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Mechanism
of Erythrocyte
Aggregation
By Thomas
Unstirred
suspensions
aggregates
cal
depends
Erythrocyte
upon
the
size.
suspending
suspensions
these
after
of erythrocytes
of uniform
radius
are
undergo
formed.
stable
spheri-
tor
spheres
port
Aggregation
is a two-
step
process:
first.
erythrocytes
associate
in long chains
(rouleau
formation).
Next,
these
chains
form spheres
of
uniform
size. The requirements
for this well-defined
process are an electrolyte
and a neutral
or negatively
charged
macromolecule
in the solution
and a metabolically
active
red cell. If these
conditions
are not met, red cells either
will
not aggregate
at all or will form
amorphous
aggregates.
Rouleau
formation
and sedimentation
are inhibited
by
4,4’-diisothiocyanatostilbene-2,2’-disulfonic
acid, an inhibi-
T
HE
ERYTHROCYTE
(ESR)
is a useful
cific disease
activity.’
limited
by three major
tion is not
measurements
low
in several
inflammatory
bowel
disease,2
bly in congestive
heart
attributed
to increased
(fibrinogen,5
etc),
but again
process
occurs
cell
certain
there
is only
and
ESR
plasma
very
sedimentation
hour is only
of
formation
of statistical
quantita-
rate as
meaningful
the
if
deviation
from
one parameter
to occur.
Perelson
and Wiegel,7
using
mechanics,
showed
that the average
rouleau
size
rocytes
kinetic
increases.
Samsel
model
for rouleau
rouleaux
increases
grow
gates.
Evans
the surface
as the adhesion
large
energy
between
and Perelsont
developed
formation
and pointed
they
form
rings
and
eryth-
an elegant
out that as
branching
aggre-
related
them
interpretation
to aggregation.
of the sedimentation
rate
is
From the Department
of Medicine,
Division of Gastroenterology.
The Mount
Sinai
School
of Medicine
and The Mount
Sinai
Medical
Center, New York.
Submitted
May 2. 1 986; accepted
July /3, 1987.
Address
reprint
ment
ofMedicine.
Sinai
Medical
The
to Thomas
Mount
Center,
Sinai
New
York,
NY
costs
ofthis
article
payment.
This
article
must
“advertisement”
indicate
1987
in
accordance
with
this fact.
by Grune
& Stratton,
0006-4971/87/7005-0045$3.00/0
1572
School
publication
charge
©
requests
Inc.
L. Fabry.
MD,
ofMedicine
PhD,
and
may
provide
an
inexpensive
plasma
protein
and erythrocyte
some less common
disorders.
membrane
screening
test
abnormalities
of
in
Depart-
The
Mount
AND
METHODS
Blood
specimens
anticoagulated
with K3EDTA
were obtained
from healthy
volunteers
and were processed
immediately
after
collection. Red cells were suspended
in autologous
plasma to obtain
different
final hematocrit
values (Hct).
For the inhibition
experiments, washed red cells were incubated
with 4,4’-diisothiocyanatostilbene-2,2’-disulfonic
acid (DIDS)
(0.1 mg/mL)
for 30 minutes at
37#{176}C.
This is the same concentration
of DIDS that is used to inhibit
the chloride/bicarbonate
antiporter
of the erythrocyte
membrane.
After incubation
the cells were washed with isotonic saline containing 10 mmol/L
glucose and then reconstituted
with plasma.
Ouabain
(Sigma Chemical
Co, St Louis) was dissolved
in water
(0.01 mol/L stock solution;
final concentration
of incubation
mixtures, 0.1 mmol/L).
DIDS was prepared
in HEPES
buffer immediately before use. Other chemicals
were obtained
from standard
sources.
Sedimentation
experiments
were performed
in Kimble disposable
tubes at pH 7.4 and at 25 ± 2#{176}C.
Experiments
were completed
within three hours of sample preparation
to avoid
artifacts
from irreversible
aggregation
of red cells. To obtain the
photomicrographs,
erythrocyte
suspensions
were allowed
to sediment
in rectangular
cross-section
tubes 0.2 x 5 or 0.3 x 5 mm and
100 mm long (Vitro
Dynamics,
Rockaway,
NJ). The kinetics
of
sedimentation
in this tube is the same as in a Westergren
tube filled
to 100 mm. The tubes were placed flat side down on the microscope
stage in different phases of the sedimentation,
and photographs
were
taken at 4x and lOx magnification.
