Vol.3, No.6, 319-325 (2011)
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
The antithrombotic effects of onion filtrates in rat s and
Kanae Hyodo1, Izumi Horii1, Masaru Nishino2, John C Giddings3, Junichiro Yamamoto1*
1Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University and Cooperative Research Center of Life Sciences, Kobe
Gakuin University, Kobe, Japan; *Corresponding Author: yamamoto@nutr.kobegakuin.ac.jp
2Hyogo Prefectural Technology Center for Agriculture, Forestry and Fisheries, Awaji Agricultural Technology Institute, Awaji, Japan;
3Wales College of Medicine, Cardiff University, Cardiff, UK.
Received 10 February 2011; revised 29 March 2011; accepted 1 April 2011.
The prevention of arterial thrombotic disease
has a high priority in developed countries. An
inappropriate diet is known to enhance the risk
for acute thrombotic events, and a regular diet
with proven antithrombotic effects might be a
beneficial way to prevent disease. The present
study was undertaken as part of a series of in-
vestigations to examine various vegetables and
fruits for antithrombotic activity, and to add to
the previously reported data on different onion
varieties produced in the northern part of Japan
(Hokkaido). For this purpose, a sophisticated
method to assess shear-induced platelet reac-
tivity/thrombolysis in vitro (The Global Throm-
bosis Test, GTT) was used to screen 5 different
varieties o f on ion p roduced in the middle part of
Japan (Awaji Island). The different onion varie-
ties demonstrated a variable effect on thrombo-
sis, and one particular variety, designated
ONA-03, appeared to exert an antithrombotic
effect. Another variety, ONA-01, appeared to
have prothrombotic activity by inhibiting spon-
taneous thrombolytic activity. The especially
effective variety was further investigated using
an in vivo, laser-induced thrombosis model in
mice. The heat stable antithrombotic activity in
vitro and in vivo w as demonstrated to be due to
antiplatelet activity. The present findings added
to the list of antithrombotic fruits and vegeta-
Keywords: Cardiovascular Dise ase; Stroke;
Atherothrombosis; Onion; Quercetin
The prevention of “lifestyle-related atherothrombotic
diseases” such as myocardial infarction and stroke has
become an important and urgent social task in many
developed countries. Studies have provided clear evi-
dence that an inappropriate diet, such as the Western-
style high fat diet, plays a causative role in the patho-
genesis and clinical outcome of thrombotic diseases [1].
The so-called French Paradox and red wine hypothe-
sis [2,3] has prompted many laboratory studies on anti-
thrombotic fruits and vegetables, and epidemiological
studies have provided evidence that intake of fresh fruits
and vegetables could help to prevent cardiovascular dis-
ease and stroke [4-7].
Platelets play a pivotal role in arterial thrombotic dis-
eases. Platelet-function in vitro is commonly assessed
using platelet aggregometry, which measures platelet
aggregation induced by various chemical agonists. In
clinical practice, however, beneficial tests for the diag-
nosis and treatment of patients with thromboembolic
disorders remain to be fully defined. Tests using native,
non-anticoagulated blood in the presence of physiologi-
cal shear force are likely to be much more relevant to the
in vivo environment than those using anticoagulated
blood and chemical platelet agonists [8-9]. We have
demonstrated that shear-induced platelet reactivity tests
in vitro, using non-anticoagulated blood, significantly
correlate with the in vivo helium-neon (He-Ne) laser-
induced thrombosis model in animals [10].
We have established in our laboratory a shear-induced
platelet-rich thrombosis/coagulation test (Haemosta-
tometry), a novel, commercially available shear-induced
platelet-rich thrombosis/thrombolysis method (The Global
Thrombosis Test, GTT) and a He-Ne laser-induced
thrombosis model to investigate specific fruits and
vegetables for antithrombotic activity. We have shown
that different varieties of tomato, onion and strawberry
can be classified according to shear-induced platelet-rich
thrombotic activity (Haemostatometry), and that varie-
ties of mulberry and carrot can be classified on this basis
K. Hyodo et al. / Health 3 (2011) 319-325
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
together with spontaneous thrombolytic activity (GTT)
[11-15]. We have also demonstrated using Haemosta-
tometry, that one onion variety cultivated in the northern
part of Japan (Hokkaido) was notably antithrombotic [12]
but the availability of this product remains limited. In the
present study we have expanded our studies on the anti-
thrombotic effects of onions using potentially more
readily available onion varieties produced in the central
area of Japan (Awaji).
