no restriction on language or date of publication.

Database Search strategy Number of Articles
PubMed (Medline, PubMed central) Text word (“Plants”[Mesh]) AND the title/abstract (“Platelet Activation”[Mesh]) 990
Text word (“Plants”[Mesh]) AND the title/abstract (“Platelet Activation”[Mesh]) Filters: Clinical Study; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase III; Clinical Trial, Phase IV; Clinical Trial, Veterinary, Randomized Controlled Trial 96
Text word (“Plants”[Mesh]) AND the title/abstract (“Platelet Activation”[Mesh]) Filters: Clinical Study; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase III; Clinical Trial, Phase IV; Clinical Trial, Veterinary: Search (“Plants”[Mesh]) AND “Platelet Activation”[Mesh] Filters: Clinical Study; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase III; Clinical Trial, Phase IV; Clinical Trial, Veterinary; English 89
Full-text articles assessed for eligibility 46
Related 28
Table 1.The strategy used for searching in PubMed

Eligibility Criteria

The PICOS eligibility criteria were:

Population: healthy volunteers or participants with atherosclerosis risk factors

Intervention: any herbs

Comparator: placebo or herb

Outcomes: inhibition of platelet aggregation

Study design: randomized controlled trials

Inclusion and Exclusion Criteria

We included the studies that met the following criteria: 1) randomized controlled trials on healthy volunteers comparing any herb with placebo, another herb, or the same herb with a different dosage, 2) evaluating any herb that can inhibit platelet aggregation, 3) administration of herbal medicines orally, and 4) publications with available abstracts and full-texts.

We excluded in vitro or in vivo studies, review studies, systematic reviews, studies without controls, clinical trials on preparations containing more than one herbal remedy, commentaries, letters to editors, protocols, abstracts, and non-English full-text studies.

Study Selection

After removing the duplicates, two authors (SN, NO) separately evaluated the titles/abstracts to include the relevant articles in the study. The same authors read the full texts of the selected articles to assess the eligibility criteria. In case of any doubt or disagreement, the authors would discuss the respective study. The management of the search results was carried out by EndNote software (EndNote X8; Clarivate Analytics, Philadelphia, PA, United States of America).

Data Extraction and Quality Assessment of the Studies

The authors had a predefined checklist, and two authors (SN and NO) independently extracted the data. Data extraction was done using Microsoft Excel (Microsoft, USA). The data extracted from each study included: the study publication year, the number of participants, studied plant, comparators, part of the plant used in the study, drug dosage/form, duration of treatment, and outcome. We used the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist for the qualitative evaluation of the studies. 24

Synthesis of Results

The results of the studies and their characteristics were summarized and compared in tables 2 and 3.