Curve fitting and statistical
calculations
were carried out by using
the computer
programs
SAS”
and Statgraphics.’2
The EinsteinStokes equation
was used as derived by Hiemenz.’3
200-mm
and Buxbaum9
and Buxbaum
et al’0 quantified
affinities
of erythrocyte
membranes
for macro-
molecules
and
Quantitative
mentation
MATERIALS
must be used to describe
the process.
Chien6
laid the foundation
for interpreting
the rheology
of
red cell suspensions.
He established
the need for electrolytes
and macromolecules
to be present
in the suspending
medium
for rouleau
techniques
transport,
but not by ouabain,
a cation
transinhibitor.
The kinetics
of erythrocyte
sedimentation
reflects
the aforementioned
mechanism:
no sedimentation
occurs
during
rouleau
formation.
Once
the
spheres
of
uniform
size are formed,
they
will settle
according
to the
Einstein-Stokes
equation.
In this model,
parameters
of
sedimentation
kinetics
are the delay before
sedimentation
starts,
the rate of sedimentation
in the steady
state,
and
the radius
of the sedimenting
aggregate.
The radius
can be
calculated
from
the
rate
of fall
of the
aggregates
and
agrees
well with the microscopically
observed
radius.
It is
inversely
proportional
to the
hematocrit,
which
explains
the elevated
sedimentation
rates
in anemia.
C 1987
by Grune
& Stratton,
Inc.
possi-
has been
proteins
poor
over time. Any
that
more
than
means
forms
disease,3
Increased
of some
the
at one
uniformly
kinetics
zero-order
(eg,
sickle
failure4).
amounts
tive correlation.
Expressing
amount
of sedimentation
the
diseases
of anion
possible
by developing
a kinetic
model
based on the underlying mechanism.
This may make erythrocyte
sedimentation
a
useful
tool for investigating
the pathophysiology
of some
diseases. Furthermore,
quantitative
interpretation
of sedi-
SEDIMENTATION
RATE
qualitative
empirical
index of nonspeIts clinical
usefulness
is, however,
problems:
(a) quantitative
interpreta-
possible,
(b)
there
is a poor correlation
with
of other acute phase
reactants,
and (c) it is
paradoxically
Sedimentation
L. Fabry
of the
and the hematocrit.
sedimentation
only
medium
will
aggregates
form
The
and
Westergren
10029.
were
defrayed
therefore
/8
U.S.C.
be
in part
hereby
§1734
by page
RESULTS
marked
solely
to
Kinetics
of erythrocyte
sedimentation
and the effect
of
Hct.
Erythrocyte
sedimentation
follows
an S-shaped
curve
with time (Fig 1 and Table
I ). There
is a delay in the start of
sedimentation;
during
Blood,
this
time
the
rate
Vol 70, No 5 (November),
of sedimentation
1987: pp 1572-1576
is
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ERVTHROCVTE
AGGREGATION
AND
SEDIMENTATION
1573
2.
Table
Effect
of Anion
and Cation
Transport
Inhibitors
on Sedimentation
E
Concentration
E
(iunol/L)
Inhibitor
z
0
Slope
ESR
0.6
28
0.5
23
Blank
DIDS
z
w
1
DIDS
Oubain
0
10
0.1
5
100
0.6
23
w
(I)
DISCUSSION
TIME
The
(minutes)
delay
either
Fig
1.
values.
zero
Hct
0.
of 26;
(phase
linear:
phase
as a function
Hct of 28; i, Hct
Sedimentation
,
I of the
sedimentation
3 the rate
curve).
The
of time at different
of 34; A, Hct of 45.
next
segment
(phase
continues
at a constant
rate.
levels off to zero: sedimentation
pleted.
At different
red cell concentrations
the shape
of the curve
is qualitatively
Effect
of membrane
DIDS,
inhibits
an
both
transport
irreversible
rouleau
dose-dependent
effect on the
formation
manner.
sedimentation
the sedimentation
inhibitor
concentration.
inhibitors
inhibitor
bf
and
10 to 50)
however,
sedimentatransport,
sedimentation
and
the
ESR
as
a
change.
It
can
Westergren
pension
spheres
network
spheres
be
(Fig 2) that,
of equal
size.
observed
has
slope
no
of
of
sedimentation
suddenly
visible
late in this phase,
This is a sudden
becomes
granular
at the sides of the
eye
in appearance,
tube.
In phase
in the
cell suswith the
2 these
spheres
sediment
at a steady
rate
(Fig 3). Figure
4 is a
photomicrograph
of the interface
between
the sedimented
cells
and
the plasma.
The
sedimenting
entities
are the
spheres
does
formed
not change
from the rouleaux.
