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Cover
Title Page
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Chapter 1: Human Blood Platelets and Their Role in the Development of Cardiovascular Disease
1. Abbreviations Used in This Chapter
2. 1.1 Introduction
3. 1.2 Human Blood Platelets: Structure and Function
4. 1.3 Platelet Activation Pathways
5. 1.4 Platelets and Vessel Wall Interactions
6. 1.5 Roles of Platelets in Atherosclerosis and Inflammatory Processes
7. 1.6 Platelets and Their Role in the Development of Cardiovascular Disease
8. 1.7 Conclusions
9. References
Chapter 2: Epidemiology of Cardiovascular Disease
1. Abbreviations Used in This Chapter
2. 2.1 Introduction
3. 2.2 Dietary Lipids and Cardiovascular Disease
4. 2.3 Environmental Factors and Cardiovascular Disease
5. 2.4 Genetic Basis of Cardiovascular Disease Incidence
6. 2.5 Fruits and Vegetables Consumption and Cardiovascular Disease Risk Reduction
7. 2.6 Conclusions
8. References
Chapter 3: n‐3 Fatty Acids and Human Platelets
1. Abbreviations Used in This Chapter
2. 3.1 Introduction
3. 3.2 Epidemiology of n‐3 Fatty Acids Intake and Cardiovascular Disease
4. 3.3 n‐3 Fatty Acids and Platelet Function
5. 3.4 Platelet Function and Eicosanoids
6. 3.5 Clinical Trials with n‐3 Fatty Acids
7. 3.6 Dietary Recommendation and Sources of n‐3 Fatty Acids
8. 3.7 Conclusions
9. References
Chapter 4: Effects of Garlic, Onion, Ginger, and Turmeric on Platelet Function
1. Abbreviations
2. 4.1 Introduction
3. 4.2 Effects of Garlic (Allium Sativum) on Platelet Function
4. 4.3 Effects of Onion (Allium Cepa L.) on Platelet Function
5. 4.4 Effects of Ginger (Zingiber Officinale) on Platelet Function
6. 4.5 Effects of Turmeric (Curcuma Longa) on Platelets
7. 4.6 Conclusions
8. References
Chapter 5: Herbs and Platelet Function
1. Abbreviations Used in This Chapter
2. 5.1 Introduction
3. 5.2 In Vitro Platelet Aggregation Studies: Effects of Different Herb Extracts
4. 5.3 Effects of Herbs on Signaling Molecules in Human Platelets
5. 5.4 Conclusions
6. References
Chapter 6: Tomato Extract and Human Platelet Functions
1. Abbreviations Used in This Chapter
2. 6.1 Introduction
3. 6.2 Epidemiology of Tomato Consumption and Cardiovascular Disease Risk Reduction
4. 6.3 In Vitro Studies with Water‐Soluble Tomato Extract on Human Blood Platelet Aggregation
5. 6.4 Fruitflow^®: Compositional and Structural Aspects
6. 6.5 Human Trials
7. 6.6 Comparing the Dietary Anti‐Platelet Fruitflow with the Anti‐Platelet Drug Aspirin
8. 6.8 EFSA Approval of Fruitflow
9. 6.8 Conclusions
10. References
Chapter 7: Dietary Nitrates and Their Anti‐Platelet Effects
1. Abbreviations Used in This Chapter
2. 7.1 Introduction
3. 7.2 Nitrate and Cardiovascular Health
4. 7.3 Effects of Nitrates on Human Blood Platelet Function In Vitro