2.1. Animals
Male Wistar ST rats, at least 13 weeks old, and male
C57BL/6 mice, 10 weeks old were purchased one week
before use (Japan SLC Co. Ltd., Hamamatsu, Japan).
Rats were fed a standard solid chow (MF, Oriental Yeast
Co. Ltd., Osaka, Japan) and mice were similarly fed with
standard solid chow (MF, Japan Clea CO. Ltd., Tokyo,
Japan). Animals were allowed tap water ad libitum, and
were maintained in compliance with the “Guiding Prin-
ciples for the Care and Use of Animals in the field of
Physiological Sciences,” published by Physiological
Society of Japan. The protocol was approved by the
Animal Experiment Committee of Kobe Gakuin Univer-
sity. Animals were sacrificed using Somnopentyl fol-
lowing the experimental procedures.
2.2. Onions
Five varieties of onion, designated ONA-01, ONA-02,
ONA-03, ONA-04 and ONA-05, were sown and har-
vested in August on the same test field of the Hyogo
Prefectural Technology Center for Agriculture, Forestry
and Fisheries, Awaji Agricultural Technology Institute,
Awaji, Japan.
2.3. Preparation of Onion Filtrate
Six brown skin peeled bulbs per each variety were
graded to a standard size using a plastic grader at room
temperature to avoid inter-individual variation. The juice
was centrifuged (3000 rpm, 15min, 4) and the super-
natant was filtered (FP30/5.0 CN-S, 5.0 μm, Whatman
PLC, Kent, UK). Clear filtrates were stored at –80
before use.
2.4. In Vitro Assessment of Shear-Induced
Platelet Reactivity and Spontaneous
Thrombolytic Activity using the
Global Thrombosis Test (GTT)
The technique has been described in detail elsewhere
[15-16]. The instrument was purchased from Montrose
Diagnostics Ltd., London, UK (www.globalthrombosis.com).
Figures 1 and 2 illustrate the principles of the technique.
A flat segment created along the inner wall of a conical
Figure 1. Schematic illustration of the GTT apparatus.
Figure 2. Schematic diagram showing the principle of the
K. Hyodo et al. / Health 3 (2011) 319-325
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
plastic tube forms the basis of the technique. When per-
fectly round steel ball-bearings are placed into the coni-
cal tube, the flat segment prevents the spheres from oc-
cluding the lumen. Blood is added, flows through the
narrow gaps and exits in droplets into an adjacent col-
lecting tube. The latter is trans-illuminated by a light
emitter, and a sensor opposite the light source generates
a signal whenever a drop of blood interrupts the light
path. In essence, the instrument detects the time interval
(d, sec) between consecutive blood drops. At the start,
blood flow is rapid and hence (d) is small. Subsequently,
the flow rate gradually decreases and hence (d) increases.
When the actual (d) exceeds 15 seconds (occlusion-d),
the instrument displays “Occlusion Time (OT)”, which is
the time elapsed from the detection of the first drop of
blood until (occlusion-d). Later, flow is completely ar-
rested. Eventually, due to thrombolysis, flow is restored
as indicated by the further detection of blood droplets.
There is also an arbitrarily pre-set (d) (200 seconds) for
lysis measurement (lysis-d). When (d) between the last
drop before and the first drop after occlusion exceeds
this (lysis-d), the instrument displays “Lysis Time (LT)”.
