From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
Red
Blood
By
The
Cell
Piet
A.
hematocrit
platelet
crit
is
adherence
causes
order
We
have
arteries
one
of
the
Our
studied
and
a
cells
95
cu
HE
concern
using
increased
cu
platelet
cu
adherence
0 to 0.6.
range.
an
cells
blood
no
of Baumgartner.3
For
unknown
tem.4’t We report
that the volume
one of the main determinants
for
platelet
adherence.
the
cells
of
of
the
reasons,
Blood
blood
citrate.
Bank.
drawn
with
healthy
blood,
were
size
One
accidentally
found
to have
the
influencing
in this syscells
is
of
METHODS
Blood
cord
was
in three
the
sideroblastic
anemia
were
of perfusions
with
runs
in our
size.
of
from
be studied.
in
the mixed
red blood
blood
was obtained
adult
goats.
Goat
healthy
run,
Utrecht,
tal
and
the Department
Utrecht,
runs
Pure
Address
Medical
performed.
The
volume
for
by the Netherlands
Physics.
Medical
Hospital
University
Heart
Hospi-
Foundation
Research
Organizationfor
mM
Fungo.
September
Physics.
by Grune
7, 1982;
requests
accepted
February
University
Hospital
The Netherlands.
& Stratton,
Inc.
Utrecht,
respiratory
disease
clinical
In both
were
laboratory
cases,
blood
two
separate
collections
from
citrate,
obtained
from
perfusion
were
the umbilical
yielding
from
puncture
runs,
using
40-60
ml
3 perfusion
2 or 3 newborns
by cardiac
rabbit.
For
at a total
runs
for each
run.
from
three
different
blood
from
one
puncture,
each
and
animals
prior
yielding
perfusion
of 6 perfusion
washed
ofthe
goat
run,
runs.
The
was stored
to perfusion
about
the
blood
whole
of
blood
overnight
at 4#{176}C,
experiments.
Perfusates
final
pH
resuspended
Catharijnesingel
and
platelet
Malinckrodt,
Petten,
containing
Free
radiolabel
of
g,
according
red
(with
500
with
out simultaneously
jCi
oxine
(Brit
in 90%
ethanol)
10 M
aspirin,
was
were
Ringer
with
both
to prevent
adhesion.
platelet-poor
plasma
at pH
51CrO4
House,
incubated
Pool,
(Byk,
U.K.)
platelet
for
15 mm
(6.5
suspen-
at 37#{176}C.
(10
mm,
500
exhibited
procedures.
The
formation.
were
and
to enhance
This
6. 1 . Platelets
platelets
6. 1 to
(Amersham
by 2 washes
labeling
a
suspension.7
and,
thrombus
The
gave
was added,
Drug
pH
citrate
“In-oxine
removed
buffer,
mM
which
10 Ci
was added.67
20
51Cr or “In
in this
Na2
or
1
NaCI,
g, 20#{176}C)and
and glucose)
Netherlands)
behavior
19
mm,
Labeling
U.K.)
platelet
(10
blood
of PRP,
was added,
citrate
100
was performed
with
platelets/MI
pelleted
donor
107 mM
containing
Amersham,
45 I
whole
1 volume
KCI,
glucose
suspension,
Kreb’s
adherence
The
Ringer
and aspirin
20#{176}C)
with
remaining
27 mM
were
The
efficiency,
disolved
interfere
Na2SO4)
and
was carried
Ltd.,
the
2mM
(4 mM
of iO platelets/ml.6
International
treatment
solution
Platelets
from
190 g, 20#{176}C).To
Ringer
treatment
9 ml
was obtained
mm,
in Kreb’s
sion,
of
(PRP)
(10
of 6.1.
is
1, 1983.
Department
plasma
concentration)
labeling
(Grant
which
the Advancement
to Dr. P. A. M. M. Aarts,
hemato-
with
by draining
were
obtained
were
NaHCO3,
(plasma
same
0006-4971/83/6106-0031$0l.00/0
214
University
cell
How-
the
liver
separate
by vena
newborns,
a concentration
secondary
(Z. W.O.).
reprint
was
of a Kreb’s
mg/mI
by the Netherlands
351 1 GV Utrecht,
© 1983
ofMedical
the Foundation
Research
Submitted
101.
in part
and
subsidized
Haematology,
range,
in our
cells.
two
cells
Six
was used,
and
The Netherlands.
