Mini-revue
Sang Thrombose Vaisseaux 2010 ;
22, n° 3 : 137-43
Role of red blood cell aggregation in tissue perfusion :
New findings
Oguz K. Baskurt, Herbert J. Meiselman
Copyright © 2017 John Libbey Eurotext. Téléchargé par un robot venant de 88.99.165.207 le 14/06/2017.
Department of Physiology, Faculty of Medicine Akdeniz University, Antalya, Turkey and Department of Physiology
and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Abstract.
Red blood cell (RBC] aggregation is a process in which single cells form
face-to-face linear aggregates then combine to form three-dimensional
structures. This process is reversible : increased shear forces disperse
aggregates while they reform at low shear or stasis and hence blood is a
non-Newtonian fluid whose viscosity increases with decreasing shear. The
in vivo effects of enhanced aggregation are yet to be fully defined, but
include : 1] increased flow resistance in larger (i.e., > 1 mm] venous
blood vessels ; 2] abnormal RBC flux in microcirculation resulting in
decreased tissue hematocrit ; 3] more-pronounced cell-poor zone at
vessel wall and hence decreased near-wall blood viscosity ; 4] lower wall
shear stress and thus impaired endothelial cell function. It is important to
note that the influence of RBC aggregation on endothelial function should
depend on the mechanism by which aggregation is increased : enhanced
aggregation as the result of changes of RBC properties without altering
plasma characteristics or as a result of modified plasma composition and
hence higher plasma viscosity without altering RBC characteristics. The
effects of enhanced RBC aggregation on wall shear stress may thus be
partially or totally offset by increased plasma viscosity, and it is possible
that discrepancies between studies investigating relations between RBC
aggregation and vascular pathophysiology may be due to the manner by
which higher red cell aggregation is achieved.
Key words: red blood cell agregation, flow resistance, tissue hematocrit, vessel wall,
endothelial cell function
doi: 10.1684/stv.2010.0466
Résumé
Le phénomène d’agrégation érythrocytaire : de nouvelles découvertes
Tirés à part :
O. Baskurt
Le phénomène d’agrégation érythrocytaire est un processus au cours
duquel les globules rouges s’empilent les uns sur les autres comme des
assiettes pour former des rouleaux linéaires. Ensuite ces rouleaux
s’associent pour former une structure en trois dimensions. Ce phénomène
est réversible : l’augmentation des forces de cisaillement disperse les
agrégats érythrocytaires alors que ces derniers se reforment dans des
zones à cisaillement faible ou de stases. Ainsi, le sang est un fluide non
STV, vol. 22, n° 3, mars 2010
137
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138
newtonien dont la viscosité augmente lorsque le cisaillement diminue.
Les effets in vivo d’une agrégation érythrocytaire accrue ne sont pas
encore complètement connus, mais il est d’ores et déjà établi qu’une
hyper-agrégation conduit à : 1] l’augmentation des résistances
vasculaires dans les compartiments vasculaires veineux larges (> 1 mm] ;
2] un flux érythrocytaire anormal dans la microcirculation provoquant une
diminution de l’hématocrite tissulaire ; 3] une zone vasculaire au niveau de
la paroi endothéliale appauvrie en éléments figurés conduisant ainsi à une
réduction de la viscosité sanguine au niveau de la paroi vasculaire ; 4] une
contrainte de cisaillement exercée sur l’endothélium plus faible participant
ainsi à l’altération de la fonction endothéliale. Il est important de souligner
que l’influence de l’agrégation érythrocytaire sur la fonction endothéliale
est fonction du mécanisme par lequel l’agrégation est augmentée. Une
agrégation érythrocytaire accrue peut être soit la conséquence de
changements au niveau des propriétés cellulaires des globules rouges
sans altération des caractéristiques plasmatiques, soit le fruit d’une
modification de la composition plasmatique, et ainsi de la viscosité
plasmatique, sans modification des propriétés cellulaires des globules
rouges. Les effets d’une agrégation érythrocytaire accrue sur la contrainte
de cisaillement à la paroi vasculaire peuvent ainsi être partiellement ou
totalement contrebalancés par une augmentation de la viscosité
plasmatique, et il est probable que les divergences d’une étude à l’autre à
propos des relations entre les phénomènes d’agrégation érythrocytaires et
la pathophysiologie vasculaire soient liées à la manière dont une
agrégation érythrocytaire accrue est obtenue.