Study Plant comparator Number of participants Comparator Part of plant Drug Dosage/form Duration of treatment Results
Palomo I 18 Tomato 99 Placebo Tomato Pomace Extract Different doses of tomato pomace extract (1 g, 2.5 g/ once daily) 5 days Consumption of aqueous extract of tomato pomace exerted an inhibitory activity on platelet aggregation.
Lazarus SA 26 20 Placebo Tomato juice, 250 mL/day Tomato juice, 250 ml/day 3 weeks Platelet aggregation decreased following supplementation with tomato juice as compared with the placebo group.
O’Kennedy N 27 90 Placebo Tomato extract Tomato extract syrup, 200 mL, single dose 3 hours Significant reductions in ex vivo platelet aggregation induced by ADP and collagen were observed three hours after supplementation.
Morris J 28 Garlic 14 Placebo Oil extract 1 gelatin capsule/day (equivalent to 15 g of raw garlic) 5 days There were no significant differences in platelet aggregation with adenosine diphosphate, platelet-activating factor (PAF), or collagen between groups.
Steiner M 23 23 15 Placebo Aged garlic extract Capsule 800 mg of Aged garlic extract 3×TDS 11 months AGE administration produced inhibition of some of the platelet functions.
Steiner M 16 34 Placebo Aged garlic extract 3, 6, 9 capsule/day (each 800 mg Aged garlic extract) 6 weeks×3 duration AGE exerted selective inhibition on platelet aggregation and adhesion.
Kiesewetter H 29 60 Placebo Powdered garlic Coated tablets (400mg of powdered garlic) /QID 4 weeks The parallel-group comparison (garlic versus placebo) revealed a significantly different ratio of circulating platelet aggregates after four weeks of treatment.
Scharbert G 30 18 Placebo Raw garlic Raw garlic, 4.2 g/day 1 week Platelet function was not impaired by single and repeated oral consumption of raw garlic
Legnani C 31 31 12 Placebo Dried garlic powder Tablet 900 mg/day 14 days Platelet aggregation values were significantly lower after 7 and 14 days of garlic treatment.
Karlsen A 32 Kiwifruit 102 Antioxidant-rich diet group, habitual diet group Fruit 3 kiwifruits per day (195 g fruit) 8 weeks In the kiwifruit group, a 15% reduction in platelet aggregation was observed.
Brevik A 33 24 Kiwifruit doses in a different order Fruit One kiwifruit per day in the first period, two in the second, or two per day in the first period, one in the second 4 weeks×2 Green and golden kiwifruit extracts inhibit both ADP and collagen-induced whole blood platelet aggregation (to different degrees).
Duttaroy AK 20 30 Kiwifruit doses in a different order Kiwifruit extract Period 1: group A: 2 kiwi /d, group B: 3 kiwi/d 28 days periods separated by at least two-week washout periods Kiwi fruit produced effective inhibiting effects on platelet aggregation induced by collagen and ADP in human volunteers.
Period 2: group A: 3/d, group B: 2/day
Innes AJ 34 Theobroma cacao L. 30 White chocolate (no cacao) Dark Chocolate (75% cacao content) 100 g/day of dark chocolate, single-dose 4 hours Dark chocolate inhibited collagen-induced platelet aggregation in platelet-rich plasma.
Milk chocolate (20% cacao)
Ottaviani JI 35 34 Placebo (CF-free control capsules) Cacao extract of seed Ranging from 2-4 capsules (corresponding to 1000 to 2000 mg/d cacao flavanols) during weeks 1-3 12 weeks There were no significant differences in platelet function between groups.
Ostertag LM 36 42 White chocolate Dark chocolate 60 g, single-dose Six hours Platelet aggregation-induced ADP was significantly reduced two hours after consumption of dark chocolate.
Rein D 37 37 30 Caffeine-containing control beverage or water Cacao beverage 240 mL, single-dose Six hours Platelet micro-particle formation decreased two and six hour after cacao consumption but increased after caffeine and water consumption.
Keevil JG 38 Vitis vinifera (Grape) 10 Orange and grapefruit juices Juice of purple grape Grape Juice, 5-7.5 mg/Kg/day One week Purple grape juice reduced the whole blood platelet aggregation induced by collagen.
Bazan-Salinas IL 39 30 Arachis hypogaea oils in one group and no oil in other Oil of the grape seed 1 g/d, Oil of grape seed Seven days Consumption of plant oils from grape seeds and peanuts had a lowering effect on platelet aggregation.
Polagruto JA 40 23 Placebo Flavanol-Rich Grapeseed Extract (FRGSE) 2×200 mg capsules, single-dose Six hours The FRGSE supplement, but not the placebo, significantly decreased ADP-stimulated platelet reactivity at one, two, and six hours following intake.
Ras RT 41 70 Placebo Grape seed extract (GSE) 1 capsule /day (each capsule containing 300 mg GSE) Eight weeks Grape seed extract intervention did not change platelet aggregation as induced by several agonists when compared with placebo.
Köhler S 42 Ginkgo biloba 50 Placebo Dry extract from Ginkgo biloba leaves Tablet 120 mg×2 /day Seven days, of crossover treatment, with three weeks of washout None showed any evidence of an inhibition of blood coagulation, or platelet aggregation.
Kudolo GB 17 12 Placebo Root Tablet, 20mg /day Three months Ginkgo tablet inhibits platelet aggregation by inhibiting thromboxane B2 production.
Djurica D 43 Strawberry 25 Placebo Freeze-dried strawberry powder Powder, 50 g daily One week Platelet activation markers were not significantly different between groups.
Allman MA 44 Linum usitatissimum (Flaxseed) 11 Sunflower seed oil Flaxseed oil 40 g /d flaxseed oil 23 days Aggregation response induced by collagen was decreased in the flaxseed oil groups.
Kaul N 45 86 Fish oil, hemp seed oil, placebo Flaxseed oil Capsule 1 g×2, flaxseed oil 12 weeks Flaxseed did not alter platelet aggregation.
Edel AL 46 40 Different doses of flaxseed Milled flaxseed 10 g, 20 g, 30 g, or 40 g 10 g, 20 g, 30 g, or 40 g /d in four groups 30 days There were no changes in platelet aggregation, even at the highest dose of flaxseed.
Johansson AK 47 Sea buckthorn berry 12 Coconut oil Extracted oil of berry Capsule 500 mg×10/ day (5g /d) Four weeks A clear decrease in the rate of ADP-induced platelet aggregation was observed in the oil of the Sea buckthorn berry group.
Velmurugan S 48 Argania spinose (Argan) 39 Butter Oil of kernels of Argania Spinosa Argan oil 25 mL /day Three weeks In the argan oil group, thrombin-induced platelet aggregation was lower.
Table 2.Eligible randomized clinical trials focused on the effect of an herb on platelet aggregation inhibition
Component Plant Study
Polyphenol Grape, grape seed 41
Theobroma cacao L. 36
Tomato 18
Ginkgo biloba 49
Kiwi 32
Sea buckthorn berry 50
Strawberry 10
Organosulfur Garlic 51
Unsaturated fatty acids Flaxseed (Omega-3) 46 , 45 , 52
Argan (Omega-6, oleic acid) 53
Sea buckthorn berry (Omega-3, Omega-6) 47
Grapeseed 39
Table 3.Bioactive contributing components to the inhibition of platelet aggregation