The extent
during
phase 2. To demonstrate
cells form fairly stable
aggregates
sedimentation
(ie, after the delay
gently
inverted
continued
at
(ie,
the
turned
same
during
period)
upside
steady
rate
of aggregation
that the red
the steady
the ESR
down).
phase of
tube was
without
a second
delay
period.
Table
Hct
25.8
1 . Measured
and Derived
5o
suggests
settle
until
or cooperatively
increases
with
is not
would
not
compatible
require
the
with
rate
Our
data
cells to form
uniform
spheres.
formation
has been extensively
to
allow
further
each
other
cells
repel
charge
from
sialic
acid
they are attracted
by the
electrodynamic
in nature.
determines
the
electrolyte
a discoid
lated
of the
most
that
mecha-
distance
only
this
For
present
in
sucrose
electrolytes,
transiently
but
rouleau
formation
in the suspending
most
would
nm
there
the Curves
to occur,
medium.’6
decreasing
ionic
unchanged.
(This
in the absence
of
Therefore,
stable
of cells
in
configuration
attached
not
form
stable
of
to the
would
structures.
if the
macromolecules
must be
Chien
and Jan’7 showed
Delay
(mm)
6.5
152
±
2
3,081
±
82
29
±
3
2.1
123
±
4
4,629
±
239
31
±
9
1.6
13.0
80
±
10
±
1,545
±
35
0.5
30.0
-38
the
by their
in Fig 1
2.4
is a
increases
the repul-
will not form
rouleaux
electrolytes
only.
(1 00 x mm/sI
2
in an
this energy
is small
relative
motion
(kT);
therefore,
cells
reason
red cells
solution
contains
11±2
with
solutions.)
is a chain
However,
Brownian
Describing
cells
forces.
Assuming
Absolom’
calcu-
of 103
forces
are
formation
the
time
which
are
two forces
in the potential
energy
in isotonic
saline.
The
increases
suspensions
surfaces.
from
negative
same
of red
of other
Oss and
ergs/cell
suspended
potential)
eg,
of
erythrocyte
For
the
closest
approach
for erythrocytes
electrolyte
concentration
because
(
presence
align
their
arrangement
and the van der Waals
why there is no rouleau
electrolytes,
flat
stable
at an intercellular
force
strength
explains
energy
of
At
van der Waals
forces,
The balance
of these
of -4.6
x I02
of erythrocytes
distance
of the
with decreasing
sive
because
residues.
solution
in the absence
shape
for red cells, van
minimum
distribution
Para meters
elaboration
The
inves-
35.8
26.324
either.
sedimentation
28.6
44.7
aggre-
(ie, the
time).
Red
of aggregation.
a,
2,645±56
152±2
will
increase
with
an increasing
concentration
of erythrocytes
(Hct);
in fact, the opposite
occurs.
As shown
in the Appendix, the equation
describing
sedimentation
kinetics
does not
fulfill the criteria
for cooperativity.
suspending
Sedimentation
kinetics
aggregation
nism
a
function
with
the naked
tube:
the homogeneous
sedimentation
Simple
tigated.’4
Direct
observation
of aggregation
during
sedimenta(ion.
In phase
I the homogeneous
red cell suspension
forms
a three-dimensional
rearranges
to form
constant
cell
surface
in
sedimentation
cells
size are formed)
for the sedimentation
rate
Red
on
suspension
red
Aggregation
of red
mechanism
of rouleau
(Fig 1): the
2 decreases.
Hct value.
Ouabain
(0.1
mmol/L)
rate. Table
2 shows the
curve
2) is
anion
cell
(ie,
gates of sufficient
Finally,
in
is com-
(Hct range,
the same;
there is a shift to the right as the Hct increases
delay
(phase
1 ) increases
and the slope in phase
This results
in slower sedimentation
at a gher
(ion.
Hct
in red
aggregation
8.0
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THOMAS
1574
Fig 2.
Photomicrograph
(original
magnification
magnification
x 1 6) of sedimenting
erythrocytes
diameter
tube. The rouleaux
are starting
to form
ofFig 1.
that increasing
increase
the
the length
intercellular
rouleau.
He concluded
bridges
two erythrocytes
of sufficient
length
can
fibrinogen
place
in serum.
however,
negatively
that the
charged
The
receptor
erythrocyte
shown
that
x40;
current
in a 0.2-mmspheres:
phase 1
red
(dextran)
cells
in
will
the
Fig 4.
that
the macromolecule
actually
and only elongated
macromolecules
serve
this function.
For example,
but not albumin
meets
erythrocytes.
Therefore,
cross-link
take
of a macromolecule
spacing
of the
It has
not
macromolecule
(as opposed
the shape
requirements
sedimentation
will
been
made
clear
until
site for the macromolecule
membrane
has not been
identified.
