From www.bloodjournal.org by guest on May 6, 2016. For personal use only.

Monitoring

the

Entry

of New

Platelets

Ingestion
Giovanni

By
There

have

recovery

been

of

function

after

studies

employed

enzymatic

ingestion

of

studied

after

aspirin

arachidonic

by preventing

to

72

hr.

by radioimmu-

response

to

formation

PLATELETS
aggregation

and

We

of

in vivo
ex vivo
of arachi-

entry

of new

ments

with

originating

ase

has

dose

of aspirin

In those
a single

does

not occur

studies,
cyclooxygenase
activity
aggregating
agent was studied.

has

24-48

Inc.,

not

Chemie,

denied
blood.

taking
any drugs
for
Nine volumes
of blood

citrate,

3.8%.

Company,
ml)

were

days.
over

taken

a period
and

Blood,

used

loss incurred

3 days.

within

affected

preparation.

Counter,

Vol. 61, No. 6 (June),

1983:

Blood

(PRP),

was kept

were

(PFP)

3200

collagen

plus

circulation
whose

5 mm

were

Co.,

St.

AA

of plate-

cyclooxygen-

at

room

adenosine

Louis,

isotonic

collagen

(col)

temperature

West

as described

(epi)

Elkins-Sinn

reagent

and

MN.

epinephrine

solution)

Germany;

Elysian,

5-diphosphate,

MO;

(Kollagen

arachidonic

Solutions

Inc.,

Horm),

Hormon

acid

of sodium

(>99%

arachidon-

elsewhere.2

powder

(Crystalline,

Freshly

Sigma

in 0.3 M sodium

was dissolved
prepared

solutions

(Merck,

dissolved

in 95% ethanol.

Dilutions

were

in Tris

Platelet

Sharp

Aggregation

These

studies

records

the

Havertown,

and
PA).

experiment.

Indo-

agents,

was

aspirin,

or

0.1 54 M, pH 7.4.

from

the

(secreted

luciferin

The sensitivity

that

interaction

with

395,

was such

also

of released

simultaneously

(Chronolume

as low as 0. 1 gM could

ATP

Louis,
at 4#{176}C.

Dr. J. Schrogie,

in a Lumi-Aggregometer3

(ATP)

luciferase

each
from

ofaggregating

resulting

triphosphate

firefly

for

St.

and kept

Secretion

performed

luminescence

Co.,

solution

a gift

buffer,

and

were

used

& Dohme),

made

Chemical

acetate

were

methacin

yr. who

aspirin

at daily

plasma

3 hr after
plasma

mg

NY).

and then

Platelet-rich

in an Eppendorf

25-59

intervals

was

centrifuge

pp. 108

in the range
obtained
(Brinkman

counts

for 3
120 ml
by

tempera-

by centrifuging
Instruments,

Advanced
leave

that

ADP)

Chrono-Log

concentrations

be detected.

The

apparatus

from

Submitted
Jefferson

Foundation

Jefferson
in part
and

208/8.

Training

G.DIM.

EEC

Istituto

and

Department

of Pharmacolo-

University,
Philadelphia.
by National
Institutes

PA.
of Health

is a fellow

of the

Italian

di Semeiotica

of

Ministero

Medica

II

the

Grants

Program

of

Lavoro,

on

del

Policlinico,

Napoli,

Italy.
Address

of PRP,

of 350-400

the Cardeza

Thomas
Supported

HL-14890

(20

prepared

at room

Platelet

1-1085

was

From
gy,

(Bayer

samples

by any one subject

I 5 mm,

a Coulter

aged

650

York,

at 200 g for

Platelet-free
PRP

New

were

METHODS
7 females)

ingested

2 and 4 hr later

blood
of

Inc.,

of
the

g for

employed

Prep.,

indomethacin

10 days prior
to the study,
donated
were drawn
into I volume
trisodium
then

Drugs

blood
using

l09/iiter.