5. 7.4 Clinical Studies with Dietary Nitrate: Effects on Ex Vivo Platelet Function
6. 7.5 Conclusions
7. References
Chapter 8: Kiwifruit and Human Platelet Function
1. Abbreviations Used in This Chapter
2. 8.1 Introduction
3. 8.2 Kiwifruit and Its Bioactive Phytochemicals
4. 8.3 Kiwifruits and Human Blood Platelet Function
5. 8.4 Human Trials Using Kiwifruit and Kiwifruit Extract
6. 8.5 Conclusions
7. References
Chapter 9: Polyphenols and Human Platelets
1. Abbreviations Used in This Chapter
2. 9.1 Introduction
3. 9.2 Polyphenols: Structure and Activity
4. 9.3 Sources of Polyphenols
5. 9.4 Dietary Intakes and Bioavailability of Polyphenols
6. 9.5 Roles of Polyphenols in Platelet Function
7. 9.6 Conclusions
8. References
Chapter 10: Effects of Ginkgo Biloba, Ginseng, Green Tea, and Dark Chocolate on Human Blood Platelet Function
1. Abbreviations Used in This Chapter
2. 10.1 Introduction
3. 10.2 Ginkgo Biloba Extract and Platelet Function
4. 10.3 Clinical Trial with EGB761
5. 10.4 Ginseng and Platelet Function
6. 10.5 Green Tea (Camellia Sinensis) and its Effects on Platelet Function
7. 10.6 Dark Chocolate and Platelet Function
8. 10.7 Conclusions
9. References
Chapter 11: Plant Alkaloids and Platelet Function
1. Abbreviations Used in This Chapter
2. 11.1 Introduction
3. 11.2 Alkaloids as Anti‐Platelet Agents
4. 11.3 Mechanism of Actions of Alkaloids
5. 11.4 Conclusions
6. References
Chapter 12: Strawberries and Human Platelet Function
1. Abbreviations Used in This Chapter
2. 12.1 Introduction
3. 12.2 Polyphenols in Strawberries
4. 12.3 Strawberry and its Cardio‐Protective Effects
5. 12.4 Anti‐Platelet Factors in Strawberry
6. 12.5 Discussion
7. References
Chapter 13: Effects of Metal Ions on Platelet Function
1. Abbreviations Used in This Chapter
2. 13.1 Introduction
3. 13.2 Zinc and Human Blood Platelet Function
4. 13.3 Calcium and its Regulation of Platelet Function
5. 13.4 Chromium and Platelet Function
6. 13.5 Iron (Fe) and Platelet Function
7. 13.6 Magnesium and Platelet Function
8. 13.7 Platelet Function and Selenium
9. 13.8 Conclusions
10. References
Chapter 14: Individual Compounds with Anti‐Platelet Activity Isolated from Plant Sources
1. Abbreviations Used in This Chapter
2. 14.1 Introduction
3. 14.2 Effects of Taurine and Glycine on Human Platelets
4. 14.3 Anthocyanins and Human Platelets
5. 14.4 Coumarins and Their Anti‐Platelet Effects
6. 14.5 Atractylenolides and Their Anti‐Platelet Effects
7. 14.6 Flavonolignans and Blood Platelet Function
8. 14.7 Protocatechuic Acid on Human Platelet Aggregation
9. 14.8 KOK and Platelet Function
10. 14.9 Inhibitors of Platelet Granules Secretion
11. 14.10 Hydroxychavicol and Platelet Function
12. 14.11 Compounds Isolated from Guttiferae Species with Anti‐Platelet Activity
13. 14.12 Conclusions
14. References
Index
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List of Tables