Hence, lysis time is calculated as follows: LT = (time of
first drop with d > (lysis-d)) – (time of last drop with d <
(lysis-d)). Blood flows by gravity at 37oC through the
narrow gaps formed between the larger ball bearing and
the inner wall of the tube, and the resulting high shear
stress (175 dyne/cm2) activates platelets. These activated
platelets remain single, since the very short transit time
and high shear prevent aggregation. In contrast, in the
space distal to the large ball bearing, i.e. between the
two ball bearings, the low shear and turbulent flow favor
large platelet aggregate formation. Furthermore, in this
space between the ball bearings, activated platelets gen-
erate thrombin and initiate blood coagulation. Flow then
carries these fibrin-stabilised platelet aggregates into the
lower gaps where they are captured, resulting in occlu-
sion and arrest of flow. Increased or decreased OT indi-
cates inhibition or enhancement of platelet reactivity,
respectively. Increased or decreased LT indicates inhibi-
tion or enhancement of spontaneous thrombolysis, re-
spectively. Measurements were made six times (n = 6) in
each sample.
Animals were fasted overnight but allowed water ad
libitum. Blood was obtained from the abdominal aorta
30 minutes after anesthesia with sodium pentobarbital
Somnopentyl, 64.8 mg/ml, Kyoetsu Seiyaku Co. Ltd.,
Tokyo, Japandiluted 5 times with saline (65 mg/kg,
intramuscularly). Non-anticoagulated blood was mixed
with saline (1:1). 3.6 ml of the diluted blood and 0.4 ml
of onion filtrate or saline (control) (blood: filtrate = 9:1)
were mixed in a syringe by inversion and the mixture
was applied to GTT tube.
2.5. In Vivo Assessment of the
Antithrombotic Effects Using
the Laser-Induced Thrombosis
Test in Mice Carotid Arteries
The He-Ne laser-induced platelet-rich thrombosis
method has been previously described in detail [17,18].
Mice were anaesthetised with Somnopentyl (65 mg/kg,
intramuscularly). A polyethylene tube (PE10, Becton
Dickinson and Company, New Jersey, USA) was placed
into the left femoral artery to inject dye and the carotid
artery (450 - 500 μm in diameter) was exposed by inci-
sion. The mouse was placed on a specially adapted mi-
croscope stage (Olympus Model BH-2, Olympus Co.
Ltd., Tokyo, Japan) and Evans blue dye (30 mg/kg,
Merck, Darnstadt, Germany) was injected intra-arterially.
The centre of the exposed carotid artery was irradiated
with a laser beam (Model Neo-50MS, 25 mW under an
objective lens, Neoark Co. Ltd., Osaka, Japan). Throm-
bus formation at the site of irradiation was monitored
under epi-illumination and simultaneously recorded on
videotape using a CCD camera (Model TMC-7, Take-
naka System Co. Ltd., Kyoto, Japan).
2.6. Oral Ad ministration of Onion Filtrates
to Mice
The vegetable filtrate or saline only (control) was ad-
ministered through a gastric tube at 15.4 ml/kg (un-
heated filtrate) and 15.4 or 30.8 ml/kg (heated filtrate).
Half volume of filtrate or saline (7.7 ml/kg (unheated
filtrate) and 7.7 or 15.4 ml/kg (heated filtrate) was re-
peatedly given at 30 minute interval as previously de-
scribed [11]. The mouse was then anaesthetised and the
thrombosis experiments commenced 90 min after the
second oral administration. Antithrombotic or prothrom-
botic effects were assessed by estimating total thrombus
2.7. Calculation of Thrombus Size
Details of this technique have been described else-
where [18]. Images of thrombus formation were com-
puter-analysed at intervals of ten seconds. The area of
thrombus was delineated and the mass of thrombus cal-
culated by multiplying gray scale and area using Image J
software (Image Processing and Analysis Java version
1.30, National Institutes of Health, Maryland, USA).
Thrombotic status was expressed as the total sum of
thrombus mass after the first 10 minutes of irradiation.
