WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Mandal.
World Journal of Pharmacy and Pharmaceutical Sciences
SJIF Impact Factor 6.041
Volume 5, Issue 6, 2165-2184
Review Article
ISSN 2278 – 4357
RHEOLOGY OF BLOOD: BIOPHYSICAL SIGNIFICANCE,
MEASUREMENT, PATHOPHYSIOLOGY AND PHARMACOLOGIC
THERAPY
*Dr. Manisha Mandal
Department of Physiology, MGM Medical College and LSK Hospital, Kishanganj,
Bihar-855107, India.
Article Received on
19 April 2016,
ABSTRACT
Viscosity is a very important biophysical factor affecting blood flow
Revised on 09 May 2016,
Accepted on 29 May 2016
and normal circulation and an unusual rise in blood viscosity is closely
DOI: 10.20959/wjpps20166-6985
associated with the progression of many chronic diseases, including
cerebrovascular and cardiovascular disease, diabetes, polycythemia,
*Corresponding Author
vascular dementia, Alzheimer’s, and other disorders. Measurement and
Dr. Manisha Mandal
improving blood viscosity lead to improvements in diseased conditions
Department of Physiology,
and provide direction for therapeutic interventions. Measurement of
MGM Medical College
blood viscosity at different stages of disease during treatment that
and LSK Hospital,
Kishanganj, Bihar855107, India.
control it is essential for monitoring the effectiveness of treatments and
determining the correlations between hemorheological parameters and
other clinical parameters is pertinent to the diagnosis of the disease and
to understand the mechanism of action. Thus it is essential to have a better understanding of
the fundamental concepts related to the rheology of blood, role of viscosity in physiology,
principles of blood viscosity measurement as an important component of patient
management, and pathophysiological conditions associated with hemorheological alterations.
The purpose of the present communication is to present a review on the facts and
phenomenon on the importance of viscosity in disease states, the affecting factors, and the
clinical methods of measurement based on the search of electronic database on research
papers in SCI and non SCI journals.
KEYWORDS: Hemorheology; Biophysical significance; Alterations; Measurement.
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INTRODUCTION
Viscosity is an intrinsic property of fluid related to the internal friction by virtue of which it
opposes the relative motion between its adjacent layers sliding past one another. The factors
affecting blood viscosity are hematocrit, erythrocyte deformability, erythrocyte aggregation,
shear rate, temperature, plasma viscosity and composition[1] and understanding these factors
are essential to understand the correlation between anomalous blood viscosity and disease
states. The implication of abnormal blood viscosity in the pathogenesis, development, and
prognosis of cardio-cerebrovascular disease, diabetes, hemorrhagic shock, cognitive
dysfunction and other diseases received considerable attention in recent decades with the
development of hemorheological theory with emphasis on manipulation of blood viscosity
for disease prevention and treatment.[2] Although there are conventional methods of
measuring viscosity and yield stress of materials but there is a scarcity of information on
rheometers that are uncomplicated and suitable for clinical application as practical automated
or semiautomated techniques. The viscosity at which symptoms related to hyperviscosity
syndrome develop is inconsistent, but they seldom appear below a serum or plasma viscosity
of 3 cP.[3] An accurate measurement of blood viscosity is important for the clinical
management of patients prone to hyperviscosity syndrome. Measurement and improving
blood viscosity should lead to improvements in diseased conditions and provide direction for
therapeutic interventions. Measurement of blood viscosity at different stages of disease
during treatment that control it is essential for monitoring the effectiveness of treatments and
determining the correlations between hemorheological parameters and other clinical
parameters is pertinent to the diagnosis of the disease and to understand the mechanism of
action.
The purpose of the present communication is to present a review on the facts and
phenomenon on the importance of viscosity in disease states, the affecting factors, and the
clinical methods of measurement based on the search of electronic database on research
papers in SCI and non SCI journals.
VISCOSITY: BIOPHYSICAL PROPERTIES OF BLOOD
Fluids displaying a constant viscosity regardless of flow rate are called Newtonian fluids for
which a straight line relationship between shear stress and shear rate at a given temperature
with a constant slope known as the viscosity of the fluid that is independent of shear rate, is
obtained. Water, air, ethanol, benzene, glycerol, blood plasma are Newtonian fluids.
