Food and Public Health 2015, 5(1): 1-9

DOI: 10.5923/j.fph.20150501.01

Effect of the Flavonol Quercetin on Human Platelet

Function: A Review
Sapha Mosawy

Heart Foundation Research Centre, Griffith Health Institute, Griffith University, Gold Coast Campus, Qld, Australia

Abstract Quercetin (Que) is one of the most abundant and potent naturally occurring antioxidant. Que has been shown to
exert many biological activities, including antiplatelet activity. Indeed, Que was shown to inhibit platelet aggregation in
response to platelet agonists, such as ADP, collagen, thrombin and arachidonic acid. However, the lowest Que concentration
that significantly inhibits agonist-induced platelet aggregation remains contradictory. In addition, to anti-aggregatory effects,
Que was demonstrated to inhibit platelet dense and alpha granule exocytosis when stimulated by different platelet agonists.
Que was also shown to inhibit multiple platelet protein kinases, including, PI3K, Akt, PLC and PKC. The main aim of this
review focuses on the inhibitory effects of Que on human platelet function.
Keywords Flavonols, Que, Platelet, Thrombosis

suggest inadequate cardiovascular protection by these

1. Introduction agents [9].
Epidemiological studies have suggested that consumption
Platelets play an important role in the development of of a flavonol rich diet is associated with reduced mortality
cardiovascular disease (CVD) and the formation of arterial due to CVD [10]. Indeed, the Rotterdam study showed
thrombosis [1, 2]. Nitric oxide (NO) from the endothelial reduction in the occurrence of fatal myocardial infarction
cells regulates platelet aggregation by increasing cyclic with flavonol consumption [11]. Furthermore, flavonols
guanosine monophosphate (cGMP). However, in CVD, the have been shown to exert both antioxidant and antiplatelet
endothelial cells are damaged and as a result the activity in vitro [12-14]. Rechner et al. [15] had shown that
subendothelial matrix and collagen are exposed [3]. Platelet dietary polyphenolic compounds inhibit platelet aggregation,
adhesion to subendothelial matrix is a crucial step in the and Hubbard et al. [16] reported that following ingestion of
formation of platelet rich thrombus. Platelet adhesion and the naturally occurring flavonol Que, collagen-induced
activation is initiated by binding of collagen and von platelet aggregation was inhibited. In addition, previous
willibrand factor (vWF) to their platelet receptors. studies have shown that ingestion of flavonol rich foods and
Following the initial adhesion and activation, platelets beverages reduce platelet aggregation induced by different
undergo further activation by releasing their granule content agonists [17-19]. The present review focuses on the effect
that include adenosine diphosphate (ADP) and formation of of the flavonol Que on human platelet function.
thromboxane A2 (TXA2) [4]. Platelet activation leads to a
conformational change in platelet fibrinogen receptor
GPIIbIIIa, which acts as a bridge between activated 2. Flavonols
platelets, resulting in platelet aggregation [5]. Flavonols are a subgroup of flavonoids. Flavonoids are
Antithrombotic agents are regularly used for the low molecular weight phenolic substances widely found in
secondary prevention of cardiovascular events in diabetic plants, fruits and vegetables [12, 20]. Flavonols are well
patients and in primary prevention of high risk individuals known to be potent scavengers of free radicals. This
[6]. Furthermore, antiplatelet therapy is the standard important biological activity is principally based on the
treatment for patients undergoing percutaneous coronary redox properties of their phenolic hydroxyl groups, and the
intervention (PCI). Despite the clinical benefits achieved structural relationships between different parts of their
with antiplatelet therapy, some patients still develop chemical structure. Flavonols have three structural groups
thrombotic episodes [7, 8], and there is growing data to that determine their antioxidant activity, which are: the
o-dihydroxy (catechol) structure in the B-ring, the 2,
* Corresponding author:
s.mosawy@griffith.edu.au (Sapha Mosawy)
3-double bond conjugated with a 4- oxo function and the
Published online at http://journal.sapub.org/fph presence of hydroxyl (OH) groups. These structural features
Copyright © 2015 Scientific & Academic Publishing. All Rights Reserved and particularly the number of OH groups present are
2 Sapha Mosawy: Effect of the Flavonol Quercetin on Human Platelet Function: A Review