subjects

again

Maximum

obtained
fresh

The

Sterling

centrifuging
ture

AND
(7 males,

NJ;

prepared

Aspirin
MO)

Corp.,

subjects

12,000

Sigma

MUnchen,

of released

MATERIALS

and

platelets

Aspirin

hr.5#{176}

by aspirin.

normal

and

Agents

Nuchek

with

Fourteen

collagen

aggregation

acetylated.

hydrochloride,

ate were

obtained
of aspirin
thrombox-

has not been

at

(ADP)

Hill,

adenosine

that

full

into

the
experi-

aspirin-treated
of

megakaryocytes

NY)

(epinephrine

with

activity

In vitro

aspirin-free

entry

completely

thromboxane

and

combination

agents

salt

ane in response
to stimulation
by the combination
of
arachidonic
acid (AA)
and collagen.
The consequent
progressive
recovery
of these platelet
functions
appears
to reflect
the entry
into the circulation
of new platelets
cyclooxygenase

been

Westbury,

sodium

in response
to
We report
here

that platelets
in platelet-rich
plasma
(PRP)
from
normal
subjects
4 hr after
ingestion
aggregate,
secrete
nucleotides,
and produce

early

from

not

Aggregating

has been presented

activity
after a single

for at least

the

(20-22#{176}C).

pure),

activity

by aspirin.
Evidence
ofcyclooxygenase

of

of

to

collagen.

reflecting

circulation.

produce

2.5%

the

of

combination

could

only

Use

lets

new

been affected
that the return

when

return

aspirin-free
the

(AA)

1 .Lg/ml

combination.

the

of
that

in response

with

this

into

mixtures
acid

of aspirin

a linear

by

showed

demonstrates

Cherry

cyclooxygenase

was

platelets

arachidonic

bition
is irreversible,
the return,
after
an interval
of
time, of the ability
to form Tx by platelets
in circulating blood should
reflect
the entry into the circulation
of
whose

there

stimulated

Aggregating

acid
(AA)
to cyclic
endoperoxides
and subseto thromboxane
(Tx) A2.4
Because
this inhi-

platelets

ingestion
in combination

detected

to aspirin
secretion

transformation

After

Murphy

acid

hr.

present.

adenosine

was

72

secretion

as 4

combinations
or

to

platelets

a lumiag-

as early

collagen.

Thromboxane

the enzymatic

platelet-

formation
occurred

Up

4 hr after

with

epinephrine.

OF
platelet

up

Circulation

as 4 hr after

arachidonic

formation
the

on 14

and Scott

early

mM

stimulate

secretion

secretion
in

with

(ADP).

XPOSURE
inhibits

donic
quently

and

ingestion

acid

diphosphate

thromboxane-B2

Aggregation

as

these

to

2 and

daily

and

the

investigated

agents

and

J. Silver,

platelet

However.

subjects

aspirin

Melvin
in

and

agent
We

normal

aggregation

and

aspirin.

of aggregating

mg

platelet

noassay.

of
activity.

from

650

gregometer
hr

pairs
(PRP)

delay

activity

the

of Aspirin

Di Minno,

24-48-hr

aggregating

functional

plasmas

ingestion
a single

of some

rich

of

cyclooxygenase

the

or

effects

reports

platelet

Into

Philadelphia.

October
reprint
University,
PA

I 983 by Grune

4. 1982;
requests
Cardeza

accepted
to

December

Melvin
Foundation,

J.

Silver,
1015

3, 1982.
D.Sc.,
Walnut

Thomas
Street,

19107.
& Stratton,

Inc.

0006-4971/83/6106--0007$01.00/0

1081

From www.bloodjournal.org by guest on May 6, 2016. For personal use only.

1082

Dl MINNO.

10
0
I4-.

Fig.
0.8

COL
0.6

0
(_)

04

*4

04

***

ILt.

