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Humlni-ot.

ofHcmvrtteology and
Nentodynttmiis O.K.
Baskarl et at. (EdsJ IOS
Press. 2007 2007 IOS
Press. All rights reserved.

Compositional Properties of Blood


Michael W.RAMPLING'
School of Medicine, Imperial College. South Kensington.
London SIV7 2AZ. U K

Introduction
The function of blood is to feed all the tissues of the body with vital materials and to remove
waste. To do this in the human adult it has to traverse the complicated vascular network, which
varies in diameter from some 3 cm down to about 5 urn. Furthermore, the blood must circulate
above a limiting rate if it is to do its work effectively enough to keep the organism healthy. This
rate of circulation is determined by the driving pressure generated by the heart, by the
geometrical resistance offered by the vasculature and by the flow properties of the blood. These
(low properties are the concern of the hcinorheologisl and they are dependent on the composition
of the blood and the properties of its constituents; hence, knowledge of them is vital to any
understanding of hemorheology. This chapter gives an overview of the composition of normal
adult human blood and some indication of the ways in which il can be altered in diseased slates.
There is also discussion of the normal changes in blood composition that lake place as the fetus
develops through to the neonalal period. Finally, there is a brief review of the variations that
occur in other mammals, emphasizing the similarities and the great differences that exist
compared witli the human adult.
arc anuclcalc and have relatively complex contents consisting of vacuoles and fibres suspended
in their viscous cytoplasm. They have a role to play in hemostasis.
Plasma
The liquid phase in which the cellular components of blood are suspended is the plasma. It is a
complex solution of materials ranging in size from a few tens to millions of Daltons. These
solutes make up some 8 to 9% of plasma by weight, the rest being water.
Proteins
The plasma proteins are all very large, having molecular weights ranging from a few tens of
thousands to millions of Daltons, and make up about 7% of plasma by weight. They are

generally subdivided according to their electrophoretic mobility into albumin, a, p and y groups.
However, this approach masks the wide variety of different proteins that exist in the plasma (e.g.,
there are carriers of lipids, metals and other factors, many immunoglobulins, clotting factors and
fibrinogen). They are necessary to die carriage of many vital materials, to defense against
infection, to etc. which results in them having viscoclastic characteristics (i.e., viscosity,
elasticity) much greater than those associated with the red cells. Second, they generally have
somewhat larger volumes than the red cells. There are several varieties of leukocytes (i.e.,
monocytes, granulocytes and lymphocytes), all of which arc larger than the red cell: the largest
(the monocyte) has a mean volume of about 23011, while for Ihe smallest (Ihe lymphocyle) il is
abom 12011. Il is now thought lhal. in a healthy individual. Ihe white cell population confers an
overall rcsislancc lo microeirculalory How similar to that of the whole red cell mass. It is
inlercsling lo nole the number concentration of the leukocytes is normally 4-8 xlO^ per liler
while thai for Ihe red cells is about 5xl0 i: per liter (i.e.. some 3-orders of magnitude dillerence).
thus implying Ihe individual leukocyte has a Mow rcsislancc. in small vessel flow, some 3-orders
of magnitude greater than that of Ihe red cell; ihe lalter poini has been proven by micropipet
studies [10]1.2.3. Platelets
From a hcmorhcological poinl of view the platelets arc of little importance, even Ihough they
have relatively complex internal contents with considerable viscosity. The reason lor Ihis finding
is thai they arc much smaller Ihan cither the erythrocytes or leukocytes, having diameters of Ihe
order of 2-3 um; their overall volume in normal blood is even less than thai associated with Ihe
leukocytes. The consequence is lhat Ihey neither influence whole blood viscosily nor
microvascular rcsislancc lo any significant degree. Their primary role is lo participate in Ihe
hemostatic mechanism, and as such they do have a major pah to play in whal is essentially ihe
solidification of blood as il clots [ 11.