Supported
76090)
of
size
Red
volume.
bronchitis
trisodium
Data
for each
deficient
aspirin
Department
cell
performed.
blood
blood
I 10 mM
sample.
were
Platelet-rich
To
the
blood
caused
red
adherence.
alcoholic
was obtained
using
by centrifugation
hemachromatosin.
From
blood
from
each
with
of
that
average
pro-
red
anemia
indicate
examination
large
for
were
In this case, two separate
were
Small
human
with
blood
patients
with
because
that
cells.
parameter.
blood
into
Preparation
blood
case
red
Patients
the
this
cells
(MCV
Cross
patient
one
These
showed
normal
platelet
asthmatic
newborns
anemia
with
Only
two phlebotomies
performed
iron
cells
data
from
birth
and the red cells
normal,
clinic.
perfusions
treatment.
from
a Red
Three
became
trisodium
from
sideroblastic
red cell
phlebotomy,
separate
blood
were
treated
and
lower
phlebotomy
could
from
red cell size deviating
who
with
obtained
mM
red
normal.
patient
after
100 ml
110
small
deficiency
in the
by routine
with
0.4.
performed.
enhancement
of
one
exceptionally
runs
with
than
dominant
suffering
and
blood
sideroblastic
differences
patient
red
to
important
the
insufficiency
large
was
for
in platelet
with
iron
These
is more
increase
hematocrit
similar
importance
remains
each
volume
polycythemia
from
phlebotomies
with
of a known
treated
studied
obtained
1/9
donors
patients
because
polycythemia,
in
from
iron-deficient
chosen
with
of the patients,
drawn
Human
from
patient
2-3 rabbits
was
Blood
Blood
diameter
adherence.
perfusion
Collection
Fresh
was
AND
cell
a
Rabbit
MATERIALS
red
for
crit
with
was
to
at
Experiments
patients
major
ever.
to
of red blood
the
cells
confirmed
adherence
diameter
newborns
is one of the main
factors
transport
towards
the vessel
wall
hematocrit
platelet
vided
of
a larger
red
further
Platelets
and Jan J. Sixma
caused
.t)
normal
patients.
i.t)
is
A widely
used method
to study
platelet
to the vessel
wall in vitro is the perfusion
technique
cu
incre-
subendothelium
of the vessel wall is an early and
critical
event in the formation
of a hemostatic
plug or
thrombus.’2
adherence
two
decreased
Rabbit
platelets
from
Small
intermediate
from
were
platelet
red
cu
than
results
70
umbilical
caused
i)
caused
of
perfusion
human
from
blood
ADHERENCE
cell
human
hematocrit
i)
Red
of red
role
Normal
25
an
M. Heethaar,
1 10-130
adherence
of about
of Blood
Robert
(MCV
hemato-
an annular
with
same
70
influencing
the
Adherence
S. Sakariassen,
Kjell
the
accumulation
(MCV
adherence.
Bolhuis,
factors
increases
in the
(MCV
in
s)
A.
Raising
system.
goats
in adherence
increase
Subendothelium
main
effect
hematocrit
from
erythrocytes
Artery
wall.
studies
steady-flow
as the
erythrocytes
for
Piet
vessel
this
Is Important
to Baumgartner.
(MCV
sevenfold.
T
Aarts,
of platelet
according
ment
M.
an increase
chamber,
blood
M.
to the
of magnitude.
size.
Size
the
aspirin
It does
not
resuspended
to a concentration
of
in
190,000
plasma.
blood
to Beutler’
cells
were
and
two
washed
times
once
on
a cellulose
by centrifugation
Blood, Vol. 62. No. 1 (July), 1983:
(3,000
column
g, 10
pp. 214-2
17
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
RED
CELL
SIZE AFFECTS
mm, 20#{176}C)
in
isotonic
types
cells
of
red
reconstituted
washed
saline.
experiment.
wanted
donors
and
newborns,
rabbits,
or goats.
cells
a healthy
human
donor
with
and
perfusions
was used,
same
goat
and
blood
rabbit
in perfusions
group
red cells
plasma
For each
and platelets
donors
or of
red
as control.
the
0-positive
of newborns
For
human
of patients,
was used.