DIDS,
an inhibitor
of anion transport,
in either
inhibits
to
not
now,
or
on the
We have
interferes
plasma
or dextran.
the chloride-bicar-
bonate
exchange
across
the red cell membrane.’5
This suggests that the macromolecule
binds
at the anion
transport
site. DIDS
also reacts
with lysine residues
on the membrane
surface.
If the fibrinogen
dues, then DIDS
would
latter
possibility
is the
binding
interfere
fact
that
involves
these lysine
at this point.
Against
there
are
106 anion
Photomicrograph
(original
magnification
x 40; current
x 1 6) of sedimenting
erythrocytes
in a 0.2-mmdiameter
tube at the interface
between
the clear plasma
and the
sedimented
red cells: phase 3 of Fig 1 . Note that the sedimenting
entities
are spheres
formed from rouleaux
and not individual
red
magnification
has to be either
neutral
to positively
charged).
(binding)
with formation
of the aggregates
DIDS
at similar
concentrations
resithis
transport
cells.
sites
(band
3 protein)’9
fibrinogen
molecules
are
Because
fibrinogen
binding
sites
tude.
In the
per
bound
erythrocyte
and
about
I0
to each cell at equilibrium.20
is weak,
the
to bound
molecules
is the
case of rouleau
formation,
binding
right
the
macromolecule
bind
to adjoining
aggregates.
In contrast
to the
aforementioned
charged
macromolecules
cytes
and
ited
in this
form
fashion;
they
amorphous
by DIDS.
After
the
spheres
reduction
are
react
of
size
surface
the
This
the
The
spheres
contain
macromolecules
with
the findings
of fibrinogen
increased
Hct
tion:
the
availability
cules
linking
only
them
of Janzen
process
of the
Photomicrograph
magnification
diameter
spheres.
x 1 6)
tube:
phase
of
(original
magnification
sedimenting
erythrocytes
2 of Fig 1 . Note
the
uniform
x 40;
current
in a 0.2-mmsize
of the
residues
inhib-
chains
form
erythrocytes
but
forces
tend
to
also
the
This is in agreement
demonstrated
It also
the rate
aggregates
or other
plasma
binding
explains
why
of sedimentais limited
by
macromole-
the erythrocytes.
In summary,
the mechanism
spheres
of uniform
size proceeds
3.
erythro-
acid
is not
the
together.
spherical
the
the attractive
forces
that
et a122 who
of fibrinogen
the
driving
force may be the
Uniform
size is proba-
to red cell surfaces.
values
do not increase
formation
the
not
binding
sialic
rouleaux,
(Fig 3). The
free energy.
of
positively
to bridge
with
ratio
to form
mechanism,
able
aggregates.2’
formation
ofuniform
of the
not
100:1
order of magnitwo ends of the
erythrocytes
bly the result
of competition
between
between
cells and the hydrodynamic
reduce
the size of the spheres.
Fig
L. FABRY
of red
via the
cell aggregation
following
steps:
to
(a)
electrostatic
forces draw erythrocytes
together
to about
100
nm, with the discoid
shapes
lining up parallel
to one another.
This requires
the presence
of electrolytes.
(b) If a neutral
or
negatively
charged
macromolecule
of length
greater
than
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
ERYTHROCYTE
AGGREGATION
AND
100 nm is present,
it will bind
adjoining
erythrocytes.
The
stabilize
are
the parallel
formed.
reduces
Rouleaux
(c)
anion transport
sites of
of this
binding
will
of red cells,
and
to form
spheres,
rearrange
free
tation
must be described
ters (eg, delay
before
rate
to the
energy
configuration
the surface
energy.
For
Clinical
correlation:
there
rate:
(a)
are
which
an empirical
index
the sedimenting
rate
sphere
protein
can
minutes
and
sedimentation
Because
the
one
measured
can
55,
given
40.
Hct
37
38
33
44.7
22
11
36
18
analysis
see the
Sed
In clinical
(b) its dependence
on the
latter
makes
it useful
as
In Fig 5 the
The
radius
proportional
radius
of
to the
as a function
of Hct
and
is increased
by
Table
(slope in phase
2) in
function
of Hct (Fig 6),
by interpolating
to a set value,
sedimentation
of sedimentation
eg, to
can be obtained
at 30 and 60
3 shows
values
corrected
series
of
x (55 - 40)/(55
is the sedimentation
(Hct
40)
=
patients
with
is its value
inflammatory
identical
results.
Clearly
an index
of disease
activity
that
2.0
-
‘NN,AO
I
.