0.2

I
I-

0
4

24

HOURS

was

adjusted

so that

transmittance,
volume
that

PRP

of vehicle
another

mixture.

aggregating

ADP,

as well

the addition

its

or

or

AA

light

an

equal

was

added

to the

at different

as

time

in combination

1 gzg/ml

collagen,

at least

ATP

secretion

within

the

was

supernatant
and

tion

ATP

measured

10 M

50%

light

3 mm

after

agent.

solution
ATP

did

antibodies

completion

Cardeza

Foundation,
as amounts

interfere

TxB2

were

used

with

the

kindly

for

for

PA.

platelet

the

assay

of the
aggrega-

measurement
for TxB2.

provided

Philadelphia,
ofTxB2/3x

in aliquots

of tests

reagents

of
Highly

by Dr. J. B. Smith,

Individual

results

were

lO platelets.

Analysis

Students
was obtained

test for paired

comparison
from the volunteers
after

was used. Informed

approval
by the local

for threshold

concen-

Committee

in accord

with

and
<

those
0.05;

an assurance

at 4 hr are
p < 0.01,

filed

with

and

by H.S.S.

RESULTS

Platelet
Aggregation
Ingestion
Two
hours
PRP did not
(I

AA

and

Secretion

After

consent
Human

after
ingestion
of
aggregate
or secrete

mM).

aggregation
epinephrine

radioimmunoassay3

The

not
for

expressed

Statistical

after

secretion.

secretion

specific

by

course

Aspirin

inter-

with

Thromboxane-B,
TxB2

Investigation
approved

seconds

defined

Time

hr after aspirin
ingestion
indicated
as follows:
p
p
<0.005.

7 2

ASPIRIN

90%

Fifteen

were

which

OF

1.

to 0.5 ml of PRP

I mm.

caused,

as I .5 iM

of the second

and

vehicle

for
agent

of aspirin

epinephrine,

transmittance

or

10%
agent

volumes

at 37#{176}C
for

agent
of this

ingestion

10 .zM

produced

concentrations

concentrations

after

INGESTION

aggregating

in microliter

at I 000 rpm

Threshold

minimal
vals

PFP

An

was added

had been stirred

later,

and

respectively.

AFTER

48

MURPHY

trations
(mean
SEM)
of AA, which in combination with ADP (10 gzM). epinephrine
(10 gM).
or collagen
(1 g/ml).
induced
aggregation
and
secretion
of ATP in PRP from 14 subjects
who
had ingested
aspirin.
See Materials
and Methods for details.
At 2 hr. combinations
of AA (1
mM)
and the other aggregating
agents
did not
produce
at least 50% aggregation
or secretion
of 1 .5 sM ATP.
Higher
concentrations
of AA
were
not used because
they
cause
lysis of
platelets.
Significant
differences
between
the
concentrations
of AA required
at 24. 48. or 72

EPI

1-4

22

AND

LI

ADP

SILVER,

In addition,
occurring
(10 sM),

However,

as early

detected
response

2 waves
to AA

AA

aspirin,
platelets
ATP
in response

was

in response
or collagen

as 4 hr after
of aggregation
in combination

unable

to enhance

to ADP
(I zg/ml)
aspirin

in
to

(10 jsM),
(Fig.
I).

ingestion,

we

and ATP secretion

with epinephrine

in
or

ADP.
Actual
chart
recordings
of enhancement
of
platelet
aggregation
and secretion
in PRP (4 hr after
ingestion
of aspirin)
in response
to AA in combination
with the other aggregating
agents
are shown
in Fig. 2.
PRP
prepared
and 72 hr after
tion

and

from blood
samples
collected
aspirin
ingestion
gave similar

secretion.

The

threshold

24, 48,
aggrega-

concentration

AA 0.8

of AA

AAO.8

AGGREGATION
T

110

I mm

EPI

COL
+

10
ADP

10

AA

AA 0.8
AA

I
0.8

08

ATPI.5uMJ

ATP

SECRETION
AA

0.8

OR

EPI

10
AA

Fig.

2.

Typical

and epinephrine

tracings

are tM.

of aggregation
for

collagen

g&g/mI.

and

ATP

and

for

secretion
AA

mM.

obtained

0.8

in PRP

OR
samples

ADP

AA

10

collected

4 hr after

aspirin

ingestion.

