Handbook of Hemorheology and Hemodynamics
O.K. Baskurt et al. (Eds.)
IOS Press, 2007
© 2007 IOS Press. All rights reserved.
267
Comparative Hemorheology
Ursula WINDBERGERa,1 and Oguz K. BASKURTb
Decentralized Biomedical Facilities, Core Unit for Biomedical Research, Medical
University of Vienna, Austria and bDepartment of Physiology, Akdeniz University
Faculty of Medicine, Antalya, Turkey
a
Introduction
Hemorheological values vary widely among the animal species. To understand the
structure-function relationships of red blood cells (RBC) together with associated
physiological mechanisms, comparative studies are still a classical approach. Some
animal species show extraordinary values of blood viscosity and RBC indices which
would be pathologic for man. These differences can reflect an adaptation process to a
specific environment or way of life. Different species also use different mechanisms to
maintain blood flow, and in some cases these differences might indicate which
variables limit the demand for oxygen delivery in a species or under certain
circumstances. Nevertheless, when comparing values to man, it should be kept in mind
that every hemorheologic “disturbance” in a healthy animal reflects a physiologic
circumstance. It is necessary to know that the hemorheological profile of an animal
cannot be judged by a single rheological value, but must be considered as part of the
cardiovascular system in which the blood is flowing. That is, the hemorheological
profile of an animal species is a conglomerate of properties which has to be considered
in evaluating its cardiovascular relevance in a species-specific manner. These speciesspecific differences look chaotic at first sight, and no clear guiding principle has been
found to combine these profiles to a universal “logic” at present. Therefore changes in
parameters during disease, after interventions, or during environmental or associated
changes need to be related to their species-specific reference values; describing an
animal’s clinical or physiological condition using comparisons to values from other
species is most likely not a valid approach.
1. General Aspects
RBC of the different classes of vertebrates have different sizes and shapes, variations
which are sometimes huge due to the nucleus within non-mammalian RBC. This
variation and the diversities of RBC cytoplasm and membrane constituents, together
with variations in blood cell count and blood plasma composition between the species
markedly influences bulk blood flow in different parts of the vasculature. A list of
1
Corresponding author: Decentralized Biomedical Facilities, Medical University of Vienna, Borschkegasse
8a, 1090 Vienna, Austria; E mail: [email protected]
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U. Windberger and O.K. Baskurt / Comparative Hemorheology
hematological parameters is given by Hawkey et al. [1] or can be found in textbooks
[2, 3].
The first group of parameters which have to be considered in hemorheology are
cell size and geometry. RBC size differs widely among the species – and to a lesser
extent also between individuals within a species - with fish having the highest and
mammals the lowest values although exceptions exist. For example, fish RBC volume
can be more than 100-fold higher than those of a mammal [4]. Diversity in mammalian
RBC volume alone is much smaller, ranging from a mean value of 18 fl in goat to 160
fl in giant anteater [5]. The size of the mammal has no association with its RBC
volume; large species like horse may have smaller RBC than smaller species like
rabbit. Mean cell volume (MCV) correlates strongly and inversely with RBC count [1,
6]. Besides hydrodynamic forces and RBC membrane mechanical properties, RBC size
is most important in determining the effectiveness of tissue perfusion since it is easier
for RBC to enter and transit capillaries if the cell size matches the vessel caliber and if
vessels are more or less straight. Capillary geometry differs between various tissues
(e.g., brain vs. kidney or skeletal muscle), with capillary density also affected by tissue
metabolic demand which is measurable by capillary density per mitochondrial number.
In case of skeletal muscle for instance, capillary geometry depends on the activity of
the animal or on the environment the animal is adapted to [7]. Differences in
rheological behavior of blood may also help to optimize O2 supply to tissues in various
species [8-11]. Mean capillary diameters in species reach values from 3 μm in pigeon
and rat, up to 20 μm in frog with tuna, hummingbird, bat, and rabbit lying in between
[12-14]. In a small number of species, capillaries have been found to be smaller than 3
μm [15], but in most animals corrosion cast measurements show capillary diameter
values below 5 μm [15-17], which is indeed smaller than the diameter of most animal
RBC. As part of an in vivo study of capillary diameter and RBC geometry, frog RBC
were found to travel through the capillaries with their major axis predominantly
parallel to the flow direction [13]. In the presence of a greater mismatch of capillary
caliber and RBC diameter as in fish, in vivo capillary transit time might be increased as
suggested by results of in vitro filtration tests [4, 18]. However, an increased capillary
transit time should enhance the time for O2 delivery, which might be an advantage in
animals adapted to cold temperature since it would compensate for the left shift of the
O2 dissociation curve. On the other hand, mammalian RBC are much smaller, which
should facilitate O2 diffusion across the RBC membrane by providing a greater
membrane surface per unit volume of blood; the smaller size also reduces the energy
required for RBC to enter and pass the capillaries. Due to the inverse correlation of
RBC size and number, a greater amount of small RBC may be associated with the
increased metabolic capacity in animals with constant body temperature.