Mots clés : agrégation érythrocytaire, résistance vasculaire, hématocrite tissulaire,
paroi endothéliale, fonction endothéliale
RBC aggregation is the major determinant
of blood viscosity at low shear stress
Blood is a complex, two-phase fluid consisting of various
cell types suspended in a salt and protein solution termed
plasma. The rheological (i.e., flow] behavior of blood is
also complex, with its resistance to flow dependent on
flow conditions. Blood viscosity is a function of shear
rate or applied shear stress during flow and hence is a
non-Newtonian fluid [1]. In vitro measurements of blood
viscosity over a range of shear rates clearly demonstrate
this shear dependence : normal blood has a viscosity on the
order of 102 mPa. s at shear rates of 10-2 s-1 and 100 mPa.
s at shear rates of 102 s-1 [2]. This flow behavior is entirely
due to the presence of cellular elements, most importantly
red blood cells (RBC] which constitute 99.9 % of the
formed elements and have a volume fraction of 0.4 to
0.5. The flow behavior of plasma is Newtonian and is
not affected by shear.
RBC deformation and alignment with flow streamlines
accounts for the marked decrease of blood viscosity
at high shear rates [2]. As shear rate is decreased, RBC
return to their biconcave-discoid shape and tend to form
multi-cell aggregates at lower shear forces or at stasis [3].
These aggregates are comprised of linear, face-to-face
RBC-RBC structures termed rouleaux, with rouleaux
associating to form three-dimensional structures. RBC
aggregation is physiological phenomena which strongly
depends on both plasma composition (e.g., fibrinogen
concentration] and cellular properties [4]. Shear forces
are important determinants of the extent of aggregation
since aggregates can be dispersed by such forces yet
reform when the forces are lower or absent [4]. Plasma
composition and cellular factors also determine the time
course of aggregation during the transition between two
shearing conditions (e.g., from high to low shear rate or
to stasis] [5].
Given the above brief discussion of factors affecting RBC
aggregation, it should be anticipated that RBC aggregates
are expected to be formed in low flow regions of the in vivo
circulatory system (e.g., post-capillary region including
venules and larger venous blood vessels]. Kim et al.
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demonstrated the formation of RBC aggregates in postcapillary venules using high-speed videomicroscopy [6]
and suggested that the rate of aggregate formation in this
region is determined by RBC collision frequency [7].
These findings strongly support earlier reports indicating
the importance of physiological levels of RBC aggregation
in maintaining normal venous flow resistance and hence
microcirculatory flow dynamics [8].
The influence of RBC aggregation on microcirculatory
blood flow has been studied using intravital microscopy
techniques, with results suggesting increased flow resistance with enhanced aggregation induced by infusion of
high molecular dextran solutions [9-12]. However, in
experiments using whole-organ preparations rather than
a particular vascular bed, the effects of RBC aggregation
were found to be determined by the degree of aggregation, thus suggesting that enhanced aggregation may tend
to decrease, have no effect or increase flow resistance
[13-15]. The reasons for such conflicting findings in different studies have been previously discussed [16, 17]
and include factors related to methodological differences
and also to various in vivo mechanisms sensitive to the
degree of RBC aggregation.
In vivo hemodynamic mechanisms affected
by RBC aggregation
The influence of RBC aggregation on blood flow resistance in larger venous blood vessels (i.e., diameter >1 mm]
can be explained by the increased effective particle size
with aggregation [3]. This mechanism of enhanced flow
resistance may only be effective in flow regions with
shear forces low enough to allow sufficient RBC aggregation. If the mean values of shear forces in the arterial blood
vessels are considered, it might be assumed that such high
shear forces indicates that RBC aggregates are unlikely to
exist in a wide range of arterial vessels. However, as presented below, there is experimental evidence suggesting a
significant influence of altered RBC aggregation on arterial hemodynamic mechanisms.