0.8

Units

for

ADP

From www.bloodjournal.org by guest on May 6, 2016. For personal use only.

PLATELET

RETURN

diminished

AFTER

significantly

tion

of these

j.tM

indomethacin

AA

to

PRP

with

for

of the respective

acm

had

Preincuba-

).

aspirin

abolished

the

aggregation

concentration

the ingestion
platelets.

platelets
aspirin.

Two

in PRP
response

did not
to AA

of TxB2

the limit
collected

hours

after

form
either

Percentage

concentraor indometh-

ingestion

collected

0.18
TxB2/3

was found
ingestion

of aspirin,

or

in
of

(Table
amounts

I). These
of TxB2

collagen.
TxB2
in PRP collected

combinations
at 24 hr.

0.5

mM

aspirin

completely
the

or

20

suppressed

combination

of

was
4 hr

.tM

indomethacin

for

formation

in response

(I

and

at

incubation

each

day

mixture

Table

1.

TxB2

of

Formation

mM)

and

60

in Response

Agents

Compared

to Pairs

aspirin

PFP

ingestion,

(prepared

in Response

to Pairs

(Mean

tion,

whereas

single
when

agents
varying

(data

Agents

SEM

Stimulus

Collagen

Before

+ saline

(1 gg/mI)

976
+

sa-

755.4

were

carried

minimum

out

number

in an

of aspirin-

AA in combination
of individual
PRPs

light
in

with
I tg/mI
were incubated

(1 sM)

and

collagen

(I tg/ml),
determined
platelets

to achieve
50% light transmission
and at
secretion
in response
to each agent

none

was

produced

(Fig. 3B).
amounts

in response

Similar
results
of aspirin-free

to the

were obtained
platelets
were

a normal
subject
blood was taken

Before

and

at Different

Time

Intervals

After

Aspirin

Ingestion

PRP)

n (pmole/ml/3

x 108 Platelets)
After

Aspirin

Ingestion

24

48

<0.5

<0.5

<0.5

<0.5

23.3

3.2

103.2

<0.5

<0.5

<0.5

<0.5

19.8

7.3

98.3

<0.5

<0.5

2.7

0.3

5.3

3.2

40.2

7.8

<0.5

3.2

1.5

6.9

2.4t

43.9

3.2

28.2

151.3

234.6

77.3

ASA

128.3

studies

Agents

ATP

Hours

mM)

Aggregating

not shown).

of 14 Different
TxB2 Formatio

AA(1

to
Formation

ofAggregating

mixed
with platelets
in PRP
from
who had ingested
aspirin
2 hr before

these

to Single

the

to AA

required
1 .5 j.M

to

of Aggregating

TxB2

were required
tc obtain
50%
at least
1 .5 .tM ATP
secretion

to I pM
Samples

(1

the

from

that
and

Needed

and

alone
(Fig.
3A).
In contrast,
about
2.5% aspirin-free
platelets
sufficed
when
the aggregating
agents
were
employed
in combination.
In like manner,
a mixture
containing
2.5% aspirin-free
platelets
produced
measurable
amounts
of TxB2 in response
to the combina-

the vehicle
for aspirin
or
For each individual
PRP
after

of in vitro

to determine

in response

were
least

mm

collagen

Secretion,

either
individually
or in combination,
were
immediately.
About
1 59o-20%
aspirin-free

produced
Progressively

TxB2

zg/mI).
Controls
employing
indomethacin
had no effect.
tested

In Vitro

tion
in
or

In vitro incubation
of these
after aspirin
ingestion)
with

AA

always

for 60 mm with either

sodium
acetate
(0.3 M)
or
aspirin
(0.5 mM)
added
in microliter
volumes.
At the
end of the incubation
period,
varying
percentages
of
aspirin-free
platelets
were mixed
with aspirin-treated
platelets,
and aggregation,
secretion,
and TxB2 forma-

greater
amounts
ofTxB2
were formed
in response
to all
combinations
at the ensuing
time periods.
As controls,
the following
were checked.
PRPs (i.e., PRPs collected

(1 tg/ml)

TxB2.