A second important parameter for RBC function is cytoplasmic viscosity, reflected
by mean cellular hemoglobin concentration (MCHC). MCHC is different among the
species. Very high MCHC has been observed in seals, possibly to optimize O2 storage
during long-term dives [19]. The cost of this is an increased cytoplasmic viscosity
which may affect RBC deformability, although the RBC function of carrying O2binding proteins to guarantee adequate O2 supply seems to be more important under
such circumstances. MCHC is increased by about 20% in birds compared to mammals
due to the presence of a nucleus which displaces part of the cytoplasm [1, 20].
Besides size and cytoplasmic hemoglobin concentration, RBC also differ in
specific structural characteristics. Only mammals have RBC without a nucleus.
U. Windberger and O.K. Baskurt / Comparative Hemorheology
269
Additionally, in animals other than mammals, a complex tubulin structure is present
which anchors to the plasma membrane and affects the specific shape of RBC [21-26].
Both nucleus and tubulin filaments increase cell stability against shear forces and lead
to a specific orientation of RBC in the flow field. In contrast, mammals including man,
have biconcave disc shaped RBC, and shear forces can induce greater modifications in
RBC shape (e.g., folding) than in other animals. Differences in the extent of shape
changes during various levels of shear stresses do exist among mammals, allowing
reduction of whole blood viscosity through this mechanism. As an exception, camelids
have a more intermediate status among the mammalian species. They do not have a
nucleus, however their RBC are spindle shaped and some authors report the presence
of a marginal band [27]. Such basic morphologic diversity between mammals and other
zoological classes are among the reasons for the pronounced differences found in RBC
deformability and aggregation.
These principal species differences influence both single RBC behavior and bulk
blood flow. However, the prediction of blood flow phenomena in a living animal using
in vitro viscometry or measurements of single cell properties is difficult because of the
impact of the vascular function and geometry on the organization or stabilization of
flow [14].
2. Specific Aspects
2.1. Mammals
Mammals are the most widely investigated zoological class due to their agricultural
and experimental use. Many mammals have been tested. However a list of
hemorheological values may never be complete, and although relevant differences
might exist even among relatives, common characteristics include the following
principles: mammalian RBC are non-nucleated hemoglobin-carrying biconcave disks
of various sizes; hematocrit varies from 30 to 50%; RBC aggregation and
deformability varies strongly among mammals.
2.1.1. Plasma and Whole Blood Viscosity
Plasma viscosity (PV) depends primarily on plasma protein concentration, indicating
that PV can vary in disease [28-30]. The highest PV within a group of 9 species was
found in cattle (mean: 1.72 mPa.s) and the lowest in rabbit (mean: 1.30 mPa.s) with
horse, cat, dog, pig, rat, mouse, and sheep being between 1.3 and 1.7 mPa.s. These
values are higher than those obtained for man by the same investigator [31]. Although
PV contributes to the value of whole blood viscosity (WBV), PV and WBV values do
not correlate between species. A species with low physiologic PV, compared to a
“standard” of human values, can have high values of WBV. For example, horse has an
increased WBV, however, its PV is less than cattle due to the high plasma fibrinogen
concentration in the latter species. This high PV in cattle, however, is accompanied by
a low WBV at low shear rates [31]. For further description of plasma protein
concentration and PV in animal species see Chapter II.2.