This study was reported under the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 25 Due to the heterogeneity of the studies included in this review, we did not perform the meta-analysis.

Results

The flowchart of the systematic search is demonstrated in figure 1. Out of 136 records, 28 articles were entered into the qualitative synthesis for critical appraisal and data extraction. All the studies had case and control groups. The characteristics and the main results of all the studies are outlined in table 2. Following data extraction, ten plants, including tomato, garlic, kiwifruit, cacao, grape, strawberry, ginkgo, flaxseed, sea buckthorn berry, and argan, were reviewed in 28 studies. Except for strawberry, the other plants had inhibitory effects on platelet aggregation to some extent. A number of these plants, including garlic, cocoa, grape, ginkgo, and flaxseed, had shown a diverse effect on inhibiting platelet aggregation.

Figure 1. A Diagram of the systematic search according to PRISMA shows the exclusion and inclusion of the studies.

These plants were categorized into three main groups according to bioactive compounds contributing to the antiplatelet effect. These categories were “polyphenols”, “organosulfur”, and “unsaturated fatty acids” (table 3).

Discussion

Out of 10 plants evaluated in the clinical trials, nine had inhibitory effects on platelet aggregation. Studies suggest that polyphenols are the major components involved in the inhibition of platelet aggregation. Based on duration, dosage, and route of administration, plants have shown various effects on the inhibition of platelet aggregation.

In vitro, high doses of herbal compounds with antiplatelet activity would suppress platelet aggregation. On the contrary, low dose concentrations in vivo would have a minor effect. 54 The antiplatelet activity of herbal compounds could be due to the synergistic function of all properties, rather than individual components. 55

Several clinical trials have shown that tomato, cacao, grape, kiwi, and ginkgo have an inhibitory effect on platelet aggregation. Based on these studies, the major components involved in the inhibition of platelet aggregation in these plants are polyphenols. Polyphenols are common bioactive compounds mainly derived from fruits, vegetables, and traditional medicinal herbs. Previous studies reported that polyphenols could influence the cardiovascular system by lowering blood pressure, improving endothelial function, increasing antioxidant defenses, inhibiting low-density lipoprotein oxidation, and reducing inflammatory responses. 56 In most of the in vitro and in vivo studies, polyphenols had inhibitory effects on platelet aggregation to some degree. 57

The inhibitory effect of polyphenols supplementation on platelet aggregation is attributed to several different molecular mechanisms. Tomato extract, 58 cacao, 59 kiwi, 20 and ginkgo 49 inhibit collagen- and ADP-induced platelet aggregation. Grape juice and grape seed extracts inhibit platelet aggregation induced by collagen and thrombin-receptor agonist peptide (TRAP) and increase basal levels of tyrosine phosphorylation. 21