Chapter 1: Human Blood Platelets and Their Role in the Development of Cardiovascular Disease
1. Table 1.1 Platelet granules contents released on activation.
2. Table 1.2 Hyperactive platelets associated with disease.
Chapter 5: Herbs and Platelet Function
1. Table 5.1 Effects of spices/herbs on platelet function.
2. Table 5.2 Effect of various herbs and plant extracts on human platelet aggregation induced by ADP. Adapted from [11].
Chapter 6: Tomato Extract and Human Platelet Functions
1. Table 6.1 Composition of active components.
Chapter 8: Kiwifruit and Human Platelet Function
1. Table 8.1 Effect of different fruit extracts on platelet aggregation induced by ADP.
2. Table 8.2 Effects of kiwifruit consumption on ex vivo platelet aggregation in human volunteers.
Chapter 11: Plant Alkaloids and Platelet Function
1. Table 11.1 Plant alkaloids with anti‐platelet properties.
Chapter 12: Strawberries and Human Platelet Function
1. Table 12.1 Polyphenols present in strawberries.

List of Illustrations

Chapter 1: Human Blood Platelets and Their Role in the Development of Cardiovascular Disease
1. Figure 1.1 The role of platelets in the blood vessel.
2. Figure 1.2 Expression of fibrinogen receptors.Fibrinogen receptors (GPIIb/IIIa complex) on the platelet surface represents the final common pathway, whereby platelet stimulation by various agonists leads to fibrinogen binding, platelet aggregation, and thrombus formation. Aspirin can inhibit collagen, adrenaline and, to some extent, ADP‐induced expression of fibrinogen expression, but not the thrombin‐induced expression of GPIIb/IIIa complex on platelet surface.
3. Figure 1.3 The multiple roles of platelets in different diseases.
4. Figure 1.4 Platelet activation pathways.All the signaling events converge upon the final common pathway of platelet activation, the functional upregulation of integrin adhesion receptors. The most important is the activation of the GPIIb/IIIa receptor, which results in the cross‐linking of fibrinogen or vWF between receptors, leading to platelet aggregation. This further promotes the recruitment of additional platelets to the site of vascular injury, allowing subsequent thrombus formation. Thrombin is the most potent platelet agonist, and is also responsible for converting fibrinogen into fibrin to stabilize the platelet plugs.
Chapter 2: Epidemiology of Cardiovascular Disease
1. Figure 2.1 The haemostatic system: roles of human platelets.
2. Figure 2.2 Effects of composition and amounts of fatty acids on three limbs of hemostasis – platelet, blood coagulation and fibrinolysis.
Chapter 3: n‐3 Fatty Acids and Human Platelets
1. Figure 3.1 Classical n‐6 and n‐3 fatty acid LCPUFA synthesis pathways and their dietary sources. For details, please see the text.
2. Figure 3.2 Thromboxane receptors of human platelets.The receptor for TxA₂ (designated TP), is expressed as two isoforms, designated TPα and TPβ. The TP receptors mediate phospholipase C activation. The regulation of myosin light chain (MLC) phosphorylation, which has been suggested to be involved in the induction of platelets, can be controlled through a Ca²⁺/calmodulin‐dependent regulation of MLC kinase and through a Rho/Rho‐kinase‐mediated regulation of myosin phosphatase.
3. Figure 3.3 Eicosanoids synthesis from different fatty acids series. For details, please see the text.
4. Figure 3.4 Mode of actions of different dietary compounds at different steps of human platelet activation/aggregation.Modulation of platelet activation/aggregation response can be modulated by EPA by replacing ARA. Additionally, Flavonoids can lower the activity of lipases and cyclooxygenase via reduced formation of TxA₂.
5. Figure 3.5 Biological effects of arachidonic acid, 20:4n‐6 (ARA) and Eicosapentaneoic acid, 20:5n‐3 (EPA). For details, please see the text.
6. Figure 3.6 Overall effects of n‐3 fatty acids in the body. For details, please see the text.
Chapter 4: Effects of Garlic, Onion, Ginger, and Turmeric on Platelet Function
1. Figure 4.1 Cardio‐protective property of spices.
2. Figure 4.2 Effects of spices/herbs at different platelet‐activating pathways.
Chapter 5: Herbs and Platelet Function
1. Figure 5.1 The thromboxane pathway in platelets.
Chapter 6: Tomato Extract and Human Platelet Functions
1. Figure 6.1 Hyperactivity of platelets and their roles in the development of CVD. Platelets play an important role in CVD, both in the pathogenesis of atherosclerosis and in the development of acute thrombotic events. Hyperactive platelets are involved in the development of atherosclerosis by different mechanisms, such as membrane shedding, growth factor secretion, and expression of several adhesive factors. In addition, hyperactive platelets are involved in the well‐known penultimate thrombotic events. Adapted from [6].