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Table 1. References for hemorheological values in healthy animals
Mammalian
Species
Non-Mammalian
Reference
Species
Reference
Birds
Horse
[31, 32, 37-50]
Chicken
[51-54]
Rat
[6, 31, 39, 47, 55-60]
Turkey
[4, 60, 61]
Cow
[31, 32, 44, 45, 47-50, 59]
Pigeon
[62]
Sheep
[4, 31, 32, 34, 47, 49, 50, 55,
63, 64]
Penguin
[65, 66]
Goat
[4, 34, 45, 47, 64]
Antarctic birds
[66]
Rabbit
[6, 31, 32, 45, 55-58, 60]
Reptiles
Pig
[31, 36, 47, 49, 50, 57, 63]
Turtle
[4, 60, 62, 67-69]
Mouse
[6, 31, 47, 55]
Snake
[60]
Hamster
[6, 47, 57]
Lizard,Crocodile
[70, 71]
Guinea pig
[6, 55, 56]
Amphibians
Gerbil
[58]
Bull frog
[4, 60, 67, 72-75]
Dog
[4, 6, 31, 34, 47, 55, 58, 63, 64,
76]
Toad
[77]
Cat
[31, 57, 58]
Fish
Elephant
[4, 32, 34, 47, 64, 78]
Trout
[18, 79-83]
Camel, Llama
[32, 47, 60]
Carp
[84, 85]
Seal, Whale
[19, 35, 36, 47, 66, 86-89]
Arctic, Antarctic
fishes
[90-92]
Zoo Animals
[32, 45, 47]
Congo eel
[4, 11, 60]
Primates
[32, 47, 93]
Other fishes
[94, 95]
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Table 2: Whole blood viscosity (mean and median values) of various mammalian species
Low
Shear
Viscosity
(mPa.s)
High
Shear
Viscosity
(mPa.s)
Low/High
Shear Rate
(s-1)
Hct
(%)
T1
(°C)
Device
Ref.
Cat (median)
30.2
4.4
0.7 / 94
40
37
LS302
[31]
Cattle (mean)
6.7
5.8
1 / 150
30
20
OCR-D3
[50]
Cattle (mean)
5.4
3.6
0.277 / 128
35
37
LS30
[32]
Cattle (median)
6.6
4.8
0.7 / 94
40
37
LS30
[31]
Deer (mean)
45
4.7
0.277 / 128
42
37
LS30
[32]
Dog (mean)
10.4
5.7
1 / 150
37
20
OCR-D
[50]
Dog (median)
62
5.3
0.277 / 128
50
37
LS30
[76]
Dog (median)
22.9
5.6
0.7 / 94
40
37
LS30
[31]
28.3
5.4
0.7 / 94
37
37
LS30
[78]
53
5.6
0.277 / 128
43
37
LS30
[32]
Horse (mean)
93
4.4
0.277 / 128
41
37
LS30
[32]
Horse (mean)
12.8
6.5
1 / 150
44
20
OCR-D
[50]
Horse (median)
38.2
5.2
0.7 / 94
40
37
LS30
[31]
Horse (mean)
8.3
4.0
5.75 / 230
40
37
Brookfield
DV-II4
[37]
Goat (mean)
5.1
3.4
0.277 / 128
31
37
LS30
[32]
Mouse (median)
13.4
4.9
0.7 / 94
40
37
LS30
[31]
Pig (mean)
14.3
7.2
1 / 150
45
20
OCR-D
[50]
Pig (median)
24.7
4.9
0.7 / 94
40
37
LS30
[31]
Rabbit (mean)
12.4
3.8
0.277 / 128
40
37
LS30
[32]
Rabbit (median)
8.3
4.0
0.7 / 94
40
37
LS30
[31]
Rat (median)
35.4
6.3
0.7 / 94
40
37
LS30
[31]
Sheep (mean)
4.4
3.9
1 / 150
31
20
OCR-D
[50]
Sheep (mean)
5.0
3.3
0.277 / 128
36
37
LS30
[32]
Sheep (median)
6.6
4.4
0.7 / 94
40
37
LS30
[31]
Human (median)
33.5
6.0
0.7 / 94
40
37
LS30
[31]
Species
African elephant
(median)
Asian elephant
(mean)
1
Measurement temperature
LS-30 Couette viscometer (Contraves GmbH, Zurich, Switzerland)
Oscillating Capillary Rheometer and Densitometer OCR-D (Paar GmbH, Graz, Austria)
4
Brookfield DV-II cone-plate viscometer (Brookfield Engineering Laboratories Inc., Stoughton, MA)
2
3
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Table 3. Plasma viscosity (mean and median values) of various mammalian species
1
Plasma
Viscosity
(mPa.s)
Device
T1
(°C)
Reference
Cat (median)
1.7
OCR-D
21
[31]
Cattle (mean)
2.5
OCR-D
20
[50]
Cattle (mean)
1.9
Capillary2
20
[41]
Cattle (median)
1.7
OCR-D
21
[31]
Deer (mean)
1.3
LS30
37
[32]
Dog (single value)
1.1
Coaxial2
37
[4]
Dog (median)
1.6
OCR-D
21
[31]
Dog (mean)
1.6
OCR-D
25
[96]
African elephant (median)
1.9
OCR-D
21
[78]
Asian elephant (mean)
1.6
LS30
37
[32]
Horse (mean)
1.5
LS30
37
[32]
Horse (mean)
1.5
Capillary2
20
[41]
Horse (median)
1.7
OCR-D
21
[31]
Horse (mean)
1.6
OCR-D
21
[97]
Goat (mean)
1.6
LS30
37
[32]
Mouse (median)
1.3
OCR-D
21
[31]
Pig (median)
1.6
OCR-D
21
[31]
Rabbit (mean)
1.1
LS30
37
[32]
Rabbit (median)
1.3
OCR-D
21
[31]
Rat (mean)
1.0
Harkness3
37
[98]
Rat (median)
1.6
OCR-D
21
[31]
Sheep (mean)
1.8
OCR-D
20
[50]
Sheep (median)
1.5
OCR-D
21
[31]
Sheep (mean)
1.6
OCR-D
25
[96]
Human (median)
1.2
OCR-D
21
[31]
Measurement temperature
Custom made device [41]
3
Harkness viscometer (Coulter Electronics Ltd., England, UK)
2
U. Windberger and O.K. Baskurt / Comparative Hemorheology
273
Viscometric data from a wide range of animals have been presented by Johnn, et
al. [32], with other authors describing smaller numbers of species (see Table 1). Whole
blood viscosity is strongly and directly related to hematocrit and is inversely related to
temperature in species, but relations between species vary. For example, in some
animals living in a cold environment (e.g., bowhead whales), WBV does not increase
with decreasing temperature to the extent that would be expected for human blood [33].