In vitro experiments have demonstrated that the inhibition of platelet aggregation by phenolic compounds is generally dose-dependent. Furthermore, the effect of polyphenols on platelet aggregation in humans and animal models is strongly dependent on their absorption and metabolism. 60 The inhibitory effect of ginkgo supplementation on platelet aggregation developed after three months. 17 However, it had no effect within seven days of administration. 42 Grape juice 38 and grape seed oil 39 have an inhibitory effect on platelet aggregation in an adequate dosage and a proper duration of treatment. An in vitro study showed that extracts of grape seed and skin lead to a dose-dependent inhibition of platelet aggregation. 61 Strawberry, as a source of polyphenols, had no inhibitory effects on platelet aggregation with a dose equal to 50 g of dried powder /day for one week. 50 Nonetheless, this effect was observed in in vivo studies. 10 , 13 The estimated sufficient dose of strawberry extract to inhibit platelet aggregation in humans is about 70 mg/Kg based on an in vivo study, 13 which is much higher than the prescribed dose in the randomized clinical trial (RCT) on strawberry mentioned above. 43

Both single 27 and multiple doses 18 , 26 of tomato extract had a similar inhibitory effect on platelet aggregation. Interestingly, studies on a single dose of cacao 34 , 36 , 37 reported significant antiplatelet effects, whereas long-term cacao administration 35 had no inhibitory effect on platelet aggregation. One could argue that if the long-term dosage of cacao was equal to or greater than a single dosage, it might result in higher circulating concentrations of phenolic compounds, and would be effective in platelet aggregation inhibition. Moreover, the accumulation of phenolic compounds and their metabolites might occur in many tissues. 62

Numerous clinical trials have demonstrated that garlic would inhibit platelet aggregation. This biological property of garlic is mainly attributed to the high content of organosulfur compounds found in garlic and onion. 63 Moreover, organosulfur compounds of garlic possess anti-atherosclerotic properties by reducing serum cholesterol levels in humans, inhibiting cholesterol biosynthesis, suppressing low-density lipoprotein (LDL) oxidation, lowering plasma fibrinogen, and increasing fibrinolytic activity. 64

Organosulfur compounds inhibit platelet aggregation by interfering with cyclooxygenase activity and blocking thromboxane A2 formation. This leads to suppressed intraplatelet Ca2+ mobilization and raised levels of intraplatelet cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). 22

Administration of garlic oil extract with a dose equal to 15 g of raw garlic per day for five days 28 and raw garlic at 4.2 g /day for a week 30 had no inhibitory effect on platelet aggregation. However, powdered garlic or aged garlic extract at 900 mg/day for two weeks, 31 (3,6,9 capsule) ×800 mg/day for six weeks for three periods of time, 16 400 mg/every six hours for four weeks, 29 and (three capsule) ×800 mg/every eight hours for 11 months 34 showed inhibitory effects on platelet aggregation. According to previous studies, 16 , 31 dry extracts of garlic demonstrated more activity on platelet aggregation than the oil, which could be attributed to the higher concentrations of organosulfur compounds in the garlic powder tablets. 44

Several clinical trials have shown that flaxseed, argan, sea buckthorn berry, and grape seed have antiplatelet properties. Unsaturated fatty acids, including polyunsaturated fatty acids (PUFAs) 39 , 45 - 47 , 52 , 53 and monounsaturated fatty acids (MUFAs), 53 are the major components for inhibiting platelet aggregation in these plants. omega-6 (linoleic acid) and omega-3 (α-linolenic acid) are two types of polyunsaturated fatty acids. These essential fatty acids are found in fatty seeds, nuts, and some vegetables. 65 In this review, flaxseed oil (as a source of omega-3), sea buckthorn berry oil (as a source of omega-6 and omega-3), and argan oil containing balanced proportions of MUFAs (oleic acid) and PUFAs (omega-6) 53 showed inhibitory effects on platelet aggregation. Previous studies have revealed that PUFAs can significantly prevent cardiovascular diseases. 66

According to animal and human studies, flaxseed, argan, and sea buckthorn decreased thrombin- and collagen-induced platelet aggregation. 52 , 53 , 67

Oil extract of flaxseed at a dose of 2 g/day for 12 weeks 45 did not inhibit platelet aggregation compared with 40 g/day for 23 days. 44 The difference in the inhibitory effects could be attributed to the fact that omega-3 fatty acids in large doses reduce platelet aggregation, but smaller amounts have modest platelet inhibitory effects.