#{163}:4NA
Hct),
(equation
observed
at the
corrected
both Sed (observed)
and
to Hct 40 by using equation
obtained
(observed)
-
and
ESR
are experimentally
40) and ESR (Hct
-
determined
40) are the calculated
(see
corrected
the
text).
values.
prac-
obtain
the value at an Hct of 40 from the value
at any other
Hct by the relationship:
Sed (Hct
=
Sed
(hct
in the sedimentation
multiplying
their difference
by 2 (this way the
will have a value that is similar
to the ESR).
value of the slope approximates
0 when Hct =
and
40)
-
42
eliminates
the variations
in the sedimentathe changes
in Hct.
In practice
a good
40) = Sed (observed)
I ), where Sed (observed)
(Hct
46
is directly
estimation
of the steady-state
by measuring
the amount
40)
35.8
is shown
be made
-
two independent
paramestarts
and steady-state
Because
the steady-state
sedimentation
the range of Hct 10 to 50 is a linear
an Hct of 40. This
tion rate due to
(Hct
41
decreasing
correction
ESR
1
ESR
40
the Hct or increasing
the plasma
protein
concentration.
Therefore,
a change
in Hct masks the effect of
changing
plasma
protein
concentration
and composition.
either
Equation
41
Hct.
concentration.
Usi ng
65
activity.
(which
by
Sad
80
for variations
of sedimentation)
entation
70
kinetics
a mathematical
of disease
Sed
(observed)
Sedim
80
its dependence
on Hct and
protein
concentration.
The
plasma
plasma
reasons
of
Correction
28.6
correctionfor
two
Hct
25.8
The
Sad
tice
3.
Hct
rouleaux
Appendix.
true
Table
of sedimen-
(d)
by at least
sedimentation
of sedimentation).
1575
SEDIMENTATION
ESR
and their
I . In a larger
bowel
Sed
is fairly
I
to Hct
(Hct
disease
=
40)
independent
we
APPENDIX
By using SAS for modeling,
the best functional
form of the
kinetics of erythrocyte
sedimentation
is as follows: sedimentation
a0 x t2/(a, + a2 x t + t2) (equation
2), where t is the sedimentation
time and the a’s are experimental
parameters.
For a cooperative
phenomenon
a2 - 0.
Two additional
descriptive
parameters
can be derived
from the
three
parameters
in equation
1 . The first is the delay before
sedimentation
starts, ie, the length of phase I . The second is the slope
of the linear part of phase 2. These two entities are related to the
parameters
in equation
2: the slope is the value of the first derivative
of equation
2 when the second derivative
is equal to zero and the
delay is the x-intercept
of the straight
line originating
from the
inflection
point of this curve and having
the calculated
slope.
Alternatively,
these can be directly
measured
from the plot of the
curves
in Fig I . Table 1 gives the values for these parameters
for the
curves
from Fig 1.
The linear part (phase
2) of the sedimentation
results as the
spheres
formed
from the rouleaux
fall in a viscous medium.
The
radius R of this sphere can be calculated
from the Einstein-Stokes
equation:
R2 = 9 V /2(a2
,)g (equation 3), where ii is the plasma
viscosity, a, is the plasma density, and o is the red cell density. The
densities and viscosities
are literature23
values, and v is the measured
rate of sedimentation
in the linear phase (phase 2).
These radii can also be measured
in the photomicrographs.
Figure
6 shows both the calculated
and measured
values for the radii as a
function of Hct for seven samples for a series of different
Hct values.
Because
the concentration
of the bridging
macromolecules
was
different
in each series, the radius is expressed
relative to that at Hct
35. There is an excellent
agreement
between
calculated
and measured values.
_
provides
of Hct.
I
I
40
50
ACKNOWLEDGMENT
Valuable
discussions
with Drs iean-Claude
iustice
and MarieClaude
Justice and the assistance
of Dr Steven Dikman
with the
photomicrographs
are gratefully
acknowledged.
I am very grateful
to Karen Sadock
for her editorial
review.
U)
.6
0
a:
0.4-
0
,
,
I
0
20
30
H EMATOCRIT
Fig 5.
Radius
values.
Erythrocytes
serum
mixtures.
the suspending
of
The
medium.
the
are
spherical
suspended
third
coordinate
aggregates
at
in autologous
is the
fraction
different
plasma
of
plasma
Hct
and
in
Fig 6.
Radius of spherical
aggregates
as a function
of Hct.
different
symbols
represent
different
blood samples.
radius is expressed
relative
to that observed
at Hct 35.
seven
The
The
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
THOMAS
1576
L. FABRY
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From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
1987 70: 1572-1576
Mechanism of erythrocyte aggregation and sedimentation
TL Fabry
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