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Newtonian fluids obey the following equation of Newton’s law of viscosity
, where μ
is the shear rate.[4] One centipoise, 1 cP (= 10-3 Pa·s or 1
is the Newtonian viscosity and
mPa·s), is approximately the viscosity of water at room temperature.
Fluids that change viscosity in response to varying flow rates are called non-Newtonian fluids
for which the slope of shear stress versus shear rate curve is not constant. Whole blood
behaves as a non-Newtonian fluid.
Model equations of non- Newtonian fluids
The behavior of non-Newtonian fluids can be expressed with the help of several model
equations:
Power-law Model
The apparent viscosity η of Non-Newtonian fluid obeying power law relationship between
shear stress and shear rate is given by,[4]
, where m, is a measure of the
consistency of the fluid and n is a measure of the degree of non-Newtonian behavior. The
power-law model does not have the capability of handling Newtonian regions of shearthinning fluids at very low and high shear rates.
Cross Model
The cross model relates shear stress with viscosities at very low and high shear rates with the
help of the following equation,[5]
Viscoplastic Fluid
Viscoplastic fluid is a type of non-Newtonian fluid which will flow when a shear stress
exceeding a critical value known as the yield stress is applied. Examples of viscoplastic fluids
are blood, drilling mud, toothpaste, grease. This yield stress is required to break up the
cohesive forces due to van der Waals-London and coulombic interaction between RBCs.[6]
Casson Model
The flow behavior of viscoplastic fluids such as blood containing solid and liquid phases is
described by Casson model,[5] originally introduced for pigment-oil suspensions which
accounts
for
both
yield
when
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stress
and
when
shear-thinning
non-Newtonian
viscosity,[6]
, where k is a Casson model constant.
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Herschel-Bulkley Model
The original power-law model and its modification is used to describe yield stress as follows,
when
when
, where m and n are model constants.[7,8]
Rheology of blood
The rheology, i.e. flow behavior of blood is based upon its non-Newtonian, shear thinning,
and biphasic nature that constitute RBC (99% of cellular elements) as the solid phase and
plasma as the liquid phase. Hemorheologic parameters include whole blood viscosity, plasma
viscosity, aggregation, and deformability of RBCs.[9] The hematocrit and serum fibrinogen
are the two most important determinants of blood viscosity with a direct effect on its increase
with increase of the either of the former variables within physiologic ranges.[10] Within the
range of 35% to 55% hematocrit, its relationship with blood viscosity is logarithmic.[11]
At low shear rate, due to the presence of fibrinogen and globulin, RBC cluster together to
form reversible aggregates known as rouleaux that increase the particle size which causes
distortion of the streamline flow of blood and increased frictional resistance between them,
thereby increasing blood viscosity. [11] The energy dependent tumbling movement of rouleaux
also causes distortion of the streamline flow of blood that causes increase in blood
viscosity.[12] At high shear rates, disaggregation of the clusters of RBC take place thereby
reducing the viscosity of blood. Deformability or rigidity is the reversible ability of RBC to
take up a new structure in response to applied forces. At high shear rates, the RBCs tend to
move along the streamline flow thus causing reduction of friction between the layers thereby
decreasing blood viscosity. Normal blood remains fluid even at a hematocrit of 98%, on
account of the deformability of its RBCs.[12] The reversible phenomenon of dispersal and
reformation of the clusters of aggregates of blood is of potential importance in the
microvascular pathophysiology of ischemic and vasospastic disorders because blood behaves
like a weak percolating physical gel at low shear rates.[13]
In addition to non-Newtonian viscosity, blood also exhibits a yield stress (Ys) which is the
force required to start movement in a stationary column of blood with existing van der
Waals-London forces and Coulombic forces among themselves.[14] The Ys value of human
blood is 0.05 dyne/cm2 within a temperature range of 10 0C to 37 0C.[15,16] The relationship
between Ys value, fibrinogen concentration and hematocrit level is represented by the
equation, Ys = 13.5 (10-6) Cf 2 (H-6)3, where Cf is the fibrinogen concentration in gm% and H
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is the hematocrit.[10] The interaction of Ys of whole blood was different with varying levels of
hematocrit H.[17] Below 50% H, the yield value
, where A is a constant in the units of dynes1/3 Hc is
following equation,
the critical H at which
was correlated to hematocrit H by the
first appears. Above 50% hematocrit, the yield value is correlated to
hematocrit by the equation,