It should be noted that garlic and ginkgo may increase the pharmacological effects of aspirin and anticoagulant agents. 68 Thus, the patients should be warned against the concurrent use of garlic/ginkgo and anticoagulant drugs, which may increase the risk of bleeding.

The main limitation of our review is that the RCTs only studied healthy volunteers. RCTs with preparations containing more than one herbal medicine and a clinical trial with a conventional drug, as a comparator, were not included in this review. On the other hand, the sample size was not included as an eligibility criterion.

Conclusion

Most of the plants in this systematic review potentially have an inhibitory effect on platelet aggregation. Accordingly, these plants could be introduced as potential sources for the primary prevention of atherothrombotic events at an appropriate dosage. Achieving convincing results requires conducting further clinical trials to evaluate the efficacy and safety of herbal medicines for the prevention of cardiovascular disease.

Acknowledgement

We are indebted to the Tehran Heart Center and Research Development for their support. This study was funded by Tehran University of Medical Sciences (grant number: 99-1-138-48021).

Conflict of Interest

None declared.

Authors’ Contribution

S.N, A.V.F, H.R, P.G, S.M.G, and N.O: Contributed to conception and design of the study. All of the authors had contribution in all phases of this study; S.N and N.O wrote the first draft; A.V.F, H.R, P.G, and S.M.G: Revised this manuscript critically for important intellectual content. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