the
of the
Plasma
from
AB-positive
because
their
blood
group
Perfusion
I
0
experiments
were
with
the
performed
perfusion
system of Sakariassen
used
umbilical
arteries
that
were
in previous
used
vessels
the
is
thickness
human
(0.2
treatment
inhibit
Tris,
with
0.1
pH
exposure
Detailed
studies
obtained
was
at a calculated
vessel
37#{176}C.Perfusates
effect
shear
shear
done
‘
5 mm
and
with
for
at
to
and
cells.9
rates
were
in
I-hr
all endothelial
no difference
for
after
was
of 800 sec
rate
the
stored
segment
vessel
experiments
preincubated
hr
less
from
treatment
of
showed
24
use of
the
the
to remove
Perfusion
wall
were
birth,
within
Aspirin
of
isolated
after
Everting
the
arteries.7
were
in
we
arteries
of the
because
used
sufficient
renal
von
the data
performed
3 or S
mm
37#{176}Cprior
at
to
perfusion.
Determination
Platelet
artery
Inc.,
ofPlatelet
adherence
segments
Bedford,
formed
by
sectioning
was determined
by 5’Cr or
MA).
light
of
As
a control,
microscopy
the
vessel
was
Fixation,
were
was according
In counting
600,
morphometric
used.
segments
Staining
‘ ‘
(Trigamma
of the
Baird
with
goat
Mean
counter
Average
scope
F.R.G.)
based
ofRed
Atomic,
cellular
volume
(Model-S.
cell
(Leitz
with
(MCV)
Coulter
diameter
was
cells,
800 zg/ml
to
was determined
Wetzlar
calibrated
on the measurement
dialux
eye
with
2OEB,
piece
E.
ocular
a Coulter
England).
a phase-contrast
Leitz
GmbH
(magnification
micro-
Unsheared
globin
levels
180
plasma
nation
contained
about
of the platelet-poor
of 100 cells.
The
dependence
of blood
platelet
adherence
on the
controls
after
perfusion
showed
that
red
blood cells from goats and rabbits
did not adhere to the
human
subendothelium
or agglutinate
with the platelets or with each other.
Platelet
count
after
perfusion
not
significantly
red cells.9
red cells,
and 300 g/ml
perfusates
,g/ml,
and
with
had
fresh
70 itg/ml.
plasma
perfusates
the decreased
human
size
Confirmation
for platelet
with
were
red
cells from newborns,
1 20 cu /s and mean
cells of 2 patients
was accidentally
with
alcoholic
red
cells
citrate
recombihemoglo-
platelets
showed
(<I0
still
with the labeled
to influence
our
of the importance
adherence
to
perfusion
hemo-
and
0.4 gave platelet
human
red cells.
adherence
platelet
subendothelium
of goat platelets
washed goat red cells
is therefore
not likely
human
However,
of these
fresh
for
free
with
goat
is not caused
by substances
Goat platelets
in human
plasma
of human
blood
cells that
normal.
As large
hematocrit
is shown
in Fig. I . The larger
red blood
cells of men and rabbits
enhanced
blood platelet
adhesion, whereas
the red blood
cells of goats,
which
are
about
the same
size
as human
platelets,
did not.
Microscopic
of
presence
obtained
RESULTS
was
fresh
human
red cells at hematocrit
adherence
in the normal
range for
Wetzlar,
l,000x)
cells
for rabbit
affinity
for human
cm). Competition
on
red
red cells.
and rabbit
red cells
released
by hemolysis.
according
after perfusion
with human.
rabbit.
perfusate.
with hematocrit
increasbased on 6-8 runs of perfusions.
(0)
diameter
8 es). (I) rabbit (MCV 70 cu
(MCV 25 cu i. diameter
3 p).
for human
human
Therefore,
Harpender,
I
0.6
Goat and rabbit
red cells exhibited
more hemolysis
than
human
red cells. Free hemoglobin
level in the
plasma
after
perfusion
was 900
.tg/ml
for goat
red
and
determined
Ltd.
rabbit
as reported
per-
Size
Electronics
I
0.5
evaluation
performed
Cell
I
0.4
embedding,
to Huber.’3
Blood
I
Q3
and
decreased,
in the
Determination
I
Q2
Fig. 1 .