, where D and B are constants. Under a nontrivial
spatiotemporal organization of blood elements involving confined linear shear flow is
reported to trigger ample oscillations of the normalized value of blood viscosity given by,
as a function of hematocrit ϕ where
=solvent viscosity.[18]
Blood also exhibits the phenomenon of thixotropy which is time dependent and arises due to
aggregation of RBC. Viscosity of a solution increases when the solute molecules interact
strongly with one another to form aggregates. With increasing shear rate and/time, dispersion
and formation of RBC aggregates occur which influence the rate of blood flow. Blood
thixotropy is observable on account of the relatively long time taken by RBCs to stabilize
following a rapid change in the rate of flow.[19] The revival of quiescent structure occurs in
about 50 s while the high shear rate structure is achieved in few seconds.[9]
Temperature has a remarkable effect on the viscosity of both whole blood and plasma. With a
decrease in temperature, viscosity of a fluid increases as a result of decrease in kinetic energy
of molecules required to overcome the resistance due to intermolecular attractions and also to
disrupt the intermolecular hydrogen bonds of associated liquid.[20] At low temperatures,
whole blood viscosity increases due to reduced RBC deformability in blood and increased
plasma viscosity.[16] For each 1 0C reduction in temperature, blood viscosity rises about 2%
and blood viscosity measurements are preferably carried out at body temperature of 37 0C.[16]
Viscosity also depends on the size, shape, flexibility and rotational diffusion coefficient of
the constituent molecules of the fluid. Fluids containing large, elongated molecules exhibit
high viscosity. The radius of gyration
of the constituent macromolecule provides an
estimation of the shape of the molecule that in turn affects viscosity. When
the macromolecule is spherical. When
is
is
of radius,
, the macromolecule is rod shaped where
the length of the rod is large compared to its diameter. When
is
, where
is
is the mean
square end to end distance.
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ROLE OF VISCOSITY IN PHYSIOLOGY
Under physiological conditions, shear stress, the frictional force generated by blood flow,
controls the orientation of endothelial cells in the direction of flow, is dependent on velocity
gradient across the vessel wall, local blood viscosity and affects arterial remodeling. [2] Blood
viscosity not only controls endothelial shear stress, but also diminishes peripheral vascular
resistance and enhances blood flow to the lower extremities thus preventing initiation and
progression of atherosclerosis in peripheral arterial disease.[21]
Under pathological conditions, acute shear stress decreases the arterial diameter through
endothelial dysfunction with decreased liberation of nitric oxide, endothelin-1, prostacyclin,
prostaglandin I2; activation of transcription factors nuclear factor (NF)kB, c-fos, c-jun, SP-1;
activation of transcriptional genes, such as ICAM-1, MCP-1, tissue factor, platelet-derived
growth factor-B, transforming growth factor-β1, cyclooxygenase-II, and endothelial nitric
oxide synthase, along with increased production of reactive oxygen species, fibrinogen,
immunoglobulins, augmented hematocrit, leading to aberrantly increased blood viscosity in
the circulation.[22]
Rosenson et al (1996) evaluated hemorheological profiles in terms of viscosity measurement
of blood, plasma, and serum with coaxial cylinder microviscometer in order to predict
clinical manifestations of atherothrombotic vascular disease; they showed blood viscosity
(3.26 mPa.s, 4.37 mPa.s, and 5.46 mPa.s, at shear rates of 100 s-1, 50 s-1, and 1 s-1
respectively) correlated inversely with HDL cholesterol and positively with fibrinogen;
plasma viscosity (1.39 mPa.s) correlated with fibrinogen, total serum protein, and triglyceride
concentrations whereas serum viscosity (1.27 mPa.s) correlated with total serum protein and
LDL cholesterol.[11]
Analysis of the viscoelastic components of blood complex viscosity indicating significant
increase of both components accompanied by an increase of erythrocyte aggregation and
decrease of deformation may lead to creation of unordered packets of erythrocytes which can
result in hindered blood flow as has been shown for a group of patients with circulation
disorder involving ischemic stroke and myocardial infarction, however the hematocrit values
in both groups were not significantly different thus excluding the influence of hematocrit
value on the estimated rheological parameters.[23]
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Jebens E. H. and Monk-Jones (1959) using capillary viscometer reported decrease of
viscosity with age of normal synovial fluid from human knee joints which is significantly
higher than that of the traumatic and osteoarthritic groups.[24] The synovial fluid functions as
a nutrient fluid for joint cartilage and also as a lubricant to enable movement to take place