References

  1. Mokdad AH, Mensah GA, Krish V, Glenn SD, Miller-Petrie MK, Lopez AD, et al. Global, Regional, National, and Subnational Big Data to Inform Health Equity Research: Perspectives from the Global Burden of Disease Study 2017. Ethn Dis. 2019; 29:159-72. Publisher Full Text | DOI | PubMed
  2. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007; 357:2482-94. DOI | PubMed
  3. Palomo I, Toro C, Alarcon M. The role of platelets in the pathophysiology of atherosclerosis (Review). Mol Med Rep. 2008; 1:179-84. PubMed
  4. Endler G, Klimesch A, Sunder-Plassmann H, Schillinger M, Exner M, Mannhalter C, et al. Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease. Br J Haematol. 2002; 117:399-404. DOI | PubMed
  5. Shah SMA, Akram M, Riaz M, Munir N, Rasool G. Cardioprotective Potential of Plant-Derived Molecules: A Scientific and Medicinal Approach. Dose Response. 2019; 17:1559325819852243. Publisher Full Text | DOI | PubMed
  6. Harvey AL. Natural products in drug discovery. Drug Discov Today. 2008; 13:894-901. DOI | PubMed
  7. McEwen BJ. The influence of herbal medicine on platelet function and coagulation: a narrative review. Semin Thromb Hemost. 2015; 41:300-14. DOI | PubMed
  8. Rogers KL, Grice ID, Griffiths LR. Inhibition of platelet aggregation and 5-HT release by extracts of Australian plants used traditionally as headache treatments. Eur J Pharm Sci. 2000; 9:355-63. DOI | PubMed
  9. McKay DL, Blumberg JB. Cranberries (Vaccinium macrocarpon) and cardiovascular disease risk factors. Nutr Rev. 2007; 65:490-502. DOI | PubMed
  10. Naemura A, Mitani T, Ijiri Y, Tamura Y, Yamashita T, Okimura M, et al. Anti-thrombotic effect of strawberries. Blood Coagul Fibrinolysis. 2005; 16:501-9. DOI | PubMed
  11. Son DJ, Cho MR, Jin YR, Kim SY, Park YH, Lee SH, et al. Antiplatelet effect of green tea catechins: a possible mechanism through arachidonic acid pathway. Prostaglandins Leukot Essent Fatty Acids. 2004; 71:25-31. DOI | PubMed
  12. Mattiello T, Trifiro E, Jotti GS, Pulcinelli FM. Effects of pomegranate juice and extract polyphenols on platelet function. J Med Food. 2009; 12:334-9. DOI | PubMed
  13. Alarcon M, Fuentes E, Olate N, Navarrete S, Carrasco G, Palomo I. Strawberry extract presents antiplatelet activity by inhibition of inflammatory mediator of atherosclerosis (sP-selectin, sCD40L, RANTES, and IL-1beta) and thrombus formation. Platelets. 2015; 26:224-9. DOI | PubMed
  14. Briggs WH, Folts JD, Osman HE, Goldman IL. Administration of raw onion inhibits platelet-mediated thrombosis in dogs. J Nutr. 2001; 131:2619-22. DOI | PubMed
  15. Demrow HS, Slane PR, Folts JD. Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation. 1995; 91:1182-8. DOI | PubMed
  16. Steiner M, Li W. Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr. 2001; 131:980S-4S. DOI | PubMed
  17. Kudolo GB, Wang W, Barrientos J, Elrod R, Blodgett J. The ingestion of Ginkgo biloba extract (EGb 761) inhibits arachidonic acid-mediated platelet aggregation and thromboxane B2 production in healthy volunteers. J Herb Pharmacother. 2004; 4:13-26. PubMed
  18. Palomo I, Concha-Meyer A, Lutz M, Said M, Saez B, Vasquez A, et al. Chemical Characterization and Antiplatelet Potential of Bioactive Extract from Tomato Pomace (Byproduct of Tomato Paste). Nutrients. 2019; 11Publisher Full Text | DOI | PubMed
  19. Guthrie R. Review and management of side effects associated with antiplatelet therapy for prevention of recurrent cerebrovascular events. Adv Ther. 2011; 28:473-82. DOI | PubMed
  20. Duttaroy AK, Jorgensen A. Effects of kiwi fruit consumption on platelet aggregation and plasma lipids in healthy human volunteers. Platelets. 2004; 15:287-92. DOI | PubMed
  21. Bijak M, Sut A, Kosiorek A, Saluk-Bijak J, Golanski J. Dual Anticoagulant/Antiplatelet Activity of Polyphenolic Grape Seeds Extract. Nutrients. 2019; 11Publisher Full Text | DOI | PubMed
  22. Rahman K. Effects of garlic on platelet biochemistry and physiology. Mol Nutr Food Res. 2007; 51:1335-44. DOI | PubMed
  23. Steiner M, Lin RS. Changes in platelet function and susceptibility of lipoproteins to oxidation associated with administration of aged garlic extract. J Cardiovasc Pharmacol. 1998; 31:904-8. DOI | PubMed