2.8. Statistical Analysis
Data from GTT were analysed by repeated ANOVA
(General Linear Model), followed by the multiple com-
parison test (Dunnett), data from the laser-induced
K. Hyodo et al. / Health 3 (2011) 319-325
Copyright © 2011 SciRes. http://www.scirp.org/journal/HEALTH/Openly accessible at
thrombosis experiments by the unpaired t-test. Values
were expressed as means ± SEM. P < 0.05 was consid-
ered as the limit of significance. Analyses were per-
formed using Statistical Package Unistat 5.6 Light
(London, UK).
3.1. Effects of Raw Filtrates from Onion
Varieties on Shear-Induced Platelet
Thrombosis and Spontaneous
Thrombolysis in Vitro
The results are shown in Table 1. The filtrate from
ONA-01 did not affect occlusion time (OT) but signifi-
cantly inhibited spontaneous thrombolytic activity (LT),
indicating that this variety had prothrombotic activity.
ONA-02, ONA-04 and ONA-05 did not affect signifi-
cantly either OT or LT. In contrast, the undiluted filtrate
from ONA-03 significantly prolonged OT but did not
affect LT, indicating that this particular variety had anti-
thrombotic activity both in vitro and in vivo.
3.2. Heat Stability of Antithrombotic Effect
of ONA-03
The antithrombotic effects of ONA-03 in vivo, were
re-examined after the raw filtrate was heated in boiling
water for 10 minutes. The filtrate was cooled to room
temperature and the OT and LT were measured. The
results are shown in Table 2. Similar results to those
using unheated filtrate were obtained. The heated and
undiluted (x1) filtrate significantly prolonged OT but
had no significant effect on LT, again suggesting anti-
thrombotic activity in vivo.
Table 1. Effects of raw filtrates from five onion varieties on shear-induced platelet thrombosis (occlusion time, OT)
and spontaneous thrombolysis (lysis time, LT).
Variety Dilution Occlusion time Lysis time
ONA-01 control 307.9 ± 9.9 989.7 ± 70.9
× 1 265.0 ± 6.3 1520.3 ± 110.9**
× 3 327.7 ± 12.1 983.3 ± 103.4
× 10 311.5 ± 20.7 1024.3 ± 46.5
ONA-02 control 295.6 ± 4.7 855.3 ± 39.6
× 1 260.4 ± 16.2 1022.5 ± 90.2
× 3 289.7 ± 14.2 972.4 ± 76.9
× 10 289.1 ± 16.9 841.7 ± 57.9
ONA-03 control 329.1 ± 12.9 944.8 ± 24.8
× 1 457.4 ± 36.1** 977.3 ± 102.7
× 3 352.0 ± 22.5 935.3 ± 99.7
× 10 344.7 ± 16.5 900.6 ± 55.4
ONA-04 control 287.0 ± 20.7 985.0 ± 48.5
× 1 272.9 ± 25.1 1042.8 ± 80.7
× 3 294.0 ± 25.5 895.5 ± 52.2
× 10 299.5 ± 18.1 913.3 ± 78.5
ONA-05 control 304.0 ± 18.2 976.0 ± 32.4
× 1 367.1 ± 37.6 1032.4 ± 102.3
× 3 341.9 ± 19.4 891.8 ± 26.6
× 10 311.7 ± 14.9 889.3 ± 56.7
**: P < 0.01
Table 2. Effects of heat treatment on the inhibitory activity of ONA-03 in shear-induced platelet thrombosis.
Variety Dilution factor of filtrate Occlusion time Lysis time
ONA-03 saline (control) 302.7 ± 12.5 1066.7 ± 66.7
× 1 446.0 ± 19.4** 1249.6 ± 41.3
× 3 345.6 ± 9.3 981.5 ± 75.0
× 10 331.5 ± 12.7 959.2 ± 69.7
**: P < 0.01
K. Hyodo et al. / Health 3 (2011) 319-325
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
3.3. Antithrombotic Activity of Orally
Administered ONA-03
Unheated or heated onion filtrate was orally adminis-
tered to mice and the antithrombotic effect was assessed
using the He-Ne laser-induced thrombosis test on ex-
posed carotid arteries. Results are shown in Figure 3.