2. Human Juvenile
It has long been known lhal ihe blood parameters change as ihe child ages from birth through lo
adulthood. In die relatively recent past, in utero blood extraction techniques have been developed
and have allowed the substantial hematological changes that take place during fetal development
to be evaluated.
2.1. The Feins
Data have now been published on hematological values in ihe fetus from 18 to 35 weeks of
gestation [II]. They show that, over this period, there are progressive increases in hematocrit
from 32% to 48% and in plasma protein concentration from 25 g/l lo 43 g I. The most
remarkable change over the same lime period is the increase in fibrinogen con central ion; at IK
weeks the average value is 0.4 g/l but in many of the samples studied no dutiable material (i.e..

fibrinogen) was exlractahle al all, while al 35 weeks it had risen to about 2 g/l. One inevitable
hemorheological consequence of these changes in the concentrations of fibrinogen and other
plasma proteins is lhat the plasma viscosity rises from 0.9 to 1.05 mPa.s over Ihe same period.
Anodier is lhat die viscosity of the blood rises very substantially. Thus at a high shear rate (128.5
s"1) it increases, on average, from 2.5 to 3.7 mPa.s, while at a low shear rate (0.277s 1) it rises
from about 3 to 14 mPa.s. What is clear from these data is that at 18 weeks there is virtually no
shear thinning associated with the blood of the fetus (i.e. it has almost Newtonian
characteristics); this flow behavior is due largely lo the extremely low levels of fibrinogen and
other roulcaugcnic proleins in ihe blood.
There are also more subtle changes with potentially hcmorhcological consequences. One is ihe
large size of (he red cells of ihe very early Icius. Al week 24 Ihe MCV is 135 fl and. although il
decreases with gestational age. even al lenn il is still about 119 11 and Ihus larger than lhal of Ihe
adull [121. This, of course, has potential consequences to the resistance lo How in ihe
microcirculation. There are also subtle differences in ihe erylhrocylc membrane composition
compared lo lhal of the adult, with these differences affecting the mechanical properties of the
membrane 113J and Ihe innale ability of ihe fetal crylhrocyles lo form rouleaux. The hemoglobin
al this siage is predominately I IbF. rather than the adult form llbAi. but its intracellular
concentration (i.e., MCHC) changes little from 24 weeks of gestation to lent), being about 3lg<dl
and therefore a little less than that of the adult [12). Another significant difference in ihe fetus is
that ihe fibrinogen molecules arc more strongly sialinaled than in the adult [14], and although the
level of sialination steadily decreases towards term, it is still higher at term than that of the adult.
This increased sialination hinders its ability to induce rouleaux formation, and thus fetal blood
overall exhibits less rouleaux formation than the adult, the blood shows much less shear thinning,
and the overall viscosity is low compared with Ihe adult. This raises a potentially important
question lo those involved with in utero transfusion: is it reasonable to transfuse adult blood
which has such different hcmorhcological properties from that of the fetus?
2.2. Al Birth
A comprehensive study has been made of the hematologieal/hemorheological characteristics of
the blood of the pre-term babies, as early as 24 weeks, and of the term baby [I5j. As with the
fetal data discussed above, the results show a steady increase in most hematological parameters
with gestational age. 'Ihus, hematocrit rises on average from 45 to 50 % with large variations
between individuals, plasma protein concentration changes from 44 to 55 g/l. with increases in
IgCi, ctr macroglobulin and fibrinogen from 2.1 to 2.6 g/l. Comparing these values with those
obtained in utero at a corresponding gestational age, it is clear that the ex utero values arc higher;
indicating a degree of hcmoconccntration lakes place during birth. The result of the
aforementioned changes is that lite viscosities of both plasma and blood, at both high and low
shear rates, increase over the same period: the shear thinning properties become more
pronounced, with the magnitude of the changes being greater than found in the in utero study.
Low shear rale (0.277 s'1) blood viscosity increases 3-fold from 12 to 40 mPa.s while the high
shear rate (128.5 s'1) value increases by 20% from 3.7 to 4.5 mPa.s and plasma viscosity rises by
20% from 0.96 to 1.15 mPa.s, The alteration in the high shear rate viscosity can be explained