  24. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Int J Technol Assess Health Care. 2013; 29:117-22. DOI | PubMed
  25. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151:264-9. DOI | PubMed
  26. Lazarus SA, Bowen K, Garg ML. Tomato juice and platelet aggregation in type 2 diabetes. JAMA. 2004; 292:805-6. DOI | PubMed
  27. O’Kennedy N, Crosbie L, Whelan S, Luther V, Horgan G, Broom JI, et al. Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans. Am J Clin Nutr. 2006; 84:561-9. DOI | PubMed
  28. 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; 22:414-7. DOI
  29. Kiesewetter H, Jung F, Jung EM, Mroweitz C, Koscielny J, Wenzel E. Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischaemic attack. Eur J Clin Pharmacol. 1993; 45:333-6. DOI | PubMed
  30. Scharbert G, Kalb ML, Duris M, Marschalek C, Kozek-Langenecker SA. Garlic at dietary doses does not impair platelet function. Anesth Analg. 2007; 105:1214-8. DOI | PubMed
  31. 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; 43:119-22. PubMed
  32. Karlsen A, Svendsen M, Seljeflot I, Laake P, Duttaroy AK, Drevon CA, et al. Kiwifruit decreases blood pressure and whole-blood platelet aggregation in male smokers. J Hum Hypertens. 2013; 27:126-30. DOI | PubMed
  33. Brevik A, Gaivao I, Medin T, Jorgenesen A, Piasek A, Elilasson J, et al. Supplementation of a western diet with golden kiwifruits (Actinidia chinensis var.’Hort 16A’:) effects on biomarkers of oxidation damage and antioxidant protection. Nutr J. 2011; 10:54. Publisher Full Text | DOI | PubMed
  34. Innes AJ, Kennedy G, McLaren M, Bancroft AJ, Belch JJ. Dark chocolate inhibits platelet aggregation in healthy volunteers. Platelets. 2003; 14:325-7. DOI | PubMed
  35. Ottaviani JI, Balz M, Kimball J, Ensunsa JL, Fong R, Momma TY, et al. Safety and efficacy of cocoa flavanol intake in healthy adults: a randomized, controlled, double-masked trial. Am J Clin Nutr. 2015; 102:1425-35. DOI | PubMed
  36. Ostertag LM, Kroon PA, Wood S, Horgan GW, Cienfuegos-Jovellanos E, Saha 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; 57:191-202. DOI | PubMed
  37. Rein D, Paglieroni TG, Wun T, Pearson DA, Schmitz HH, Gosselin R, et al. Cocoa inhibits platelet activation and function. Am J Clin Nutr. 2000; 72:30-5. DOI | PubMed
  38. Keevil JG, Osman HE, Reed JD, Folts JD. Grape juice, but not orange juice or grapefruit juice, inhibits human platelet aggregation. J Nutr. 2000; 130:53-6. DOI | PubMed
  39. Bazan-Salinas IL, Matias-Perez D, Perez-Campos E, Perez-Campos Mayoral L, Garcia-Montalvo IA. Reduction of Platelet Aggregation From Ingestion of Oleic and Linoleic Acids Found in Vitis vinifera and Arachis hypogaea Oils. Am J Ther. 2016; 23:e1315-e9. DOI | PubMed
  40. Polagruto JA, Gross HB, Kamangar F, Kosuna K, Sun B, Fujii H, et al. Platelet reactivity in male smokers following the acute consumption of a flavanol-rich grapeseed extract. J Med Food. 2007; 10:725-30. DOI | PubMed
  41. 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; 110:2234-41. DOI | PubMed
  42. Kohler S, Funk P, Kieser M. Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers. Blood Coagul Fibrinolysis. 2004; 15:303-9. DOI | PubMed
  43. Djurica D, Holt RR, Ren J, Shindel AW, Hackman RM, Keen CL. Effects of a dietary strawberry powder on parameters of vascular health in adolescent males. Br J Nutr. 2016; 116:639-47. DOI | PubMed
  44. Allman MA, Pena MM, Pang D. Supplementation with flaxseed oil versus sunflowerseed oil in healthy young men consuming a low fat diet: effects on platelet composition and function. Eur J Clin Nutr. 1995; 49:169-78. PubMed
  45. Kaul N, Kreml R, Austria JA, Richard MN, Edel AL, Dibrov E, et al. A comparison of fish oil, flaxseed oil and hempseed oil supplementation on selected parameters of cardiovascular health in healthy volunteers. J Am Coll Nutr. 2008; 27:51-8. DOI | PubMed
  46. Edel AL, Patenaude AF, Richard MN, Dibrov E, Austria JA, Aukema HM, et al. The effect of flaxseed dose on circulating concentrations of alpha-linolenic acid and secoisolariciresinol diglucoside derived enterolignans in young, healthy adults. Eur J Nutr. 2016; 55:651-63. DOI | PubMed
  47. Johansson AK, Korte H, Yang B, Stanley JC, Kallio HP. Sea buckthorn berry oil inhibits platelet aggregation. J Nutr Biochem. 2000; 11:491-5. DOI | PubMed