Platelet
adherence
and goat red blood cells in the
ing from 0 to 0.6. Mean
±
SD
Human (MCV 95 cu L. average
IL. diameter
6 is), and () goat
bin-enriched
Adherence
in a gamma-counter
I
Q1
to
arteries
advantage
Arteries
and
concentration
renal
post-mortem
immediately
aspirin.
comparing
factor
with
wall.
production.
to air
the
reproducibility,
7.4)
mM
prostacyclin
et al.9 For human
than
obtained
according
of 1 5 ml perfusate
studies.6’9”#{176}The
increased
cord,
M
Willebrand
rather
of the vessel
umbilical
chamber
by recirculation
the steady-flow
variable
4
_________________________haematocrit(v/v)
Experiments
Baumgartner
short
21.
0-
Perfusion
buffer
46j
plasma
plasma
was unknown.
these
8- platelet
adherence
(106 /cm2)
perfusion
set of perfusions,
used
red cells
with
to each
the healthy
red cells,
with
on all
were
plasma
prior
were
as the patient
blood was used with
platelet-rich
of either
out
mI/experiment)
always contained
red cells
patients,
of
was carried
(I5
hematocrit
Thus, perfusates
healthy
procedure
Perfusates
the standard
to the
215
ADHERENCE
This
studied.
by mixing
red cells
from
PLATELET
with
human
larger
or smaller
cells,
we used
red
which
had a mean
diameter
of I I ,
little
human
platelets
experiments.
of the red blood
subendothelium
experiments
either
blood
only
platelets/sq
present
in the
cell
and
cell
was
red
than
blood
volume
of
red blood
in whom an increased
red cell volume
found
by routine
examination-one
hepatitis
and
the
second
unexplained
in
a patient
with chronic
respiratory
disease
and secondary polycythemia.
For experiments
with large
blood
cells, we used perfusion
times of 3 mm instead
of 5 mm
to avoid
saturation
effects.1#{176} Large
red blood
cells
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
216
AARTS
enhanced
platelet
adhesion
more
cells (Table
I).
Small
red blood
cells were
with controlled
polycythemia
ciency had been induced
mean cell volume
of the
but
the average
unchanged.
Red
mal enhancement
from
a patient
strongly
did
hemoglobin
here.
A third
sideroblastic
not
with
a MCV
cells
studied
might
be expelled
increased
platelet
would
then result
adhesion
was
visual
determination
after
hemolysis,
perfusion
less
cells
and
so
free
was
not
The
with
is large,
as
with
observations
cells
may
concerning
be
used
to
the
explain
motion
the
is for
occurs,
skimming
faster
movement
of surrounding
molecules
and small
particles.
By this mechanism,
red cells can enhance
the
transportation
of platelets.
Keller
calculated
that the
by a factor
of 6-7.
As observed
by Tschopp
and to the local shear
is only an approximation
disc-shaped
red blood
hematocrits.
However,
rigid
radius
spheres
of the
would
rotating
the hematocrit
in arterioles
cannot
account
for
be prosphere
rate.
Obviously,
this calculation
of the effect
induced
by the
cells,
especially
at the applied
it indicates
that particle
radius
the possibility
under
more
in concentrated
ence.
radial
causes
tracer
red
blood
undergo
cells
an erratic
1 . Comparis
on of Platelet
displace-
Adh erence
Artificial
MCV
Iron-deficient
Cells
)cu
Cell Diameter
()
concentration
increase
themia
anemia
Newborns
in Pertu
sions
With
increase
in platelet
and
Baumgartner,’t
from
may
of our recent
deformability
of 2.5
adherence
adeno-
red blood cells
play a role in
work indicate
an
on platelet
adher-
of red
changes
in platelet
Human
Red
Perfusion
Time
Cells
of Various
I1 O’/sq
Adherence
mean
±
cell
deformability
adherence.
Dif-
Size
cm)
S,gn,ficance
SD)
D,fference
Control With
Normal Red Cells
Experimental
65
8
5mm
5.2±
60
6
5 mm
3.2
120
11
3mm
6.8±2.0(21)
±
1.4(9)
4.8±
0.8
4.8
(1 1)
Normal
‘
of
With
Red Cells
Pared
1.2(11)
±
3.8±
liver disease
120
10
3 mm
7.7
±
1 .3 (7)
5.2
±
Asthmatic
bronchitis
1 10
9
3 mm
3.6
±
0.8
2.6
±
Number
of perfusions
Simultaneously
performed.