almosl entirely by changes in hematocrit and plasma viscosity over Ihe period, whereas Ihis
explanation is not valid al low shear rale; here there are effects due to altered rouleaux formation
secondary lo cell-specific factors [9] and lo Ihe alteration in fibrinogen sialination lhat
accompanies changes in gestational period.
mentioned above. Fourthly, they contain a hemoglobin solution of high concentration (normal
range 32 to 36 g/dl [8]) which has an effect on the speed with which they can deform under shear
forces. These properties act together to give blood a viscosity very substantially in excess of that
of plasma alone, and to endow it with prominent shear thinning properties. The relationship
between blood viscosity and hematocrit is approximately of the form:
log (viscosity) k, t k;(hematocrit)
where k, and k^ are shear rate dependent. Typical values for the viscosity of healthy blood at
shear rates of 0.277 s"1 and 128.5 s'1 are 394 and 4.30.2 mPa.s respectively for females and
486 and 4.70.2 mPa.s respectively for males 16). The gender differences arc. of course, due to
the lower hematocrit that is normal for females.
The above arguments should make it clear that the red cell mass has a huge influence on the
viscosity of normal whole blood, and hence on blood flow in large vessels. However, blood must
also pass through the microcirculation where vessels may be as small as a few um in diameter.
Here the cells arc of a size similar to the vessels, so the concept of blood viscosity is hardly
relevant because the blood cannot be approximated lo a uniform solution or suspension. When
such flow is observed under a microscope, a bolus of plasma followed by one or two deformed
cells followed by a further bolus of plasma, etc. is seen in microvcsscls. Under these
circumstances, the factors determining resistance to flow are Ihe viscosity of Ihe plasma, ihe
defonnabilily and concentration of ihe red cells as well as oiher cells (sec below), and the forces
involved in holding the red cell rouleaux together. Of course another factor is Ihe size of Ihe red
cells. The mean red cell volume (MCV) for healihy adulis is 83 to 101 II and is gender
independent |8|. However, ibis range can be misleading, as it is the average MCV across the
healihy adull population. The reason lhat ihis is misleading is lhal, within an individual. Ihe
variation in size of their red cell population is far grealer than ihis range; this is because young
cells released lo the circulation from the bone marrow have a large volume, as much as 120 11.
but subsequently progressively lose membrane, contents and size and defonnabilily as they age.
Finally. Ihcy arc dcslroyed, after about 120 days in ihe circulation, when their volume may be as
little as 60 ll.
A recenl area of sludy involving Ihe red cell concerns cell-specilic effects on erythrocyic
aggregation. It is now clear lhal individual red cells vary in their response io rouleaugenic
molecules. So, for example, young red cells, newly released from the bone marrow, respond
much less than do older cells. Furthermore, red cells from different healthy individuals differ in
their rouleaugenic response to molecules such as fibrinogen. The reasons, which arc presumably
determined by the cell membrane, are not yet clear, but the consequences are hemorheologically
significant [9].
1.2.2. Leukocytes
As implied above, ihe leukocytes have very' little role to play in dclcrmining Ihe viscosity of

normal whole blood because their volume concentration is so much smaller than that of the red
cells. However, ihcy do play a major role as a dcterminanl of flow in Ihe microcirculation. There
are two reasons for Ihis. First, lhcir internal contents are a complex array of nucleus, organelles,
fibres, cytoplasm.

ol" Ihe Ictus (i.e. it has almost Newtonian characteristics); this


flow behavior is due largely lo the extremely low levels ol*
fibrinogen and other rouleaugenic proleins in ihe blood.
There are also more subtle changes wilh potentially
hcmorhcological consequences. One is ihe large size of I he red
cells of ihe very early fetus. Al week 24 Ihe MCV is 135 11 and.
although il decreases with gestational age. even al lenn il is still
about 119 11 and thus larger than lhal of Ihe adull [121. This, of
course, has potential consequences to the resistance lo How in
ihe microcirculation. There are also subtle differences in ihe
crylhrocyle membrane composition compared lo lhal of the
adult, with these differences affecting the mechanical properties
of the membrane 113J and the innale ability of ihe fetal
erylhroeyles lo form rouleaux. The hemoglobin at this siagc is
predominately I IbF. rather than the adult form llbAi. but its
intracellular concentration (i.e., MCHC) changes little from 24
weeks of gestation to lent), being about 3lg<dl and therefore a
little less than that of the adult [12). Another significant
difference in the fetus is thai ihe fibrinogen molecules arc more
strongly sialinated than in the adult [14], and although the level
of sialination steadily decreases towards term, it is still higher at
term than thai of the adult. Ihis increased sialination hinders its
ability to induce rouleaux formation, and thus felal blood overall
exhibits less rouleaux formation than the adult, the blood shows

much less shear thinning, and the overall viscosity is low


compared with the adult. This raises a potentially important
question lo those involved with in utero transfusion: is it
reasonable (o transfuse adult blood which has such different
hcmorhcological properties from thai of the fetus?
2.2. Al Birth