  48. Velmurugan S, Kapil V, Ghosh SM, Davies S, McKnight A, Aboud Z, et al. Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. Free Radic Biol Med. 2013; 65:1521-32. Publisher Full Text | DOI | PubMed
  49. Dutta-Roy AK, Gordon MJ, Kelly C, Hunter K, Crosbie L, Knight-Carpentar T, et al. Inhibitory effect of Ginkgo biloba extract on human platelet aggregation. Platelets. 1999; 10:298-305. DOI | PubMed
  50. Olas B, Kontek B, Szczesna M, Grabarczyk L, Stochmal A, Zuchowski J. Inhibition of blood platelet adhesion by phenolics’ rich fraction of Hippophae rhamnoides L. fruits. J Physiol Pharmacol. 2017; 68:223-9. PubMed
  51. Lawson LD, Ransom DK, Hughes BG. Inhibition of whole blood platelet-aggregation by compounds in garlic clove extracts and commercial garlic products. Thromb Res. 1992; 65:141-56. DOI | PubMed
  52. Parikh M, Netticadan T, Pierce GN. Flaxseed: its bioactive components and their cardiovascular benefits. Am J Physiol Heart Circ Physiol. 2018; 314:H146-H59. DOI | PubMed
  53. Haimeur A, Messaouri H, Ulmann L, Mimouni V, Masrar A, Chraibi A, et al. Argan oil prevents prothrombotic complications by lowering lipid levels and platelet aggregation, enhancing oxidative status in dyslipidemic patients from the area of Rabat (Morocco). Lipids Health Dis. 2013; 12:107. Publisher Full Text | DOI | PubMed
  54. Ryou SH, Kang MS, Kim KI, Kang YH, Kang JS. Effects of green tea or Sasa quelpaertensis bamboo leaves on plasma and liver lipids, erythrocyte Na efflux, and platelet aggregation in ovariectomized rats. Nutr Res Pract. 2012; 6:106-12. Publisher Full Text | DOI | PubMed
  55. Antolic A, Males Z, Tomicic M, Bojic M. The Effect of Short-Toothed and DalmatianSage Extracts on Platelet Aggregation. Food Technol Biotechnol. 2018; 56:265-9. Publisher Full Text | DOI | PubMed
  56. Giglio RV, Patti AM, Cicero AFG, Lippi G, Rizzo M, Toth PP, et al. Polyphenols: Potential Use in the Prevention and Treatment of Cardiovascular Diseases. Curr Pharm Des. 2018; 24:239-58. DOI | PubMed
  57. Ludovici V, Barthelmes J, Nagele MP, Flammer AJ, Sudano I. Polyphenols: Anti-Platelet Nutraceutical?. Curr Pharm Des. 2018; 24:146-57. DOI | PubMed
  58. Biswas D, Uddin MM, Dizdarevic LL, Jorgensen A, Duttaroy AK. Inhibition of angiotensin-converting enzyme by aqueous extract of tomato. Eur J Nutr. 2014; 53:1699-706. DOI | PubMed
  59. Murphy KJ, Chronopoulos AK, Singh I, Francis MA, Moriarty H, Pike MJ, et al. Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function. Am J Clin Nutr. 2003; 77:1466-73. DOI | PubMed
  60. Natella F, Nardini M, Virgili F, Scaccini C. Role of dietary polyphenols in the platelet aggregation network - a review of the in vitro studies. Curr Top Nutraceutical Res. 2006; 4
  61. Vitseva O, Varghese S, Chakrabarti S, Folts JD, Freedman JE. Grape seed and skin extracts inhibit platelet function and release of reactive oxygen intermediates. J Cardiovasc Pharmacol. 2005; 46:445-51. DOI | PubMed
  62. Chew B, Mathison B, Kimble L, McKay D, Kaspar K, Khoo C, et al. Chronic consumption of a low calorie, high polyphenol cranberry beverage attenuates inflammation and improves glucoregulation and HDL cholesterol in healthy overweight humans: a randomized controlled trial. Eur J Nutr. 2019; 58:1223-35. Publisher Full Text | DOI | PubMed
  63. Vazquez-Prieto MA, Miatello RM. Organosulfur compounds and cardiovascular disease. Mol Aspects Med. 2010; 31:540-5. DOI | PubMed
  64. Yeh YY, Yeh SM. Garlic reduces plasma lipids by inhibiting hepatic cholesterol and triacylglycerol synthesis. Lipids. 1994; 29:189-93. DOI | PubMed
  65. Simopoulos AP. Omega-3 fatty acids in wild plants, nuts and seeds. Asia Pacific Journal of Clinical Nutrition. 2002; 11:S163-S73. DOI
  66. Wolfram G. Dietary fatty acids and coronary heart disease. Eur J Med Res. 2003; 8:321-4. PubMed
  67. Edel AL, Rodriguez-Leyva D, Maddaford TG, Caligiuri SP, Austria JA, Weighell W, et al. Dietary flaxseed independently lowers circulating cholesterol and lowers it beyond the effects of cholesterol-lowering medications alone in patients with peripheral artery disease. J Nutr. 2015; 145:749-57. DOI | PubMed
  68. Liperoti R, Vetrano DL, Bernabei R, Onder G. Herbal Medications in Cardiovascular Medicine. J Am Coll Cardiol. 2017; 69:1188-99. DOI | PubMed