It has been observed that tissue hematocrit values are affected by modified levels of aggregation. Using a doubleisotope labeling technique, myocardial tissue hematocrit
has been demonstrated to be reduced after experimentally
enhanced RBC aggregation [18, 19]. Lower tissue hematocrit values compared to large vessel hematocrit reflect a
hematocrit reduction as blood approaches the microcirculation [20]. Hemodynamic mechanisms underlying this
hematocrit reduction are mainly related to the migration of
RBC into the central zone of vessels, a phenomena known
as axial migration [21]. Axial migration of RBC results in
the formation of a cell-poor zone adjacent to the vessel wall
and a relatively higher concentration of RBC (i.e., higher
hematocrit] in the central zone. One important consequence
of this cell-poor zone is more effective plasma skimming at
side branches originating from blood vessels, especially for
diameters below 1000 μm, since side branches tend to
receive blood from near the wall of the larger vessel. If this
cell-poor zone is considered together with the higher flow
velocity in the central zone, it can be seen that the average
RBC velocity in a given vessel segment would be higher
than the average velocity of plasma. This difference in
velocity results in the Fahraeus Effect in which the hematocrit of blood flowing in a vessel is less than the hematocrit of
blood leaving that segment [21].
Enhanced RBC aggregation tendency may theoretically be
expected to promote axial migration and related hemodynamic mechanisms, and these effects of aggregation have
been demonstrated experimentally. An excellent example is
the study by Cokelet and Goldsmith in which they show
decreased flow resistance in vertically oriented glass tubes
during flow of RBC suspensions with enhanced degrees of
aggregation [22]. These findings can be interpreted as the
result of more effective axial migration and cell-poor zone
formation, thereby reducing the hematocrit and viscosity in
the marginal zone which results in lower frictional resistance. Further, it strongly suggests that other mechanisms
closely related to axial migration may also be influenced by
RBC aggregation.
The above discussion may have several important outcomes related to hemodynamic-vascular mechanisms,
especially in blood vessels near and within the
microcirculation.
1) The observed effect of enhanced RBC aggregation on
tissue hematocrit strongly suggests that RBC aggregates
should exist on the arterial side of the circulatory system,
at least locally in the central flow zone of the blood vessels
where RBC tend to accumulate and where shear forces are
low enough to allow aggregation ;
2) If RBC aggregates exist in the arterial side of the microcirculation, even locally in the central flow zone, these
aggregates must be dispersed into individual RBC in order
to transit micro vessels, and this disaggregation has an energy cost. This disaggregation energy should contribute to
flow resistance ;
3) The observed decrease of hematocrit in the marginal
cell-poor zone due to enhanced RBC aggregation, and
thus the lower viscosity in this region, should also be considered in terms local wall shear stress which is an important determinant of endothelial function.
STV, vol. 22, n° 3, mars 2010
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Role of RBC aggregation in the regulation
of vascular tone
The diameter of blood vessels can vary widely, especially
for vessels near and in the microcirculation. This variation
is an important component for the local regulation of blood
flow at the tissue level, and is also a major determinant of
flow resistance in a given circulatory region. Vascular
smooth muscle tone as a determinant of diameter changes
is affected by a variety of mechanisms including metabolic
autoregulation and autonomic control. Vascular smooth
muscle tone is also modulated by endothelium-related
factors, nitric oxide (NO] being an important example of
such mediators.
NO is synthesized by endothelium in response to various
stimuli, including local shear stress acting on the vessel
wall ; NO reduces the tone of underlying vascular smooth
muscle thereby dilating the blood vessel. In addition to the
other factors (e.g., pO2, acetylcholine], wall shear stress
(WSS] is an important factor for up-regulation of the NO
synthesizing mechanisms in endothelial cells [23]. WSS is,
in turn, determined by the velocity gradient near vessel wall
and the viscosity of the flowing blood in that region, with
the latter being a function of plasma viscosity and local
hematocrit in the marginal flow zone [24]. Therefore, it
can be hypothesized that WSS can be affected by the extent
RBC aggregation via altering the local hematocrit in the
marginal flow zone. Endothelial function may thus be
expected to be altered by modified RBC aggregation with
effects not necessarily limited to the control of vasomotor
tone.
Direct clinical or experimental evidence regarding the relations between RBC aggregation and endothelial function
have only recently been presented. Enhanced aggregation
is associated with a variety of circulatory disorders whose
origins might be considered as related to endothelial function (e.g., hypertension [25]]. However, such relationships
cannot be interpreted in terms of the mechanisms of these
alteration or in terms of their consequences : enhanced RBC
aggregation in hypertension could be the cause or the result
of an ongoing pathophysiological process [26].