A comprehensive study has been made of the


hematologieal/hemorheological characteristics of the blood of
the pre-term babies, as early as 24 weeks, and of the term baby
(15). As with the fetal data discussed above, the results show a
steady increase in most hematological parameters with
gestational age. 'Ihus, hematocrit rises on average from 45 to 50 %
with large variations between individuals, plasma protein
concentration changes from 44 to 55 g/l. with increases in IgG,
rtj-macroglobulin

and fibrinogen from 2.1 to 2.6 g/l. Comparing

these values with those obtained in utero al a corresponding


gestational age, it is clear that the ex utero values are higher;
indicating a degree of hemoconcentration lakes place during
birth. The result of the aforementioned changes is that lite
viscosities of both plasma and blood, at both high and low shear
rates, increase over the same period: the shear thinning
properties become more pronounced, with the magnitude of the
changes being greater than found in the in utero sfudy. Low shear
rale (0.277 s'1) blood viscosity increases 3-fold from 12 to 40
mPa.s while the high shear rate (128.5 s'1) value increases by
20% from 3.7 to 4.5 mPa.s and plasma viscosity rises by 20%
from 0.96 to 1.15 mPa.s. The alteration in the high shear rate

viscosity can be explained almost entirely by changes in


hematocrit and plasma viscosity over Ihe period, whereas Ihis
explanation is nol valid al low shear rale; here ihere arc effects
due to altered rouleaux formation secondary to cell-specific
factors [9] and to Ihe alteration in fibrinogen sialination lhat
accompanies changes in gestational period.
2.X Childhood
Al birlh ihe red cells are still relatively large compared lo Ihe aduli and still contain
predominantly HbF. Over the following 6 to 12 months the hemoglobin of the red cell population
is progressively replaced by I IbA and the red cells acquire a similar size to ihose of adults. There
are no hematological differences between males and females in pre-pubescent children, but post
puberty the red cell parameters slowly diverge as the male red cell count increases beyond thai of
ihe female to give the normal differences found in adult humans described above.
3. Changes of Hcmorhcological Significance Associated With Pathology
Because of space limitations only a review of the general principles will be given here.
3.1.

Plasma Proteins

In healthy blood it is the plasma protein concentration, especially of (he larger proteins, that is
mainly responsible for the elevation of plasma viscosity above that of water, so conditions
associated with dramatic changes in plasma protein composition can be expected to change ihe
hcmorhcological

properties

of

blood.

Two

obvious

examples

are

Waldenstrom's

macroglobulinaemia and multiple myeloma. In these conditions the concentration of large


macroglobuhits increases massively and has a very large effcel on plasma viscosity, often with
up to a 20-fold increase in the viscomctric effcel of these proteins. Furthermore, many of the
proteins in these conditions are abnormal and highly rouleaugenic. The consequent large increase
in ihe strength and size of rouleaux leads to markedly increased low shear rate blood viscosity.
These effects have deleterious effects on blood flow in all vessels of the circulation, especially
those in the microcirculation [5),
As discussed above, the plasma protein with the greatest rouleaugenic effect is fibrinogen, and
hence Ihe relevance of plasma fibrinogen concentration increases in association with many
clinical conditions. Examples are diabetes mcllitus, hypertension, pregnancy, post surgical
trauma, infection, etc. This means lhat the strength of rouleaux formation and the shear thinning
of blood is frequently elevated in association with these conditions [16].
3.2.

/erythrocytes.