uniquely arranged giving different flavonols varying adhesion to the damaged vessel wall leading to a platelet rich
antioxidant capacity [21, 22]. Flavonols have been shown to thrombus.
exert different biological activities. These include
antioxidant, antimicrobial, antiviral and antiplatelet activities 3.1. Antiplatelet Therapy
[12-14]. Aspirin has been the drug of choice for patients with
cardiovascular disease or as a prophylaxis for many years,
2.1. Quercetin because it is cost effective and readily available [36, 37].
Que (3,5,7,3’,4’-pentahydroxyflavone) (Fig 1) is one of Aspirin inhibits platelet function via the irreversible
the most abundant flavonols, and due to its chemical acetylation of COX 1, by inactivating its catalytic activity.
structure is one of the most potent naturally occurring COX 1 catalyses the formation of arachidonic acid to
antioxidants within the flavonoid subclasses. It is prostaglandin H2, and finally TXA2 formation [38].
ubiquitously found in a variety of fruits, vegetables and plant Inhibition of TXA2 results in the blockade of platelet
derived beverages [21]. Table 1 shows Que concentration in activation through the thromboxane receptor.
different pants and plant- derived beverages. In food, Que is Although aspirin has been the most common antiplatelet
lipophilic, and is mainly bound to sugars, phenolic acids or agent for many decades, there are some limitations and
alcohols [23]. However, following ingestion, Que and its concerns associated with it that must be taken into
derivatives are hydrolysed mostly in the gastrointestinal tract, consideration. It has been shown that that aspirin is a weak
then absorbed and metabolised, Que absorption rate depends platelet inhibitor [8, 39]. Furthermore, CVD patients on
on the food source being ingested. The absorbed forms of aspirin are becoming less responsive to aspirin [40, 41],
Que are mainly glucosides and aglycones [21]. In addition to where patients with CVD have recurrent thrombotic events
Que antioxidant and cardiovascular beneficial properties, it while on aspirin therapy [38, 42]. Therefore, many of such
has been was found to produce several other important patients are placed on dual antiplatelet therapy such as
biological effects, including anti-inflammatory, antiplatelet aspirin and clopidogrel [43].
and anti-hypertensive effects [24, 25]. Clopidogrel and ticlopidine (ADP receptor antagonists)
[36] have been shown to be effective antiplatelet agents.
However, there is an increasing body of evidence
suggesting increased non responsiveness to clopidogrel
amongst cardiovascular patients on a standard dose [41, 44].
Table 1. Que Content in Common Plants and Beverages

Food mg/100 g Beverage mg/100 mL

Apple 10 - 26 Apple juice 0.25
Apricot 5.3 Grape juice 0.44
Pear 2.8 Grapefruit juice 0.49
Plum 0-1.5 Lemon juice 0.74
Figure 1. Molecular structure of Que
Red grape 3.7 Orange juice 0.34 - 0.57
Broad bean 134 Red wine 0.4 -1.6
3. Platelet and Arterial Thrombosis Broccoli 0.6 Black tea (loose) 1.6
Cauliflower 3.1 Black tea (bags) 1.7- 2.5
It is well established that platelets play an essential role in White onion 54 Green tea 1.4 - 2.3
the formation of arterial thrombosis and vascular Lettuce 32 - 47 Tomato juice 1.3
complications [26]. Platelets from vascular disease patients Ref [21, 45-47]
were found to be hyperactive, and there were increased
number of circulating monocyte-platelet aggregates [27, 28].
In addition to their high sensitivity to agonists, platelet 4. Anti-platelet Properties of Que
secrete chemokines and cytokines that attract monocytes and
neutrophils [29], hence further contributing to the ongoing Platelet aggregation is the final step in the thrombus
inflammatory processes at the vessel wall, accelerating the formation process. Platelet aggregation is stimulated by
progression of atherosclerosis and development of CVD different agonists via different pathways. The effect of these
[30, 31]. Injury to the vascular endothelial lining exposes the agonists is mediated by an increase in intracellular calcium
highly thrombogenic subendothelial matrix on which concentration, which induces the activation of different
collagen and vWF are found [32, 33], the damaged vascular enzymes such as myosin light chain kinase (MLCK) and
wall releases tissue factor, while coagulation factor VIIa is calcium – dependant phospholipase A2. The activation of
released from platelet alpha granules initiating the these enzymes leads to phosphorylation of actin filaments
coagulation cascade [34, 35]. Collagen and vWF bind to and induces platelet shape change. Following shape change
their specific platelet receptors causing platelet tethering and platelet undergo release reaction in which platelets’ dense
 Food and Public Health 2015, 5(1): 1-9 3