between the cartilaginous surfaces. The velocity of joint movement generally decreases with
age along with an increase of body weight; hence a decreased viscosity would be
disadvantageous for the functional efficiency of the joint and may cause rapid onset of
osteoarthritic changes.[25]
When the hematocrits of two samples are widely disparate, their viscosities are compared by
measuring viscosity index (
) that provides a correction for the
effect of hematocrit due to the fact that the relationship of apparent relative viscosity (ARV,
given by the ratio of time taken by blood and time taken by water) to hematocrit is linear
between hematocrits of 30 and 50 and that the slope of the line representing this portion of
the relationship is constant.[26]
Rosenblum (1968) studied the effects of anticoagulants on the flow properties of blood and
indicated that the ARV increased if hematocrit is reduced by using anticoagulants which
induce erythrocyte shrinkage, such as citrate and oxalate while citrate did not alter viscosity
in ACD solution (mixture of sodium citrate, citric acid and dextrose) which prevents cell
shrinkage; plasma viscosity was unaffected and EDTA did not affect blood viscosity as it did
not alter cell size or shape.[27]
For fast, low-volume biofluid viscosity measurements, Haidekker et al. (2002) tested
molecular rotors, which are a group of fluorescent molecules with viscosity dependent
quantum yield, for use as fluorescence-based plasma viscometer modified by the addition of
pentastarch (molecular mass 260 kDa, 10% solution in saline) and measured with a
Brookfield viscometer and they found a mathematical relationship between intensity (I) and
viscosity (η) to be
.[28]
A reduced carotid arterial shear stress showed association with lacunar infarction determined
through measurement of vessel wall diameters and velocities using duplex ultrasonography in
each arterial segment at peak-systolic and end-diastolic phases for estimating shear rates,
viscosity, shear stresses based on hematocrit and measurements at 300 s-1; the hematocrit-
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derived blood viscosity was calculated using the formula: Blood viscosity in centiPoise
where
is hematocrit. [29] An estimation of
blood viscosity was made using an equation, comprising blood cells types erythrocytes,
leukocytes, and thrombocytes, that involved multiplication of the dominant parameter(s) with
natural logarithm of the recessive parameter.[30]
VISCOSITY MEASUREMENT
Viscometer measures only the viscosity of the material whereas rheometer measures both
viscosity and yield stress of a material.[31] Viscometer is of two types, extensional viscometer
and shear viscometer. Extensional viscometer measures the viscosity of highly viscous fluids
and shear viscometer is applicable for viscosity measurement of low viscous fluids, such as
water and whole blood. Shear viscometers are based on either drag flow or pressure-driven
flow. In the drag flow type viscometer, the shear is created between a moving and a
stationary solid surface, and it is further divided into two types, falling or rolling object
viscometer and rotational viscometer. In the pressure-driven flow type viscometer, the shear
is produced by a pressure difference over a capillary tube.[5]
There are three basic principles of viscosity measurements viz. time to discharge, timed fall,
drag torque and accordingly three commonly used viscometer instruments include tube-type,
falling-body type, and rotational type viscometers respectively.
Falling Object Viscometer
Stokes derived an equation showing that the retarding force due to viscosity acting on a small
sphere falling through a high viscous liquid is equal to the effective gravitational force.
Hence,
or,
,where v is the terminal velocity
of the sphere, r its radius, ρ and σ are the densities of the sphere and the liquid respectively, R
is the internal radius of the cylinder, h is the depth of the liquid in the cylinder.
For objects such as cylindrical needle falling in a liquid filled in another cylinder (assuming a
wide gap, i.e., κ << 1), the shear stress τ and viscosity μ of the liquid is given by,[5]
, where
fluid,
acceleration due to gravity,
density of needle,
density of
inner radius of outer cylinder,
terminal
velocity of needle. Park and Irvine (1988) obtained non-Newtonian viscosity
as a function
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of shear rate
by changing the density of the needle and thus the shear stress , through the
use of a hollow tube filled with various amounts of dead weight.[32]
The limitations of falling object viscometer is that for clinical applications, quite a large
amount of fluid is required, and besides this method cannot be used for thixotropy studies
since the fluid is at a stationary state initially.[14]
Rotational Viscometer
In a rotational viscometer, the fluid sample is placed in a narrow space between the rotating
surface and the fixed surface and is sheared as a result of the rotation of a cylinder or cone.