Using an experimental model of chronically enhanced RBC
aggregation, it has been shown that NO related mechanisms
are down-regulated in resistance arteries [27]. The model
was based on a novel method of increasing RBC aggregability (i.e., intrinsic tendency of RBC to aggregate] by
surface coating RBC with co-polymers of specific molecular size. These hyperaggregating RBC were suspended in
normal rat plasma and exchange transfused into rats.
The results of this experiment approach are summarized
in table 1: 1] RBC aggregation was significantly enhanced
during the 4-day period following transfusion ; 2] Mean
arterial pressure of hyperaggregating rats was not different
from the control animals on the 1st day and was gradually
increased during the 4-day period ; 3] The animals were
sacrificed on the 4th day and nitric oxide related vascular
mechanisms were investigated in arterial segments
of ~300 μm diameter isolated from skeletal muscles. Both
acetylcholine-induced and flow-mediated dilation
responses were attenuated in the vessels of hyperaggregating rats compared to control animals. Specifically, there
was a ~ 70 % increase of the half-maximal efficient concentration (EC50] value for acetylcholine for blood vessels
from hyperaggregating animals. Flow-mediated dilation
of the same blood vessels was characterized by lower
percentage of maximal dilation and increased flow rate for
maximal response. Both changes indicate significant downregulation of NO-mediated vascular control mechanisms.
4] eNOS expression in the tissue samples obtained from
the same skeletal muscles was found to be significantly
decreased in rats with enhanced aggregation. This study
provides direct evidence for increased blood pressure
consequent to enhanced RBC aggregation and the role
of down-regulated NO-synthesis mechanisms in this effect ; the changes were suggested to be mediated via
modified WSS.
Table 1. Effect of RBC hyperaggregation on arterial blood pressure and NO-related vascular control mechanisms.*
Microscopic aggregation index (4th day]
1st day Mean arterial pressure (mmHg]
4th day Mean arterial pressure (mmHg]
Acetylcholine induced dilation (EC50, M]
FMD (maximum dilation, %]
FMD (flow rate at maximum dilation, μl/min]
eNOS expression (% G6PD expression]
Control
Hyper-aggregating
Change
1.14 ± 0.03
82.3 ± 2.1
83.2 ± 1.8
2.07 x 10-7
48.2 ± 7.4
17 μl
65.2 ± 5.6
2.68 ± 0.09
85.7 ± 4.2
117.4 ± 5.7
3.48 x 10-6
22.3 ± 9.6
26 μl
18.1 ± 5.5
↑ 135%
↔
↑ 41%
↑ 168%
↓ 53%
↑ 53%
↓ 72%
*Results are summarized from [27]. EC50 : Half-maximal effective concentration ; FMD : Flow mediated dilation.
140
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eNOS (% Control)
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The relationship between RBC aggregation and endothelial
function has been further investigated using an in vitro
model to provide better control of experimental conditions
[28]. These experiments utilized 1 mm ID glass tubes
coated with human umbilical vein endothelial cells
(HUVEC] on their inner surface, and were perfused for
30 min with RBC suspensions with normal and enhanced
aggregation at a flow rate to generate a nominal WSS of
15 dyn/cm2. It was observed that the degree of activation
of HUVEC NO-synthesizing mechanisms, in terms of
serine-1177-phosphorylated eNOS expression [29],
depended on the aggregation properties of RBC suspensions used for perfusion, being significantly diminished
with hyperaggregating RBC suspensions (figure 1).
Additionally, it was observed that the influence of enhanced
aggregation could be counter-balanced if the suspending
phase viscosity of the RBC suspension was also increased
(figure 1). This is obvious with comparisons between the
experiments using polymer coating to enhance RBC
aggregability and hence aggregation in native plasma
(HA-I group] and uncoated cells in plasma containing dextran 500 kDa, a polymer that induces strong aggregation, at
a concentration of 0.5 % (HA-II group]. Due to the presence
of dextran 500 the suspending phase viscosity was ~40 %
higher in the HA-II group compared to control or to HA-I ;
both HA-I and HA-II suspensions exhibited a similar
degree of enhanced RBC aggregation.