and alpha granules release their content which results in an arachidonic acid (AA) induced platelet aggregation by Que
amplification in the activation process [48, 49]. with an IC50 of 18 µM, while we showed complete inhibition
of arachidonic acid-induced platelet aggregation by Que at
4.1. Effect on Platelet Aggregation 200 µM [52]. In a different study by Raghavendra et al. [50]
While Que has been demonstrated to reduce or inhibit suggested that Que was ineffective inhibitor of AA induced
platelet aggregation, the degree of inhibition and the platelet aggregation with an IC50 of >400 µM. Table 2
effective Que concentrations are varying. Indeed, some summarises the reported effect of Que on platelet
studies have shown Que to be very effective in reducing aggregation induced by different agonists.
platelet aggregation at low concentrations, while other The difference in the effectiveness of Que and degree of
studies have reported higher concentrations were required to inhibition could be due to a number of different reasons. The
achieve anti-aggregatory affects. Beretz et al. [13] reported methods used to assess platelet aggregation were different,
inhibition of collagen induced platelet aggregation with an some studies used platelet rich plasma, while others, used
IC50 of 55 µM, while Raghavendra et al. [50] reported 100 washed platelets to measure platelet aggregation, and some
µM of Que caused only 1.7% inhibition of collagen-induced studies used photospectrometry to assess platelet
aggregation. In a study by Sheu et al. [51] demonstrating the aggregation [54]. Platelets are sensitive to extra handling,
inhibition of collagen-induced platelet aggregation by Rutin and as a result, washing or other techniques that might
(Que glycoside) at 250 and 290 µM. We have demonstrated involve extra handling may activate the platelets prematurely,
that Que at 100 µM caused >90% inhibition of and this could have an impact of the results. The
collagen-induced platelet aggregation [52]. concentration of platelet agonists used could have affected
Que was also demonstrated to have variable and the observed anti-aggregatory effects of Que. The use of
conflicting effects on platelet aggregation induced by other platelet agonists at higher concentrations is likely to reverse
platelet agonists. Landolfi et al. [53] reported inhibition of Que effects on platelet aggregation.
Table 2. The Effect of Que on Platelet Aggregation Induced by Different Agonist

Agonist Que [µM] Platelets used Inhibition (%) Ref

ADP (2.5 µmol/L) PRP & washed 97+4
2500 Janssen et al.[55]
Collagen (2.5 mg/L) platelets 95+5
ADP (18 µmol/L) 0.25,2.5,25 PRP & washed Ineffective
Janssen et al.[55]
Collagen (2.5 mg/L) & 250 platelets ineffective
ADP (2 µM) 1000 90
PRP Pace-Asciak et al.[56]
Thrombin (120 mU/ml) 95
AA (1 mM) 400 Ineffective
ADP (50 µM) 200 25
PRP Raghavendra et al.[50]
Calcium ionophore (20µM) 200 12
Collagen (0.5 mg/ml) 100 Ineffective
Collagen (2 mg/L) 50
20 Washed platelets Pignatelli et al.[57]
Collagen (4 mg/L) 43
Collagen (7 µg/ml) 1.25-20 PRP Ineffective Pignatelli et al.[58]
ADP (10 µM) >90
Collagen (2.5 ug/ml) 100 Washed platelets >90 Oh et al.[59]
Thrombin (0.1 U/ml) 80
ADP (10 µM) 10 PRP 50 1chen et al.[54]
Collagen (2 µg/ml) 4.87+1.11 50
Collagen (4 µg/ml) 4.93+1.12 50
Washed platelets Hubbard et al.[60]
Collagen (5 µg/ml) 8.69+1.05 50
Thrombin (0.1 U/ml) 27.6+1.04 50
Complete
Collagen (5 µg/ml) 40 Washed platelets Wright et al.[61]
inhibition
AA (0.5 mM)
200 100
ADP (10 µM), Collagen (5 PRP Mosawy et al.[52]
100 >90
µg/ml)
4 Sapha Mosawy: Effect of the Flavonol Quercetin on Human Platelet Function: A Review