Two commonly used geometries are couette and cone-and-plate. The more viscous the fluid,
the more difficult it is to spin.[14]
Rotational Coaxial-Cylinder (Couette Type)
The shear stress τ and shear rate
is respectively related to torque and angular velocity of the
inner cylinder by the following expression:
,
, where
,
rpm of inner cylinder. The above equation applies to non-Newtonian fluid as well for small
annular space compared to the radii of the inner and outer cylinder. At low shear rates
Couette measuring devices are effected by slip and migration that display a stress
decay during shearing period, which can however be alleviated with different surface
roughness (32 and 170 μm) of the measuring systems.[13]
Cone-and-Plate Viscometer
Here the fluid is rotated between a flat plate and a cone with a low angle to maintain a
uniform shear rate. The shear stress and shear rate is given by: [5]
and
, where
β is the angle of cone, Ω is the angular velocity, M is the torque.
Rotational viscometers are very popular instruments for the measurement of whole blood
viscosity yet they suffer from certain drawbacks. The torque measuring sensor (spring or an
electronic transducer) requires periodic calibration which is an elaborate procedure. There is
requirement of cleaning between tests which is time consuming along with potential risk for
contact with contaminated blood. Moreover, fluctuating torque readings due to high surface
tension of blood create non-uniform contact area between blood and the inner cylinder and
thus cause errors in viscosity measurement. Besides, rotational viscometers are accurate only
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within a limited range of shear rates. In addition, these viscometer require anticoagulants, to
prevent blood clotting, the presence of which may increase or decrease blood viscosity. [33]
Capillary tube-type viscometer
For Newtonian fluid such as plasma, the volume rate of flow of a fluid is given by HagenPoiseuille equation,
, ∆P is the pressure difference between the two ends of the
capillary tube, is the length of the tube.
The viscosity fluctuates with shear rate in non-Newtonian fluids such as whole blood and to
change the shear rate it is required to vary the pressure in the reservoir. This is highly timeconsuming because the reservoir pressure should be reset after each run to a new value in
order to determine the association between volume rate of flow and pressure difference.[14]
Capillary tube-type viscometer measure the viscosity of a fluid by calculating the time for
fluid to flow a predefined distance along the capillary tube. The easiest way is to employ a
volumetric pipette to measure the flow time and compare with that of the water and express
the viscosity as the ratio of the two, the viscosity of water being 1.0 cP units at room
temperature.
sample flow time water flow time. Scanning capillary tube
viscometer was applied for continuous measurement of yield stress and viscosity over whole
range of shear rates using Casson fluid model.[34]
Denning and Watson’s viscometer
It is a U-shaped capillary tube with a long arm containing a funnel at one end for blood
collection and a short arm containing a marked bulb at the other end.
Ostwald viscometer
The Ostwald viscometer comprises a smaller efflux vessel on one side and a bigger receiving
vessel on the other side of a U-tube. The sample is suctioned into a marked capillary tube
projecting from the efflux vessel, and suction released for downward flow of the sample. The
time taken to cross the marked lines is measured and the flow time is compared with that of
water or other liquids of known viscosities.
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Harkness viscometer
The Harkness viscometer contains a horizontal capillary tube and is an automated, modified
form of the Ostwald viscometer where the flow time is measured electronically. It consists of
three parts, a sample container, a saline reservoir, and a central part containing mercury for
the timing function. The lower half portion of the instrument is submerged in a water bath
fitted with thermostat.[3]
The capillary-tube viscometer is limited to measurements at high shear rate >100s-1 whereas
clinical applications require measurements at low shear rate <10s -1. However, capillary-tube
viscometer is simple in its design and uses gravity field to drive test fluid such that there is no
need for calibration.
Overall, the majority of the viscometers calculate viscosity at a particular shear rate. Hence
the procedure requires to be repeated in order to get viscosity data over a range of shear rates.
This is achieved either by changing the pressure in the reservoir tank of capillary
viscometers, or the rotating speed of the cone or cup in rotating viscometers, or the density of
the falling objects. Thus each of the technique has got its merits and demerits and is used
according to the need and suitability of the situation for the fulfillment of the objective.