WBV increases with hematocrit but the degree of viscosity increase with hematocrit is
species specific, especially at low shear rates [34]. Apparent whole blood viscosity of
mammalian blood shows shear thinning behavior, but the effect is low in animals with
low aggregation such as goat, sheep, and cow. In vitro WBV at low shear rate (0.7 s-1)
is in the range of 6-7 mPa.s (40% hematocrit, 37oC) in these species. In contrast, horse,
donkey, and zebra show pronounced shear thinning and increased low shear blood
viscosity due to their “hyper-aggregating” blood. Their WBV at low shear rate is in the
range of 38-40 mPa.s [31, 32]. Other extreme diversities in whole blood viscosity
include phocid seals [35, 36] (see below). Most other mammalian species have WBV
between the values for horse and goat. A ranking from data presently known can be as
follows: equines> felines> chimpanzee> elephant> rat> deer> bison> mouse> rabbit>
cattle> sheep> goat> camel (For references see table 1). Please note that the absolute
values can sometimes not be directly compared due to the different devices used for the
measurement by different laboratories. Table 2 and 3 give insight into species
differences of whole blood and plasma viscosity values in mammals.
2.1.2. RBC Deformability
RBC deformability data from a wide range of animals have been presented by Smith, et
al. [47]. However, due to the variability of RBC size and shape between species, values
for the term “deformability” are difficult to compare because these size and shape
influence the measurement outcome. Using small (§ 1 μm) micropipettes it is possible
to measure membrane mechanical properties (e.g., shear elastic modulus, apparent
viscosity), while larger (§ 3-5 μm) micropipettes allow aspiration of the entire cell and
hence a measure of cellular deformability (e.g., entry time at a given aspiration
pressure). It is of interest to note that membrane measurements made using small
pipettes are insensitive to cell size, whereas cellular deformability measurements via
complete cell aspiration depend strongly on the sizes of the micropipette and the cell.
There are other methods to measure deformability, including cell elongation at various
shear stresses (e.g., laser diffractometry) [47, 78, 96] or RBC capillary entry and transit
time (e.g., automated filtration method) [55, 57, 64, 76]. For example, with laser
diffractometry, RBC elongation rises with the deforming force and is characterized by
a specific elongation index (EI) – shear stress relationship for each species; increased
elongation at a given shear stress means increased deformability (Figure 1).
Figure 1 demonstrates that five species (rabbit, mouse, hamster, rat and pig) have
more deformable RBC than the other species included in this study. It is also clear that
horse and elephant RBC are the least deformable in this group, with dog RBC having
an intermediate degree of deformability. Sheep RBC exhibit unique behavior with
significantly lower EI values at the higher shear stress range; note that at such high
shear stress levels, elongation indexes appear to be reaching a maximum for most
species. Such a behavior may reflect the exceptionally small size of sheep RBC
compared to other species included in this study.
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U. Windberger and O.K. Baskurt / Comparative Hemorheology
0.7
Elephant
0.6
Horse
0.5
Dog
EI
0.4
Rabbit
0.3
Mouse
0.2
Hamster
0.1
Rat
Pig
0.0
1
-0.1
10
100
Sheep
SS (Pa)
Figure 1. RBC elongation indexs (EI) versus shear stress (SS) data obtained via ektacytometry for
nine species. EI is calculated from the diffraction image as the (length-width)/(length+width) of the
image.