4.2. Effect on Platelet Signalling Proteins It has been suggested that PI3K plays an important role in
Platelet signalling proteins play a major role in platelet GP1b-IX-V mediated, integrin – dependant platelet
activation and aggregation. Binding of fibrinogen or vWF adhesion, spreading and aggregation. Navarro-Núñez et al
to platelet αIIbβ3 transmits signals that regulate the found that Que at 50 µM completely inhibited all PI3k
extension of platelet filopodia, spreading, granule release isoforms. In a different study, Agullo et al. [65]
and aggregation. The protein kinase Syk is involved in the demonstrated Que at 60 µM caused near complete
initiation of αIIbβ3 – dependant actin polymerization and inhibition of PI3k alpha.
platelet spreading. While the protein kinase Src is needed One of PI3K functions is to phosphorylate and activate
for αIIbβ3 – dependent tyrosine phosphorylation of Syk and Akt 1 and Akt 2 via phosphoinositide dependant protein
for platelet spreading on fibrinogen [62, 63]. It is reported kinase (PDK). Akt kinases have been found to mediate
that c-Src and Lyn kinases form complexes with GPIb-IX signalling via G-coupled protein signalling
phosphoinositide 3-kinase (PI3K) and GP1b-IX-V after pathways, which leads to the amplification of platelet
vWF stimulation to induce platelet activation. Limited aggregation induced by G-protein coupled receptors and
number of studies have attempted to investigate the effect collagen [66]. Several studies have reported inhibition of
of Que on several signalling proteins, Navarro-Núñez et al. Akt by Que [59, 67].
[64] tested the effect of 50 µM Que on different platelet Protein kinase C (PKC) is expressed in human platelets
signalling proteins, the authors reported significant and it has been found to play an important role in many
inhibition of Fyn, Lyn, Src and Syk protein kinases. While, platelet signalling pathways [68]. It has also been suggested
Hubbard et al. [60] and Wright et al. [61], reported Que at that the phosphorylation of PKC regulates dense granule
0-150 µM inhibited Fyn and Syk protein kinases in a release mediated by PAR platelet receptors. Que has been
concentration dependant manner. found to weakly inhibited PKC isoforms [58]. Table 3
shows the effect of Que on platelet signalling proteins.
Table 3. Inhibitory Effects of Que on Platelet Signalling Proteins

Signalling proteins tested Que [µM] Inhibition (%) Ref

PLCγ2 0-150 Concentration dependant inhibition Wright et al. [61]
Syk
Fyn
Fyn 50 75.0+1.4 Navarro-Nunez et al. [67]
Lyn A 54.0+4.2
Src 64.0+4.2
Syk 80.0+0
ERK1 20.5+0.7
ERK2 9.0+2.8
Akt1 46.5+2.1
Akt2 51.0+9.9
p38 a 16.0+2.8
PKCA 10.0+14.4
PKCB1 24.0+4.2
PKCD 23.5+4.9
PI3K a 75.5+4.9
PI3K b 85.5+3.5
PI3K o 99.0+0
Syk 0-150 Concentration dependant inhibition Hubbard et al. [60]
Fyn
Lyn
PI3K
PLCγ2
ERK2 12.5-100 Concentration dependant inhibition Oh et al. [59]
JNK
p38
PI3K
Akt
PLC 20 93 Pignatelli et al. [57]
PKC 5 Ineffective Pignatelli et al. [58]
 Food and Public Health 2015, 5(1): 1-9 5

Table 4. Effect of Que on Platelet Granule Exocytosis and other Function Parameters

Que conc Effect Ref

1 pmol/l-100
Concentration dependant inhibition of ATP and ADP release Kaneider et al.[75]
µmol/L
Inhibition of ATP release, quinacrine release, PAC1, P-Selectin
1 mM Mosawy et al.[52]
(CD62P) expression and fibrinogen binding
Inhibition of platelet spreading on collagen or fibrinogen coated
50 µM Navarro-Nunez et al.[67]
surfaces
0 - 20 µM Concentration dependent inhibition of calcium mobilization Hubbard et al.[60]
Concentration dependent inhibition of ATP release, P-Selectin
3.1- 100 µM Oh et al.8
(CD62P) expression, fibrinogen binding and calcium mobilization
Inhibition of hydrogen peroxide production, calcium mobilization,
10 or 20 µM Pignatelli et al.[57]
platelet adhesion to collagen coated surface