2. Figure 6.2 Outline of tomato extract preparation. Tomatoes were homogenized and the juice was centrifuged at 3000 g for 25 min. The supernatant was then filtrated, using a filter with molecular cut‐off less than 1000 Da. The filtrated fraction was de‐sugarized by solid‐phase extraction with a styrene divinylbenzene cartridge at pH 2.5. Total active fraction (tAF) is 4% of the aqueous extract dry matter.
3. Figure 6.3 HPLC chromatography of total active fraction (tAF) isolated from tomato. A: The HPLC chromatogram shows the three sub‐fractions (AF1, AF2, and AF3), which are monitored by ultraviolet absorbance at 254 nm. Components within these sub‐fractions that have anti‐platelet activity in vitro (data not presented here) are numbered on the chromatogram. B: HPLC chromatogram of AF2, which was obtained under altered chromatographic conditions suitable for the separation of these components. C: HPLC chromatogram of AF3, which was obtained under altered chromatographic conditions to obtain increased component separation. Adapted from Am. J. Clin. Nutrition 2006, 84, 570–579. American Society for Nutrition.
4. Figure 6.4 Platelet activation via multiple pathways and sites of action of Fruitflow^® ingredients.Key agonists, their receptors and triggering signaling pathways involved in platelet activation and subsequent aggregation. In addition, the mechanisms by which Fruitflow^® ingredients anti‐platelet effects are detailed. VWF: Von Willebrand factor; TxA₂: thromboxane‐A2; TP: thromboxane receptor; ADP: adenosine diphosphate; PAR: proteinase activated receptor. The activation of platelets is accompanied by a conformational change in glycoprotein (GP) IIb‐IIIa exposes a binding site for fibrinogen and the release of aggregating agents such as TxA₂ and ADP. Adenosine nucleotides signal through P2 purinergic receptors (P2Y) on the platelet membrane. Activation of these receptors initiates a complex signaling cascade that ultimately results in platelet activation, aggregation and thrombus formation. Thrombin acts via cell surface Protease Activated Receptors (PARs). Both stimulate PLC, giving rise to PIP2 hydrolysis and consequent activation of PI3K. GPIV: collagen receptor. Adapted from the DSM publication.
5. Figure 6.5 The effect of supplementation with control or tomato extract treatment on ex vivo platelet aggregation, induced by ADP agonist over a seven‐hour period.ADP‐induced platelet aggregation was significantly lower than baseline values after supplementation with tomato extract, but not after supplementation with the control drink. The overall differences between the tomato extract and control drinks were significant at both optimal (overall mean Δ% in tomato extract group: −1.58 ± 0.71%; overall mean Δ% in control group: 2.10 ± 1.15%; P = 0.03) and suboptimal (overall mean Δ% in tomato extract group: −15.23 ± 2.19%; overall mean Δ% in control group: 1.86 ± 3.56%; P < 0.001) ADP concentrations.Changes from baseline aggregation were observed at each time point for the tomato extract group. When platelets were stimulated with suboptimal concentrations of ADP, significant differences from the control group were observed for the tomato extract group at three and six hours. When optimal ADP concentrations were used, the time × treatment interaction was not significant at any time point. No significant differences arising from the different carrier volumes were observed in either the control or tomato extract group at any time point.Adapted from Am. J. Clin. Nutrition 2006, 84, 570–579. American Society for Nutrition.
Chapter 7: Dietary Nitrates and Their Anti‐Platelet Effects
1. Figure 7.1 Reduction of inorganic nitrates to different metabolites.Inorganic nitrates present in fruits and vegetables are converted to nitrite (NO₂) and, subsequently, to different metabolites, including nitric oxide (NO).
2. Figure 7.2 Nitric oxide synthase inhibits platelet aggregation.Collagen or thrombin‐activated eNOS converts L‐arginine to L‐citrulline and produces NO. NO regulates cGMP via activation of soluble guanylate cyclase (sGC) and Ca²⁺. cGMP can bind to phosphodiesterase 3 (PDE3), which reduces metabolism of cAMP. Elevated levels of cGMP and cAMP can result in increased activity of protein kinase G (PKG) and protein kinase A, which inhibit protein kinase C activation and intracellular Ca²⁺ mobilization. The consequence of this signal transduction cascade is the inhibition of platelet activation, and the relaxation of vascular smooth muscle, resulting in blood vessel dilation.