Table 4. RBC elongation indexes (EI) measured at a shear stress of 5.38
Pa, calculated shear stress needed for one-half maximal deformation
(SS1/2), and mean cell volume (MCV) values for nine species. Data should
be regarded as preliminary since sample size varies among species.
Species
EI at 5.38 Pa
SS1/2 (Pa)
MCV (fL)
Hamster
0.448
2.46
47
Mouse
0.447
1.91
46
Rabbit
0.447
1.81
57
Rat
0.446
2.82
47
Pig
0.419
3.52
51
Dog
0.381
5.90
63
Horse
0.279
12.7
42
Elephant
0.238
7.71
138
Sheep
0.293
3.68
32
Since RBC elongation index-shear stress curves actually represent several pairs of
EI-stress data, (see Chapter II.6), it is difficult to provide a single index for
deformability. However, various methods have been described to derive such a
parameter by calculating the shear stress for half-maximal deformation (SS1/2) of the
cell population [100]. SS1/2 values for the EI-shear stress curves shown in Figure 1 are
presented in Table 4. It is also obvious from these values that, compared to the other
species, elephant and horse RBC require higher shear stresses to reach half of their
maximum deformation; this shear stress was 3- to 6-fold higher for elephant and horse
RBC. RBC deformability of some animals (e.g., camel, llama, bank vole Myodes
glareolus) cannot easily be measured using ektacytometry since RBC orientation is not
U. Windberger and O.K. Baskurt / Comparative Hemorheology
275
always aligned with the shear field. Rather, these cells tend to tumble and/or become
perpendicular to the lines of flow (unpublished observation). The reason for these
observations has not yet been investigated in detail, but most likely relates to the nonbiconcave shape of these cells.
To investigate factors involved in RBC deformability, some membrane
components have been tested in various species. Modifications of RBC membrane
content or the function of band 4.2 and band 3 proteins have been associated with RBC
shape changes [101, 102]. Percentages of band 4.2 protein have been shown in a large
number of species by Guerra-Shinohara and de O’Barretto [103]. Band 4.2 protein was
found to be absent in horse, guinea pig and two rodents of this study. The deficiency of
band 4.2 in horse was associated with the high appearance of echinocytes in this
species [39]. Band 3 has also been investigated in camelids and the rotational and
lateral mobility of the membrane domain of the protein has been found to be decreased,
and a tight and close connection of the cytoplasmic domain to ankyrin has been
observed [104, 105].
Membrane phospholipids [63] and glycosphingolipids [106] differ among some
species, but the role of dietary fatty acid intake on RBC membrane lipid content in this
context is not conclusive. The quantity of unsaturated fatty acids in the RBC membrane
of sheep has been observed to be twofold higher than in pig and horse [107]. This
finding is surprising since sheep RBC have a lower elongation at high shear stress and
a high concentration of unsaturated fatty acids of membrane phospholipids which
should make the membrane more deformable. This discrepancy most likely reflects the
several factors that affect RBC deformation in a shear field: membrane mechanical
properties that are mainly determined by the membrane skeletal network and not by
membrane lipid composition, surface area to cell volume ratio, and cytoplasmic
viscosity. In another study in guinea pigs, RBC deformability remained unchanged in
spite of a 50% decrease of membrane cholesterol after statin treatment [108]. Such
studies indicate that differences in membrane lipid structures do not explain species
specific differences in RBC deformability satisfactorily. A better insight would be
provided by a systematic investigation of membrane skeletal proteins and their linkage
to membrane proteins.
2.1.3. RBC Aggregation
RBC aggregation depends on cell deformability since it requires the formation of
parallel membrane surfaces; poorly deformable RBC such as those containing a
nucleus do not aggregate and thus almost all studies have been conducted using
mammalian cells [58]. Values of aggregation range from a “hyperaggregating” group
of animals (e.g., equine, rhinoceros), to a medium type (e.g., primates, pig, carnivora,
many ruminants, elephants, rabbit), and to a “no” aggregation type group (e.g., cow,
sheep, goat, camelids, rodents). However, as expected, exceptions will be found in
future (see Table 1). Phocid seals show very unusual aggregation and will be discussed
later. Interestingly, domestic bovines have very low, essentially non-measurable RBC
aggregation in contrast to some wildlife relatives [32].
The diverse aggregation of cow, sheep, and goat against horse, donkey and zebra
has been known for many decades [2]; aggregation in horse is so intense that even
echinocytes are included into rouleaux [40]. Reasons for this diverse aggregation
behaviour include variations in RBC deformability and membrane surface properties
[109-111] as well as quantitative and qualitative differences in the plasma protein
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concentrations [37, 112]. A comparative study on cow, horse, and man recently
showed a reduction of depletion layer thickness in cow, which could, according to the
depletion model of aggregation (see II.4.b), explain the low aggregation of this species
[41].