4.3. Effect on other Platelet Function Parameters platelet aggregation at the same concentration. Wright el al.
Platelet activation and aggregation is a complex and [61] also demonstrated that neither of these metabolites was
multi-step process. Platelet dense granules play an important able to significantly inhibited Fyn kinase, whereas,
role in the amplification of platelet activation by the release tamarixetin, but not Que-3’-sulphate or Que-3’glucuronide,
of signalling and activation molecules such as ATP and ADP, was able to significantly inhibit total protein
while the content of platelet alpha granules are essential for phosphorylation, Syk and PLCγ2 tyrosine phosphorylation.
platelet adhesion to endothelial cells and leucocytes [69]. These data suggest structural modification of Que following
Que has been demonstrated to inhibit the exocytosis of both ingestion decreases its potency to inhibit platelet function.
dense and alpha granules, calcium mobilization and platelet
spreading [52, 59, 67]. Table 4 summarises Que effect on 6. Conclusions
platelet granule exocytosis and other activation parameters.
It is well established that platelets are essential in the
formation of arterial thrombosis and development of CVD.
5. Effect of Que Metabolites on Platelet Therefore, antiplatelet is the mainstay treatment for patients
Function who are at high risk of developing thrombotic episodes.
However, increasing evidence has indicated inadequate
In food, Que is lipophilic, and is mainly bound to sugars, protection by antiplatelet therapy against thrombotic events
phenolic acids or alcohols [70]. However, following in some patients [8]. Several studies have therefore
ingestion, Que is hydrolysed, and then absorbed and investigated many polyphenolic compounds for their
metabolised, Que absorption rate depends on the food cardiovascular and antiplatelet potentials. Que is a
source being ingested. The absorbed forms of Que are polyphenolic flavonol that is been found to be a potent
mainly glucosides and aglycones [21]. There are many antioxidant with many beneficial activates that include
different quercetin-conjugated metabolites have been antiplatelet activity. Indeed, Que and some of its
identified [71], the main conjugates were found to be metabolites have been demonstrated to inhibit platelet
tamarixetin, quercetin-3’-sulphate, quercetin-3’glucuronide aggregation and activation. However, there are conflicting
and Que-4’-O-B-D-glucoside [71]. Many studies have data regarding the lowest Que concentration capable of
explored the antioxidant activities of many of these producing significant antiplatelet effect and whether they
conjugates [72-74]. However, the antiplatelet potential of are achievable in vivo. Furthermore, the exact mechanism/s
quercetin conjugates has not been widely investigated. by which platelet function is inhibited is not fully
Nevertheless, there is a limited number of studies that have understood. Several studies have shown inhibition of
attempted to elucidate the antiplatelet activity of some multiple platelet signalling proteins, while others
quercetin conjugates. Indeed, Hubbard et al. [16] reported demonstrated inhibition of platelet granule exocytosis. It is
that Que-4’-O-B-D-glucoside was able to inhibit likely that Que inhibits platelet function via multiple
collagen-induced platelet activation. It was demonstrated mechanisms, and at least in part due to, the inhibition of
that ingestion 150 or 300 mg of Que-4’-O-B-D-glucoside signalling molecules and granule exocytosis (Fig 2).
inhibited platelet aggregation, tyrosine phosphorylation of This review identifies several limitations associated with
SyK and PLCγ2. In a different study by Wright et al. [61] currently available data, including, the lowest effective Que
investigating the effects of the metabolites tamarixetin, concentration and agonist concentration. An effective
Que-3’-sulphate and Que-3’-glucuronide on platelet strategy to overcome the agonist concentration issue is to
function. It was found that tamarixetin and Que-3’-sulphate construct a dose-dependent curve for the agonist
completely inhibited platelet aggregation, whereas, concentrations, and then appropriately choosing the
Que-3’glucuronide did not cause significant inhibition of effective concentration.
6 Sapha Mosawy: Effect of the Flavonol Quercetin on Human Platelet Function: A Review

Figure 2. Schematic representation of agonist-induced platelet activation pathways and the proposed effect of Que leading to inhibition of platelet function.
Que has been demonstrated to inhibit platelet function via multiple pathways, including, inhibition of multiple signalling proteins, granule exocytosis and
fibrinogen binding. Effect of Que is denoted by

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