(9)
1.2 (1 1)
1.3(21)
Alcoholic
in parentheses.
be
in the
by a factor
t Test)
polycy-
Sideroblastic
.
fL)
not
However,
transport
ferences
of red cell deformability,
as measured
by
viscosimetry,
is present
in the studied
red cell types.
However,
differences
in deformability
between
the red
Platelet
Blood
platelet
would
hematocrit.
platelet
manipulation
significant
Average
Red
in size
equally
‘9
ment.’6 The radial displacement
is caused
by continuous collision
of passing
cells and will induce
displacement for platelets
and plasma
as well. The transport
Table
equal
more
the local
wall
that ADP released
turbulent
conditions
Goldsmith
that
platelets
region.
The
vessel
wall
adherence.
sine diphosphate
(ADP)
released
from damaged
red
cells
cannot
be responsible
for red-cell-dependent
platelet
adherence,
which is consistent
with our observation that replacement
of red cells by ghosts results in
unchanged
platelet
adherence.7
This does not exclude
Preliminary
results
influence
of red cell
suspensions
of
red
in
from
0 to 0.6),
as recently
by Tangelder,’7
and thus,
this
the
and shear rate are characteristic
parameters,
in agreement with the experimental
data shown
here.
A second explanation
is based on the observation
by
ghost
almost
to be
platelet
only
cells,
layer
at the
platelet
vessel
the
can
layer
(raising
observed
effect of rotating
to the squared
red
In this case,
the
platelet
transport.
According
to Keller,’4”5
red blood
cells rotate
in the shear field of the flow and cause local
small
turbulence,
leading
to a mixing
effect
and a
mixing
portional
human
by the increasing
active
red-cell-induced
mechanism
of red
enhanced
in the presence
In flowing
blood, the
of the vessel, resulting
into the skimming
concentration
in an increased
near
influenced
when
no
DISCUSSION
it
the platelets.
concentration
Several
be sought
small
red cells from goats,
the platelets,
are expected
mixed
performed.
blood
may
layer of platelet-rich
plasma
at the vessel
size difference
between
platelets
and red
a skimming
wall. If the
of 6 z, were
anemia,
cells than by normal
red cells of patients
exhibit
explanation
a so-called
“skimming
layer.”
cells occupy
mainly
the center
cell diameter
(8j)
had
remained
cells from such patients
caused
norof platelet
adhesion.
Red blood cells
with
proportionally
to the shear
rate
and the volume
of the red blood
diameter
of the cell, as we report
rate
will increase
(collision
frequency)
cell, but not to the
by repeated
phlebotomy.
The
cell was decreased
(65 cu
by these red blood
I). Perfusates
with
newborns
normal
obtained
from
patients
vera in whom
iron defi-
of 60 cu /L and an average
diameter
on two separate
occasions.
Platelet
enhanced
(Table
than
ET AL.
NS
p
<
0.01
p<0.001
1 .0 (8)
p
<
0.01
0.6
p
<
0.01
(1 1)
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RED CELL
cells
SIZE AFFECTS
of
PLATELET
newborns,
patients,
normal
controls
studied
not systematic
and
observed
differences
this article.
From this
induced
cell
rabbits,
and
the
of perfusions
run
we conclude
cells
that
were
the
platelet
the
in
size
adherence
is a critical
Although
the results
can
mixing
concept
of Keller,’4
rotation
of red cells will
hematocrits.
It
is not
be best explained
by the
it is obvious
that fully free
not occur
at the applied
unlikely,
however,
that
some
degree of red cell rotation,
according
to Keller’s
concept, will be present
at higher
red cell concentrations,
by flow-controlled
is caused
in which
motion,
goats,
in one
far too small
to account
for
in platelet
adherence
presented
study
by red
217
ADHERENCE
red
parameter.
and
this
may
be sufficient
to enhance
platelet
adher-
ence.
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1983 62: 214-217
Red blood cell size is important for adherence of blood platelets to artery
subendothelium
PA Aarts, PA Bolhuis, KS Sakariassen, RM Heethaar and JJ Sixma
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