Unheated and undiluted (x1) filtrate from ONA-03 sig-
nificantly inhibited He-Ne laser-induced thrombosis (A).
The same volume of heated filtrate did not inhibit
thrombosis (B) but administration of twice the volume
significantly inhibited thrombus formation (C). This
inconsistency between the in vitro GTT test and the in
vivo laser-induced thrombosis test might have been be
due to different sensitivity of the methods or the effects
of intestinal absorption. Nevertheless, the results dem-
onstrated that the filtrate from ONA-03 was relatively
heat stable.
Arterial platelet-rich thrombotic diseases are a social
problem in many countries, and reliable tests to assess
thrombotic tendency could be critically important in
attempts to prevent these diseases. Various methods have
been developed, including agonist-induced platelet ag-
gregation tests using anticoagulated whole blood or
platelet rich plasma. Biomarkers of coagulation and fi-
brinolysis have also been devised [19-24]. It is widely
appreciated, however, that thrombus formation in vivo is
governed by interactions between blood flow, blood
components and the blood vessel wall as proposed by
Virchow, and the pathophysiological relevance of these
tests to thrombotic status in vivo is not clear. Alterna-
tively, innovative tests, in which non-anticoagulated
blood is used and platelets are activated by shear force
under flow, have been proposed [8,9,15]. Clinical and
experimental studies have suggested that these tests may
be more relevant to thrombotic status in vivo [8-10,16].
We have utilized in vivo tests of this nature to charac-
terize various fruits and vegetables on the basis of anti-
thrombotic activity. In particular, Haemostatometry, the
GTT and the He-Ne laser-induced thrombosis test [17,
18] have enabled classification into different subgroups
In an earlier study we used Haemostatometry and the
He-Ne laser-induced thrombosis model to identify a
specific antithrombotic onion variety produced in the
northern part of Japan [12]. Distribution of this variety
was limited, however, and further studies were devised
to examine onion varieties from central Japan (Awaji
Island). These varieties were potentially more available
than others, and were classified using the GTT in place
of Haemostatometry.
The principle aim of our current series of investiga-
tions is to broadly identify fruits and vegetables with
antithrombotic activity. In addition, thrombus evolution
is largely determined by a balance between pro-aggregatory
and procoagulant mechanisms on the one hand, and fi-
brinolytic processes on the other [25], and the relation-
ship between the concentration of specific antithrom-
botic substances and overall antithrombotic activity of
fruits and vegetables remains to be defined. In this re-
spect, quercetin is reported to be important in inhibiting
collagen-stimulated platelet aggregation [26-28], but a
high concentration of quercetin in onions does not nec-
essarily mean that onions are antithrombotic, and we
Figure 3. Antithrombotic activity of unheated and heated onion filtrates from ONA-03 n: number
of measurements; *: P < 0.05, **: P < 0.01.
K. Hyodo et al. / Health 3 (2011) 319-325
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
have previously demonstrated that there was no signifi-
cant correlation between quercetin concentration of on-
ions and overall antiplatelet activity using shear-induced
platelet function tests in vitro (Haemostatometry; 12).
Furthermore, the fibrinolytic properties of onions have
been the focus of some antithrombotic studies [29] but
significant fibrinolytic activity was not evident in any of
the five varieties of onions used in the present investiga-
tions. Moreover, for clinical purposes it is important to
note that the amounts of onion extracts given to animals
in the present studies would be approximately equivalent
to 40 kg onion given to a person with a body weight 70 kg.
This is clearly impracticable, and further studies are re-
quired to identify and isolate antithrombotic substances
that could be scientifically important and lead to signifi-
cant clinical benefit. Detailed analysis of this nature is
outside the scope of the present studies, but nevertheless,
our characterization of particular prothrombotic and an-
tithrombotic fruits and vegetables could lead to the de-
velopment of novel therapeutic products to help to pre-
vent arterial thrombotic diseases.
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