In comparing two species that reflect mammalian extremes of aggregation – horse
and goat – one can postulate that in goat the distribution of RBC among a transverse
section of the vessel should be more homogenous [113, 114]. Goat blood is more
susceptible to turbulent flow due to the lower WBV which increases the Reynolds
number [115]. This may be important for engineering studies where high Reynolds
numbers are achieved, for instance during studies with mechanical devices for cardiac
assist or for experimental vascular surgery. Formation of a marginal cell-free layer is
decreased in non-aggregating blood and near-wall shear stress should be higher for this
reason. However, one should be careful in applying results obtained in glass capillaries
to in vivo conditions, since glass capillaries are over-simplified models of the
circulatory system [116]. In contrast, in horse blood the parabolic velocity profile is
expected to be blunted and the rate of axial migration is increased in vertical tubes. The
readjustment of axial migration after junctions and branching should be quicker
depending on the aggregation kinetics and tube geometrics; flow partitioning at
bifurcations might be increased.
There have been suggestions in the literature that athletic species are characterized
by higher RBC aggregation [121]. This is true for certain species such as horse, dog,
cat and antelope. However, although rodents are amongst the most active species, they
have low RBC aggregation compared to larger athletic species. Again, one can
speculate that this lower aggregation in rodents is consistent with shorter blood vessel
lengths (i.e., body size) which prevent full development of RBC aggregates within a
given vessel segment, thereby countering any hemodynamic advantage expected from
RBC aggregation-related phenomena. In contrast, it is not possible to understand the
physiological meaning of the absence of RBC aggregation in domestic bovine. The
animal kingdom is full of extreme variability in RBC aggregation, even within a given
species. For example, ringed seals blood exhibits no measurable aggregation while
Weddell seals have very high RBC aggregation [35]. It follows from the above
discussion that neither athletic capacity nor body size variations may fully explain the
variations in RBC aggregation among species.
2.1.4. Unusual Mammalian Species
2.1.4.1. Camelids
Camel, dromedary, and llama have a low hematocrit resulting in a low whole blood
viscosity [32], and their RBC aggregation is low (unpublished observation). Camelid
RBC withstand high fluctuations of osmotic pressures during dehydration and rapid
rehydration as a result of their adaptation to desert environments [122]. They also are
resistant to metabolic depletion [104]. Camelid RBC are small, elliptical discs [47, 123,
124] that have an increased thickness in the central region in contrast to other mammals
which show central depressions. Hemoglobin is homogenously distributed inside the
cytoplasm with binding sites on band 3 protein, or, alternatively, is concentrated in
crystals inside llama RBC [124]. Studies on camelid RBC membranes [125] in order to
determine their principal properties have been carried out for some time. Key findings
include: 1) RBC membranes of llama have increased amounts of sialic acid, and their
glycoproteins differ qualitatively from human RBC membranes [104]; 2) Spectrin and
U. Windberger and O.K. Baskurt / Comparative Hemorheology
277
band 4.2 concentrations are equivalent to man [103], however, band 3 protein is
increased threefold [104]; 3) The rotational and lateral mobility of band 3 is decreased
even if parts of the membrane cytoskeleton are removed; 4) Band 3 protein has a tight
and close connection to ankyrin and peripheral membrane proteins [105]; 5) Parts of a
marginal band have been found [27]; 6) RBC deformability is different from other
mammals due to structural reasons. However, further studies are still necessary to
clarify the mechanism by which membrane rigidity is elevated in camel RBC.
2.1.4.2. Marine Mammals
Most knowledge in the field of hemorheology of this group of species has been
obtained from seals. During submergence, characterized by apneic exercise with
increased environmental pressure and decreased temperature, the cardiovascular
adjustment and redistribution of blood flow in seals involves increased peripheral
resistance and reduced cardiac output [126], termed the dive response. As an adaptation
to long-term apnea, resting hematocrit, MCHC, MCV, and total blood volume are
increased [88, 127]. To overcome the body’s O2 demand during apnea, hematocrit
increases further and can reach to values of 70% when the animal is diving. Although
the spleen contributes to RBC storage effectively, time constants for hematocrit
increase and splenic contraction favor the assistance of the hepatic sinuses for RBC
delivery into the venous circulation [128]. The physiological polycythemia and the
enhanced RBC hemoglobin concentration increase WBV and RBC density. The value
of WBV increases with the hematocrit, however, the rise is lower than expected from
terrestrial animals. O2 transport capacity is improved for this reason [35, 88, 89].