It should by now be clear lhat the red cell is the most prominent hematological factor influencing
hcmorhcology. Hence, diseases characterized by alterations in this area arc generally associated
with hcmorhcological abnormalities. The most obvious is anemia due lo any cause, where the

lowering of the whole blood hemoglobin concentration inevitably reduces Ihe viscous effcel of
Ihe red cell mass. The result is lhal, though anemia itself can have serious physiological effects,
it docs nol bring hcmorhcological embarrassment. Whal makes anemia more of a
hcmorhcological problem is lhat il is often complicated by associated changes in Ihe individual
red cells. For example, in iron deficiency anemia ihe cells become smaller than normal.
while in folic acid- or vitamin Bi:-dcficicney anemia the cells increase in size. In thalassemia, the
cells arc again often smaller than normal and Ihcy arc also less deformable. Such changes may
have negative influences on microvascular (low. However, most significant of all in this respect
is sickle cell anemia where Ihe cells sickle in low oxygen conditions, become quite rigid and
have very substantial problems negotiating Ihe microcirculation. In addition, the repeated sickleunsickle cycles during llow through Ihe body eventually leads lo their membranes becoming
damaged and irreversibly rigid. As a consequence. Ihe resistance lo blood (low in large vessels is
lower than normal due lo Ihe low hematocrit, while in ihe microcirculation it can be considerably
higher, even leading to stasis .
At ihe other end ol" the scale is ihe problem of increased red cell concentration. There arc
various pathologies that lead lo ihis; examples arc respiraiory disease where Ihe resultant
hypoxia stimulates red cell production and polycythemia consequent lo malignant changes in ihe
hemopoietic tissue [I7|. Inevitably, they lead lo substantial increases in blood viscosity. Such
changes can also occur in the neonate, in that excessive production of red cells can result from
intrauterine hypoxia. However, the effects can also resuk from passive in utero events such as
transfusion between mother and foetus, between twin and twin, or as a result of delayed damping
of the cord [IK]. All of these phenomena cause the blood viscosity to increase considerably and
in extreme cases can be very deleterious to blood (low.
3.3. Leukocytes
As mentioned above, leukocytes in the healthy individual are noi of sufficient concentration to a
Ilea whole blood viscosity, whereas they do have a significant resistive effect at the
inicrocireulatory level due to their relative stiffness and enhanced viscoelastic characteristics
compared to die erythrocyte. Nevertheless, there are conditions in which ihe leukocyte count can
become extremely high: the most prominent are the classic leukemias. It is not unusual for Ihe
leukocyte count to increase by an order of magnitude or even more. Under these circumstances
they are relevant to ihe viscosity of ihe whole blood and, because of iheir large volume
concentration, relative inflexibility, irregular shape, and viseoelasticity, they can cause the
viscosity to rise enormously and so affect large vessel flow. However, equally important is lhal
now their resistive effect at the microcirculalory level far exceeds that of the red cell mass,
especially as the deformability of leukemic leukocytes is less even than lhat of normal leukocytes
[191: all of these factors have very deleterious effects on tissue perfusion with obvious
consequences [20].
4. Other Mammals
Until fairly recently the study of hcmorhcology has concentrated on the human, and other
mammals have largely been ignored. The situation is now beginning to change as investigators

look to animal models for hcmorhcological studies nol possible in Ihe human, as velerinary
workers begin lo realize lhal Ihe hcmorhcological effects in pathology found in the human may
also exisl in mammals of economic importance, and as investigators realize thai Ihe sludy of
mammalian hcmorhcology may offer new insighls into human hemorhcology. especially in
pathological slates.

Thus fascinating data arc beginning to emerge showing that some

hematological1' hcmorhcological parameters seem to be held remarkably constant across Ihe


whole class of mammals, while others vary widely.
4.1.

Plasma Proteins

Comparative data on variations across the mammalian kingdom of the concentrations of the
different plasma proteins arc difficult to locate, but data from Johnn. el al. [21] indicate lhat they
arc likely to vary significantly between mammals. In their study. 31 different mammalian types
were investigated with results indicating that the plasma viscosity varied widely: at one extreme
were the New Zealand rabbit and the cheetah wiih values of I.I mPa.s and 1.2 mPa.s respectively,
and at the other the chimpanzee and goat each with a value of 1.6 mPa.s. These variations were
only partly explained by variations in the concentrations of fibrinogen, because while the rabbit
had one of the lowest fibrinogens at 2.4 g,'l. lhal of ihe cheetah was relatively high al 3.8 g/l.
Similarly, lhal of Ihe goal was high at 5.4 g/l while thai of the chimpanzee was fairly average at
3.0 g/l. Il is notable lhat Ihcsc fibrinogen levels arc all overshadowed by the level in the black
buck which was recorded as 7.0 g/l. Plasma protein daia on nine different domestic mammals
from Windberger. et al. |22] are useful since they show lhat toial plasma protein concentrations
varied from as low as 43 g/l in the mouse to as high as 72 g/l in the cat and in caillc. However.
Ihey found only a partial correlation between plasma protein concentration and plasma viscosity.
4.2.

