Synergism Among Flavonoids in Inhibiting Platelet Aggregation and H2O2 Production
F. Violi, P. Pignatelli and F.M. Pulcinelli
Circulation. 2002;105:e53
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Correspondence
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an in vitro and dietary supplement study. Am J Clin Nutr. 1998;67:
Synergism Among Flavonoids in Inhibiting Platelet
255 262.
Aggregation and H2O2 Production
3. Pietta P, Simonetti P, Gardana C, et al. Relationship between rate and
To the Editor:
extent of catechin absorption and plasma antioxidant status. Biochem Mol
In vitro and in vivo studies carried out by Freedman et1
Biol Int. 1998;46:895 903.
demonstrated that purple grape juice inhibits platelet aggregation
4. Pace-Asciak CR, Hahn S, Diamandis EP, et al. The red wine phenolics
trans-resveretrol and quercetin block human platelet aggregation and
and production of superoxide anion and increases the platelet
eicosanoid synthesis: implications for protection against coronary heart
formation of nitric oxide. These findings are of potential rele-
disease. Clin Chim Acta. 1995;235:207 219.
vance for explaining the cardioprotective effect of grape juice
5. Pignatelli P, Pulcinelli FM, Celestini A, et al. The flavonoids quercetin
and red wine. The authors sought also to investigate the mech-
and catechin synergistically inhibit platelet function by antagonizing the
anism by which grape juice inhibits platelet function and ob-
intracellular production of hydrogen peroxide. Am J Clin Nutr. 2000;72:
served a consistent difference in terms of platelet inhibition
1150  1155.
among the 5 fractions of grape twice containing flavonoids. We
agree with the authors that flavonoids, which are constituent of Response
The findings from our study1 are in agreement with the main
both red wine and grape juice, contribute to inhibiting platelet
comments of Violi and colleagues. A central message of this
activity, but there are some issues that merit consideration.
study1 is that one isolated flavonoid is not responsible for the
The first point is to determinate whether one or more fla-
antioxidant and platelet inhibitory effects that we reported. This
vonoids contribute to the antiplatelet effect of red wine or grape
is clear from the failure of any single flavonoid group to cause
juice. Assuming that only one flavonoid inhibits platelet function
the same effects as the purple grape juice either in vitro or ex
is not realistic because the concentration of flavonoids in human
vivo. As we were not sure what the relevant flavonoids were, it
circulation is low. Surprisingly, there are no data of flavonoids
was difficult to measure specific flavonoids from the subjects
concentration in human circulation after assumption of red wine,
who drank the juice. However, we do not believe that the
but taking into account other sources, such as onions or tea, the
plasma concentration would range from 0.6 to 13 mol/L.2,3 quercetin or resveratrol are the main substances responsible for
the platelet inhibitory or nitric oxide releasing effects. Although
Assuming a similar range of concentration after ingestion of red
previous studies have shown that, in vitro, flavonoids including
wine or grape juice, it is difficult to imagine that one flavonoid
quercetin, resveratrol, and catechin inhibit platelet aggregation,2
contributes to platelet inhibition. Indeed, Freedman s study and
the physiological relevance of these findings has been questioned
others4 demonstrated in vitro that much higher concentrations,
in humans because oral supplementation with quercetin causes
for instance of quercetin or resveratrol, are necessary for inhib-
markedly increased plasma levels but does not alter total, LDL,
iting platelet function.
or HDL cholesterol levels or change thrombogenic markers
On the basis of these considerations, we combined in vitro 2
including platelet aggregation and platelet thromboxane B2
flavonoids, namely quercetin and cathechin, and demonstrated
Violi and colleagues are correct that
that they are synergistic in reducing platelet formation of H2O2 production.3 However, have provided useful information espe-
flavonoid levels would
and inhibiting platelet function by interfering with the activation
cially as a point of comparison with the antioxidant levels
of phospholipase C pathway.5 As this effect was observed with
measured from the plasma of subjects who consumed purple
concentrations of quercetin and cathechin (5 mol/L and 25
grape juice.
mol/L, respectively) close to those potentially achievable in
blood after wine assumption, we believe that the concept of Jane E. Freedman, MD
Crawford Parker III, MD
synergism among the flavonoids could help explain the antiplate-
Liqing Li, MS
let activity of red wine and grape juice in vivo. In this regard, it
Jacob A. Perlman
is crucial that future studies with red wine or grape juice provide
Balz Frei, PhD
information on flavonoid bioavailability and its relationship with
Vadim Ivanov, PhD
antioxidant activity and platelet function.
Leslie R. Deak, BS
F. Violi
Mark D. Iafrati, MD
Institute of Clinical Medicine I
John D. Folts, PhD
University La Sapienza
Boston University School of Medicine
Rome, Italy
Boston, Mass
P. Pignatelli
1. Freedman JE, Parker C 3rd, Li L, et al. Select flavonoids and whole juice
F.M. Pulcinelli
from purple grapes inhibit platelet function and enhance nitric oxide
Department of Experimental Medicine and Pathology
release. Circulation. 2001;103:2792 2798.
University La Sapienza
2. Pace-Asciak C, Hahn S, Diamandis E, et al. The red wine phenolics
Rome, Italy
trans-resveratrol and quercetin block human platelet aggregation and
eicosanoid synthesis: implications for protection against coronary heart
1. Freedman JE, Parker C 3rd, Li L, et al. Select flavonoids and whole juice
disease. Clin Chim Acta. 1995;235:207 219.
from purple grapes inhibit platelet function and enhance nitric oxide
3. Conquer J, Maiani G, Azzini E, et al. Supplementation with quercetin
release. Circulation. 2001;103:2792 2798. markedly increases plasma quercetin concentrations without effect on
2. Janssen PLTMK, Mensink RP, Cox FJJ, et al. Effect of the flavonoids selected risk factors for heart disease in healthy subjects. J Nutr. 1998;
quercetin and apigenin on hemostasis in healthy volunteers: results from 128:593 597.
1
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