During a dive, shear forces are reduced which affects WBV remarkably if RBC
aggregation is present. Indeed, RBC aggregation reaches high values in Weddell seals,
sometimes exceeding even those obtained for horse [19]. This high aggregation
develops shortly after birth of pups [35]. RBC aggregation varies extremely between
the species and can be ranked as follows: ringed seal < elephant seal < Weddell seal,
with ringed seals showing no detectable RBC aggregation or blood sedimentation. A
potential benefit of a high RBC aggregation as in Weddell seal or of “no” RBC
aggregation like in the ringed seal cannot be elucidated as yet and need further
investigations. The role of the more unsaturated fatty acid content in RBC membrane
phospholipids in elephant and fur seals compared to man might indicate some trend
toward increased RBC deformability [129].
Blood viscosity and RBC aggregation were also investigated in bowhead whales.
These marine mammals also have high RBC aggregation both in autologous plasma
and standard aggregation media [35]. In contrast, WBV was found to be lower than
human samples when the hematocrit was adjusted to 50% for both species [33].
Additionally, bowhead whale blood exhibited significantly less temperature
dependence compared to human blood, with smaller increments in WBV as the
measurement temperature decreased to 5 °C [33].
2.2. Hemorheology of Other Vertebrates
Non-mammalian RBC differ structurally from mammalian cells. They contain a
nucleus and most authors found a microtubular bundle connected to a membraneassociated cytoskeleton called a marginal band [3]. RBC are larger, elliptical, resistant
to bending, and blood cell count is decreased. Nucleated RBC are believed to exhibit
no aggregation [4, 58] although viscometric data show some degree of shear-thinning
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[62, 68, 69] which might be explained by some deformability and orientation of RBC
under flow conditions. Studies with duck blood in glass tubes showed non-alignment
between RBC and the axis of the tube [130]. This deviation was reduced at smaller
tube diameters indicating better alignment with the streamlines. The authors concluded
that the instability of cell orientation during blood flow may lead to an increase of
viscous resistance. RBC membrane rigidity is considerably greater [18, 60, 99],
although it is not clear which structures of the cell membrane are actually resisting
deformation. Additionally, the nucleus is a relevant factor causing poor RBC
deformability. Temperature of the environment and some forms of stress following
adrenergic stimulation or hypoxia may decrease RBC deformability [3, 131].
The marginal band has been described in more detail in birds; it is found at the
equator, near to the plasma membrane, in one plane only [21]. No microtubules were
observed between the nucleus and the position of the marginal band in RBC of adult
animals. The microtubules, whose main proteins are tubulins, curve with the profile of
the cell. The number of microtubules in a RBC differ significantly among species, and
has been found to vary with the size of the RBC [22]. Since polymerized actin colocalizes with the marginal band, an interaction between actin filaments and
microtubules may exist [23, 24]. The response of intact marginal bands to bending,
stretching and microtubule polarity has been tested in some amphibia [25, 26].
Blood viscosity in poikilotherm species is not a fixed value, but varies with the
animal’s body temperature [67]. Therefore, the temperature dependence of whole blood
and plasma viscosity, as well as other hemorheological values, are of interest in species
adapted to low environmental temperatures. Since warming of such blood may damage
red cells [18] by RBC swelling [83], comparative measurements should be made at a
lower temperature. For a summary of literature containing hemorheologic data from
non-mammalian vertebrates see table 1.
2.2.1. Birds
Avian RBC are spherical, lenticular, and somewhat flattened to produce an equator.
They are able to deform in a specific way by folding along their major axis [130] and
to orient in a shear field. The nucleus contains approximately 20% of the cytoplasmic
volume; the cytoplasmic hemoglobin concentration is about 15-20% greater [1, 132]
when compared with mammalian RBC and hence there is an increase of RBC density
[20]. Hematocrit is lower than most mammals and hence blood viscosity is reduced;
the reduction in WBV with increasing shear rate is very low in chicken blood
compared to mammals. During disease [51, 133], and during development [54], blood
and plasma viscosity values change as a result of variations of the animal’s hematocrit
and plasma protein concentration. In broilers, a diurnal variation of whole blood
viscosity was observed, influenced by the variation of environmental temperature and
food and water intake [134]. Deformability of avian RBC is decreased compared to
mammals [52, 130, 132], and differences in RBC rigidity is likely to exist between
avian species since a difference has been found between layer and broiler chickens
[53]. Despite relevant functional differences between avian and mammalian RBC, an
adequate tissue O2 supply has to be maintained in birds, since they have high metabolic
rates which often exceed those of mammals.