Erythrocytes

The most important finding here is Ihe remarkable constancy of ihe hematocrit and whole blood
hemoglobin across mammals. In the study by Johnn. el al. [21] mentioned above, they found Ihe
lowest hematocrit in Ihe goal at 31% and ihe highest in the wallaby at 53%. However, these are
extremes and when ihe values for the 31 mammals studied were averaged the mean and standard
deviation were 40+5%, indicating ihe narrowness of spread across ihe class as a whole. Whole
blood hemoglobin shows an even narrower range judging by data from Ciascoyne and Hawkey
[23] who show a mean and SDof I4.8r2.l g/l. This seems remarkable considering ihe large
variation in size, heart rate, life style, etc. between the animals. On the olher hand, they found
enormous differences in MCV, with the goat having ihe smallest values al 22 11 and the Asian
elephant had 6-fold greater value of 120 fl! Windberger, et al. [24] have shown that for the
African elephant the MCV is even larger at 138 11. In spile of this, the mean cell hemoglobin
concentration is remarkably conserved. Oascoyne and Hawkey [23] found a coefficient of
variation of only 8.5% (34.6-3.0, mcaiitSD). In view of the relative constancy of hematocrit and
whole blood hemoglobin concentration, ihis narrow range of hemoglobin means lhal the red cell
count varies by a similar order of magnitude to that of the MCV across ihe mammals. There is no
obvious connection between the MCV and the size, heart rate, life styles, etc. of the mammals
studied.

Johnn, et al. [21] measured the high and low shear rale (128.5 and 0.222 s 1 respectively) blood
viscosity characteristics of the 31 mammals ihcy investigated, and found lhal high shear rate
values varied by some 2-fold, with this variation almost totally explained by the variations in
hematocrits and plasma viscosities between the mammals. On the other hand, the low shear rale
values varied by some 18-fold and this could only be partly explained by Ihe hematocrit and
plasma viscosity differences. The other factor of great relevance here is the variation in the
inherent roulcaugcnicity of Ihe red cells from the various mammals. Thus, for example, in sheep
and cattle, rouleaux formation is non-existeni, while in the horse and elephant il is very increased
such lhal if il occurred in a human il would be considered pathological. The reasons for Ihe
differences may be partly due lo different levels of fibrinogen in Ihe plasma of these animals, bui
it is now becoming increasingly clear that there must be cell specific factors involved as well [9].
That is. in Ihe non-rouleaux forming animals such as sheep, some peculiarity of Ihe membrane
structure inhibits rouleaux formation. This has been shown by Kaibara (25) who found that
bovine red cells would not form rouleaux in their own plasma, bul iI* they were treated with
trypsin 10 remove significant surface protein they would then form intense rouleaux.
Furthermore, in animals where rouleaux formation is massive such as the horse, it is to be
expected that membrane factors will be found to be facilitate aggregate formation. Further study
in this area is clearly warranted.
43. Breed Variation
The dala discussed above are clear in showing large differences of some hcmorhcological I y
important variables between mammals. What is also of interest is to what extent these variable
values arc conserved across breeds within an individual mammal species. Such studies are rare;
indeed, the only one that the author has found is a study of nine different breeds of dog [261.
Very substantial differences in whole blood viscosity were found in Ihis study, so high shear rate
(128.5 s"1) values varied by 50% between the highest and the lowest, while the low shear rate
(0.277 s"'> values varied by 140%. Of the breeds, it was the more athletic, that undergo brief
periods of intense anaerobic exercise, which had the highest values (e.g.. greyhounds and
decrhounds), while the golden retriever and Springer spaniel were at the other end of the range.
However, the differences could be explained entirely by the different hematocrits between the
dogs, with such other potential factors such as cellular parameters and plasma composition not
being significantly different between the breeds. In dtis context, an interesting study was done by
Anwar and Rampling [27] who compared the hematological1' hemorheological parameters of
five different ethnic groups of humans. The only significant difference found between the groups
was that Caucasians had significantly lower concentrations of plasma proleins and hence lowered
plasma viscosity.

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