The in vitro and in vivo experimental findings confirm that
RBC aggregation can significantly influence endothelial
function, thereby lending support to a mechanism involving
50
0
Control
HA-I
HA-II
Figure 1. eNOS expression of HUVEC on the inner surface of a
glass tube exposed to 15 dyn/cm2 nominal wall shear stress for
30 min via perfusion with normally-aggregating (i.e., control, normal
RBC in native plasma] and hyperaggregating human RBC suspensions. Hyperaggregation was achieved by either suspending
surface-modified RBC in native plasma (HA-I] or suspending
unmodified RBC in plasma containing 0.5 % dextran 500 kDa
(HA-II]. The level of RBC aggregation was the same in both HA
groups whereas plasma viscosity was ~ 70 % higher in the HA-II
group (Redrawn from [28]].
changes of WSS. This effect might be viewed as a result of
more effective axial migration of RBC and phase separation, leading to lower hematocrit and viscosity in the
marginal flow zone. However, in the case of more effective
phase separation due to elevated polymer or protein levels,
plasma viscosity becomes an important factor significantly
influencing WSS. Using a hemodiluted hamster model,
Tsai et al. demonstrated that plasma viscosity is an important determinant of perivascular NO concentration [30] ;
they also reported increased eNOS expression in experiments with elevated plasma viscosity. Other studies by the
same group also confirmed the important role of plasma
viscosity in the regulation of microcirculatory blood flow
[31, 32]. Their reports suggest that the influence of plasma
viscosity is especially prominent in case of reduced hematocrit (i.e., hemodilution]. Note that the modified distribution of RBC in a vascular segment due to hyperaggregation
(i.e., enhanced axial migration] is essentially “local hemodilution” near the vessel wall.
Clinical considerations
It follows from the above discussion that RBC aggregation
should be considered as an important determinant of circulatory function, not only because it has a strong influence on
low-shear blood viscosity but also because it is an important
feature affecting endothelial function. RBC aggregation
should thus not only be considered as a factor influencing
vascular control mechanisms that regulate the distribution
of blood flow to various organs and tissues, but should also
be considered, in a more general sense, as a phenomenon
that interferes with endothelial function and vascular health.
Vascular endothelium is now considered as being central to
a number of important vascular functions, including the regulation of hemostasis, inflammatory response, angiogenesis
and vasomotor control, in addition to its classically-known
permeability barrier function [33, 34]. These endothelial
functions are regulated by a variety of biomolecules as
well as mechanical forces affecting endothelial cells [34].
It is well established that physiological levels of WSS are
required to maintain normal endothelial function and quiescent status of endothelial cells [35, 24]. Exposure of endothelial cells to reduced or geometrically altered shear forces
results in the disturbance of this quiescent status which may
lead to the development of vascular pathophysiological processes (e.g., atherosclerosis] [35]. NO generation by endothelial cells is a requirement for the continuation of this
quiescent status, and therefore NO should be viewed as an
important element of vasomotor control and as an essential
factor for maintaining vascular health.
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If the proposition that decreased WSS due to enhanced
RBC aggregation is deemed worthy, it seems possible to
extend this concept to include endothelial function in a
broader sense and hence the overall status of vascular
health. That is, enhanced RBC aggregation may have an
important influence on endothelial function by reducing
WSS and NO synthesis accordingly, thereby interfering
with the quiescence status of endothelium. However, it
should be noted that the influence of RBC aggregation on
endothelial function should depend on the mechanism by
which aggregation is altered : enhanced aggregation as the
result of changes of RBC properties without altering plasma
characteristics or as a result of modified plasma composition and hence plasma viscosity without altering RBC
characteristics. RBC cellular properties (i.e., RBC aggregability] can be modified in clinical conditions such as
diabetes mellitus [36], sepsis [37], ischemia-reperfusion
injury [38] ; plasma composition can be modified due to
increased concentrations of certain plasma proteins (e.g.,
fibrinogen] as seen frequently in case of acute or chronic
inflammatory reactions, including infectious diseases [39]
and rheumatoid disorders [40]. And, in some clinical situations, both plasma-mediated and cell-mediated mechanisms may co-exist. With both mechanisms operational, the
effect of enhanced RBC aggregation on WSS may be
partially or totally offset by increased plasma viscosity. It
seems clear that the impairment of endothelial function due
to enhanced RBC aggregation should be more pronounced
if the enhanced aggregation is the result of increased RBC
aggregability since, in this case, plasma viscosity is unaffected. It is therefore possible that the discrepancies
between clinical studies investigating the relations between
enhanced RBC aggregation and vascular pathophysiology
may be due to the manner by which higher red cell aggregation is achieved. ■
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