Chapter 8: Kiwifruit and Human Platelet Function
1. Figure 8.1 Outline of kiwifruit extract preparation.Kiwifruits were homogenized and the juice was boiled at 90°C for 15 min, then centrifuged at 22 000 g for 15 min. The supernatant was then delipidated using a Lipidex‐1000 column and followed by filtration, using a filter with molecular cut‐off less than 1000 Da. The filtrated fraction was de‐sugarized using a hydrophobic column. Adapted from [33].
2. Figure 8.2 MS spectra of the delipidated and ultra‐filtrated kiwifruit extract.MS spectrum of the KFE after removal of soluble sugars. MS scans 100–1000 Mw. The column is a Zorbax 1.8 µm particle rapid resolution C18 column (4.6 mm × 50 mm, 1.8 µm). Elution was accomplished by starting 100% mobile phase (A) water‐formic acid (100 : 0.1, v/v/v) to 100 % B acetonitrile‐formic acid (100 : 0.1, v/v/v) for 35 min.Sugar‐free KFE (—); KFE (‐ ‐ ‐). Adapted from [33].
3. Figure 8.3 Dose‐dependent inhibition of platelet aggregation by sugar‐free kiwifruit extract.Platelet plasma rich plasma (PRP) was incubated with different concentrations of sugar‐free KFE for 15 min. at 37°C before ADP‐induced aggregation was initiated. Aggregation was followed at 37°C with stirring.
Chapter 9: Polyphenols and Human Platelets
1. Figure 9.1 Involvement of oxidative stress in different diseases.A shift in the balance between oxidants and antioxidants in favor of oxidants is termed as “oxidative stress”. Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates, or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects, through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Polyphenols are usually antioxidants that can reduce oxidative stress and protect health.
2. Figure 9.2 Different structural varieties of polyphenols present in plants.
3. Figure 9.3 Action of polyphenols on platelet activation.Oxidative stress is generated by different diseases and environmental conditions, as indicated, which depletes plasma and cellular antioxidants. Under these conditions, circulatory blood platelets will be hyperactive and can contribute to CVD. Polyphenols may reduce the oxidative stress and, thus, reduce platelet hyperactivity and CVD.
4. Figure 9.4 Polyphenols action on human blood platelets.The effects of dietary polyphenols on platelet aggregation pathways are likely due to the interference at different, multiple sites and levels, as indicated, in the complex signalling network leading to platelet activation of the fibrinogen receptor (GPIIb/GPIIIa).
Chapter 10: Effects of Ginkgo Biloba, Ginseng, Green Tea, and Dark Chocolate on Human Blood Platelet Function
1. Figure 10.1 Major compounds in ginkgo biloba extract.
2. Figure 10.2 Ginsenosides – the active components of Ginseng.
3. Figure 10.3 Major flavonols in green tea.
4. Figure 10.4 Major compounds in cocoa affecting CVD.
Chapter 11: Plant Alkaloids and Platelet Function
1. Figure 11.1 Proposed mechanisms of anti‐platelet action of alkaloids.
Chapter 12: Strawberries and Human Platelet Function
1. Figure 12.1 Isolation of sugar free aqueous extract from strawberries. Unpublished data (Biswas D, Uddin M, Duttaroy AK)
Chapter 13: Effects of Metal Ions on Platelet Function
1. Figure 13.1 Main sources of intracellular Ca²⁺ increase during platelet activation. TxA₂, IP3, DAG, STIM1; Stromal Interaction molecule 1, SOCE; Store‐operated Ca²⁺ entry.
Chapter 14: Individual Compounds with Anti‐Platelet Activity Isolated from Plant Sources
1. Figure 14.1 Chemical structure of taurine, anthocyanin, protocatechuic acid, and hydroxychavicol.
2. Figure 14.2 Chemical structure of coumarins.
3. Figure 14.3 Chemical structures of atractylenolides.
4. Figure 14.4 Chemical structure of flavanolignans.

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Library of Congress Cataloging-in-Publication Data

Names: Duttaroy, Asim K., author.

Title: Nutraceuticals and human blood platelet function : applications in cardiovascular health / by Asim K. Duttaroy.

Description: First edition. | Hoboken, NJ : Wiley, 2018. | Includes bibliographical references and index. |

Identifiers: LCCN 2018000528 (print) | LCCN 2018000730 (ebook) | ISBN 9781119376002 (pdf) | ISBN 9781119376057 (epub) | ISBN 9781119376019 (hardback)

Classification: LCC RC672 (ebook) | LCC RC672 (print) | NLM WG 120 | DDC 616.1/05–dc23

LC record available at https://lccn.loc.gov/2018000528

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Nutraceuticals and Human Blood Platelet Function

Applications in Cardiovascular Health