U. Windberger and O.K. Baskurt / Comparative Hemorheology
279
2.2.2. Reptiles
Reptiles are poikilotherm animals, except for some metabolic intermediate species;
tissue perfusion varies therefore in association with changes in ambient temperature.
Blood viscosity may have a special effect on heat exchange by modulating skin blood
flow in reptiles [67]. Hematocrit and mean cellular hemoglobin (MCH) are lowered,
possibly associated with a reduced metabolic need of this group [1]. Whole blood
viscosity is therefore lower than in mammals. Viscosity values vary with temperature
[67, 70], however, a drop in temperature does not elevate viscosity as much as in
mammals [62]. WBV in the painted turtle (Chrysema picta) is a function of body
temperature: 3.5 mPa.s at 10 oC and 1.5 mPa.s at 45 oC [67]. In other turtles, plasma
viscosity was found to be 1.32 mPa.s in Mauremys leprosa [62]. Others found blood
viscosity values of Trachemys scripta at 20% hematocrit and 5 oC of 9-12 mPa.s [68].
Blood viscosity is also decreased in Chelonia mydas hatchlings despite similar
hematocrit values [69]. RBC deformability is decreased compared to mammals and
values of RBC membrane shear elastic modulus are presented by Waugh [60].
Turtles are interesting species in view of their cold adaptation during hibernation.
In Trachemys scripta, hematocrit is essentially maintained during cool room
adaptation, leading to an increase in blood viscosity. However, hematocrit standardized
values of blood viscosity were lower in cold adapted than in room adapted animals[68].
During hibernation of Sternotherus odoratus submerged in water at 5 oC for five
months, hematocrit increased but WBV did not as might be expected based on the
hematocrit increase [135], thus indicating a possible adaptation to lower temperature.
2.2.3. Amphibians
Blood viscosity of frog and toad show hematocrit (r=0.93) and temperature (r=0.96)
dependency as in other species [67, 75, 77], with the temperature dependency of blood
viscosity in the bullfrog reported to resemble that in mammals [73]. Blood viscosity
was reported to vary between 2.5 (toad at 27oC) [72] and 4 mPa.s (bullfrog at 5oC and
150 s-1) [74]. In vivo hematocrit varies with the environmental temperature, leading to a
seasonal variation in blood viscosity. Experimental data on American bullfrog showed
that hematocrit and RBC count increased when the temperature of the animals´
environment was decreased to 5oC, whereas MCV decreased under these
circumstances. In this circumstance hematocrit and blood viscosity did not vary
significantly, however, mean viscosity values, measured at native hematocrit, increased
slightly [74]. The relevance of blood viscosity for blood flow has been investigated for
toads: systemic blood flow decreased as WBV increased. [77] However, general
anesthesia during such studies might modify regulatory processes that maintain blood
flow.
2.2.4. Fish
Fish RBC are elliptical cells which bulge in the region of their nucleus. The largest
RBC volumes can be found in this class [4]. An excess of surface area is present which
enables RBC to enter small capillaries of 3μm diameter. However, the shear elastic
modulus was reported to be significantly higher for fish RBC and capillary entry time
and transit time is increased significantly compared to man [18]. Hematocrit in fishes
drops with water temperature, but it is believed that the O2 demand is satisfied due to
the increased O2 concentration in cold water and the reduced metabolic need of the
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animal in a cold environment. This hematocrit dependency on temperature should lead
to diversities in blood viscosity of fishes living at different regions. Some studies
focused on RBC deformability, and showed that membrane rigidity in trout was
dependent on the temperature [18]. In temperature-acclimated trout, however, pipette
entry time of RBC membranes has been shown to be maintained [92].
A special focus in fish hemorheology is the blood and plasma viscosity of ice
fishes. These animals live at an environmental temperature down to -2 qC which should
result in high viscosity values. However, some of these fish have blood with a very low
cellular content which thus lowers viscosity. Antarctic ice fish show an increase of
whole blood viscosity with a temperature drop from 5 to -1oC, with the thermal
sensitivity of WBV in fish being reduced compared to man. Blood of white-blooded
(i.e., almost no red blood cells) fish (Chaenocephalus kathleenae) showed nearly
Newtonian behavior [92], and the plasma viscosity of C. aceratus was comparable to
human plasma at low temperatures. Plasma viscosity of another Antarctic ice fish with
low hematocrit (7.5%) and low MCHC, Notothenia sp., was significantly lower than
the value of Chaenocephalids; however, its blood viscosity was increased due to the
presence of blood cells [90].
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