Platelets

in PRP

response
collagen.

platelets

after
aspirin
ingestion
in response
to the combination
of AA (I mM)
plus collagen
(I g/ml),
but not
response
to the combinations
of AA plus ADP
epinephrine
detectable

collagen

ofAspirin-Free

free platelets
transmission

amounts
of TxB2 in
alone or in combina-

tion with
ADP,
epinephrine,
formed
in measurable
amounts

and

0.5 pmole/ml

Aggregation,

attempt

pmole/
x 108

of detection)
2-72
hr after

(1 mM)

Obtain

A series
in PFP

was 0.73
0.5 pmole

measurable
employed

AA

less than

of

Ingestion

ofaspirin
Less than

(below
PRP

from

Aspirin

and

formed

secretion.

and

for aspirin

PRPs)

or 20

ability

and

volumes

vehicles

After

mean

PFP

mM

no effect.

Formation

108

(Fig.
0.5

60 mm
similar

tions

The

time
with

platelet

employing

TxB2

1083

samples

enhance

Controls

before
3 )(

ASPIRIN

72

line
AA

mM)

(1

ADP

(10

1,286

Epi

(10

1,320

126.6

<0.5

Lg/

2,053

238.9

<0.5

gtM)
AA

(1

mM)

gsM)
AA

(1 mM)

Col (1

30.1

5.6

72.3

27.7t

ml)
p

<

0.05.

tP

<

0.01.

<

0.005.

<

0.001.

Significant

differences

for TxB2 formation

are indicated

between

the time

in question

and the first

time

at which

TxB2 was detected.

From www.bloodjournal.org by guest on May 6, 2016. For personal use only.

DI MINNO,

1084

I0

MURPHY

B.

a:

(I)

0
U-

(I)

AND

COL

A.

SILVER,

AA
AAI

COL

U)

60
Ui

a:
I-.

x
0

I-.

53

COL

#{149}-.

AA

-J

a:

#{149}--SAA
.-..-..

10

COL

30

20
0/0

I-

1.25

40

ASPIRIN-FREE

2.5

10

20

41

PLATELETS

Fig. 3.
Platelet
aggregation
(A) and TxB2 formation
(B) in mixtures
of aspirin-free
and aspirin-inhibited
PRP in response
to collagen
(1
gag/mI) and AA (1 mM) singly or in pairs. In A. results
are expressed
as percent
light transmittance.
100% being the light transmittance
observed
for each aspirin-free
sample.
The arrows
indicate
the minimal
concentration
of aspirin-free
platelets
required
to obtain
>50%
light transmittance
and the secretion
of at least 1 .5 gM ATP. In B. percent
TxB2 formed
refers to the percent
of the TxB2 formed
in each
aspirin-free
PRP sample.
The data
reported
are the mean
SEM of 4 experiments
using PRP from 4 different
donors.

methacin

DISCUSSION

Evidence
cyclooxygenase
ingestion
at least

has

been presented251#{176} that the return

of
activity
in circulating
platelets
after

of a single
dose of aspirin
does not
24-48
hr. However,
in those studies

aggregating
measured

agent
was employed
in serum.
Our data

or TxB2 levels
show
the initiation

response
epinephrine

to the combined
or collagen,

in combination

thrombin,
or AA,
tion in PRP
from

they observed
subjects
who

10-16
hr previously.
they also reported

the

gation

and

secretion

of AA plus ADP or
shown
full aggrega-

by platelets
from subjects
who had
aspirin
4 hr previously.
Rao et al.4
some effects
of pairs of aggregating

epinephrine

In agreement
enhancement

occurring

with

irreversible
had ingested

ADP,

aggregaaspirin

with our findings,

of platelet
aggre-

4 hr after

aspirin

inges-

tion

in response
to AA plus epinephrine
or AA plus
ADP,
and this was not accompanied
by the formation
of measurable
amounts
of TxB2.
This
suggests
that
either
AA may act synergistically
with other aggregating agents
by mechanisms
other
than
prostaglandin
and thromboxane
formation,
or that
extremely
low
levels of thromboxane
may potentiate
aggregation
and
secretion

in response

to ADP

interpretation
is supported
tiation
is inhibited
by the

or epinephrine.
by the
addition

The

and
plus
by

latter

fact that this potenof aspirin

or indo-

It is conceivable

our radioimmunoassay.
the observation05

methods.

of aspirin.
We took advantage
of the fact that
form
more
TxB2
in response
to pairs
of
agents
than they do to single
agents.3
In

Using

thromboxane
required
to potentiate
aggregation
secretion
in response
to the combination
of AA
ADP
or epinephrine
were too small
to be measured

the

of TxB2

stimulus
we have

as 4 hr after

of

albumin,
platelets

ingestion
platelets
aggregating

agents.

as early

the amounts

were
of

recovery

tion and secretion

ingested
650 mg
have also studied

formation

occur
for
a single

in vitro.

that

Studies
using
approximately

day.

Using

This possibility
is supported
because
thromboxane
binds

that

50%-80%
cannot
be

of the
detected

platelets
10%

combinations

would

be in the

fore,
early

thromboxane
by the usual

formed
by
analytical

and

platelets
Within
of newly

circulation.

Our

AA,

collagen
plus AA
from
megakaryocytes
been

acetylated.

one

would

in vitro

experiments
plus AA
There-

our ex vivo data to indicate

that
ingestion
of aspirin,
the combination
can

reveal
whose

However,
expect

we saw

as early
as 4 hr
that
time
period,
formed
platelets

that the combinations

of collagen
about
2.5% of aspirin-free
platelets.

we interpret
as 4 hr after

by
to

labeled
with 51Cr6 indicate
of platelets
turn over every
of collagen

evidence
of newly
formed
after
ingestion
of aspirin.
approximately
I .5%-2%
confirmed
can detect

that

about

new platelets
cyclooxygenase
with

10%

200

pmole

as

originating
has not

turnover
TxB2/3

per

day,
x

108

platelets
24 hr after
ingestion
of aspirin
(Table
I
In
contrast,
only
30%-40%
of the
amount
of TxB2
expected
was found.
This indicates
that only 30%-40%
of the newly
formed
platelets
can form TxB2, or that
new platelets
form
only
30%-40%
of the expected
).

amount
response
linear
ment

of TxB2.
The
return
of TxB2
to the combination
of collagen
for the
persisted

first 72 hr, suggesting

in the new platelets

formation
plus AA

in
was

that this impairentering

the circu-

From www.bloodjournal.org by guest on May 6, 2016. For personal use only.

PLATELET

lation

RETURN

during

AFTER

this

ASPIRIN

period.

1085

It also

suggests

tion of the megakaryocytes

but not complete.
In conclusion,
our data

indicate

after

there

ingestion

lets

in the

is effective

of aspirin

circulating

and
secretion
agents.
Since

blood

that
are

acetyla-

long

as 4 hr

new

full

to combinations

response

lasting

as early

enough

to induce

in response
to
in vivo aggregation

that
and

plate-

used
to
platelets

aggregation

monitor
the
originating

cyclooxygenase

pairs
of aggregating
is likely to occur

of agents,

these

help to explain
why the hemostatic
ingestion
of aspirin
is relatively
mild.
strate
that the combination
ofcollagen

has

entry
from

observations

defect
following
Our data demonplus AA can be

into
the circulation
of
megakaryocytes
whose

not been

completely

acetylated.

in
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From www.bloodjournal.org by guest on May 6, 2016. For personal use only.

1983 61: 1081-1085

Monitoring the entry of new platelets into the circulation after ingestion of
aspirin
G Di Minno, MJ Silver and S Murphy

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