Microfluidic viscometers
Chip-based devices
Micro-electronic mechanical systems (MEMS) viscometers are based on flexible microfluidic cantilever chips for determining the rheometric properties of nanolitre samples,
controlled by complementary metal-oxide semiconductor type signals obtained by differential
deflection of micro-cantilevers above the supporting surface in response to immersion in
blood when a current is passed.[35] Hye et al. introduced lead zirconate titanate
microdiaphragm resonating sensor packaged in a polydimethylsiloxane chip that measured
the frequency responses of the sensor before and after injecting blood under the bottom of the
microdiaphragm.[36]
Paper-based devices
Hua et al. evaluated the viscosity change of blood as a function of its coagulation ability by
measuring the travel distance of red blood cells on nitrocellulose membrane as an indicator of
blood clotting time.[37]
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Hybrid devices
Hybrid system composed of ultrasound imaging system and microfluidic device consisting of
two identical side channels and a connecting bridge channel, was proposed for simultaneous
measurement of hemorheological and hemodynamic properties including RBC aggregation,
viscosity, velocity, and pressure of blood flows; the direction of blood flows, passing through
the bridge channel being dependent on the flow rate of reference fluid, were obtained from
microscopic images of the flow conditions in the microfluidic device.[38]
YIELD STRESS MEASUREMENT
Yield stress is the stress limit between flow and non-flow conditions and is determined by
direct method which involve independent assessment of yield stress (true value) and indirect
method which involve extrapolation of shear stress-shear rate (apparent value) at zero shear
rate.
[39]
In the indirect method yield stress is determined by extrapolation performed
graphically or numerically, or by fitting in rheological model of fluid. The direct methods are
applicable to fluids having yield stresses > 10 Pa.[39] Thus direct method is not very
convenient to use for the yield stress measurement of blood since the yield stress of human
blood is approximately 1 to 30 mPa.[40]
HEMORHEOLOGICAL
ALTERATIONS
IN
PATHOPHYSIOLOGICAL
CONDITIONS
Under pathophysiological conditions, hemorheological alterations beyond a range of values
promotes atherogenesis, thrombosis, adhesion of leukocytes, smooth muscle proliferation and
endothelial apoptosis. Increases in the viscosity of blood and plasma predict clinical
manifestations of atherothrombotic vascular disease[11] which may result from reduced
microcirculatory flow and increased shear stress against the endothelial surface, which
enhances the likelihood of plaque rupture.[41]
A direct correlation between blood viscosity and coronary stenoses as well as peripheral
arterial narrowing was found.[42] Similar correlation was found between plasma viscosity and
cerebrovascular symptoms[43] and claudication.[42] Plasma viscosity is predictive of ischemic
heart disease[44] and progression to acute myocardial infarction in patients with unstable
angina pectoris.[45] The HDL cholesterol is associated with blood viscosity attributed to the
simultaneous hypertriglyceridemia ensuing from the presence of larger triglyceridecontaining lipoproteins; HDL lessens erythrocyte aggregation and maintains erythrocyte
deformability.[11] Hypoalbuminemic disorders including nephrotic syndrome is linked with
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blood hyperviscosity due to decreased red cell deformability caused by altered membrane
lipid composition related to an increased lysophosphatidyicholine that binds to lipoproteins
and red cell membrane, causing rheological abnormalities with an increased risk for coronary
atherosclerosis and thrombosis.[46] Increased whole blood viscosity is an important factor,
associated with decreased cerebral blood flow after acute cerebral infarction, apart from other
causes including arterial blockage, increased intracranial pressure, systemic hypotension,
reduced vascular tone; this is attributed to the interaction between fibrinogen and red blood
cells causing cell aggregation at very low blood flow and shear stress levels, ultimately
leading to a greater resistance to flow and development of vicious cycle causing progression
from ischemia to infarction based on no reflow phenomenon; the cerebral blood flow is
associated
with
fibrinogen
and
hematocrit
by
a
formula
.[10]
represented
Systemic
by,
sclerosis
is
characterized by ischemia caused by microvascular anomalies such as capillary damage and
dilatation, lumen constriction in the arterioles and small arteries ensuing with severe
Raynaud’s phenomenon, diminished velocity of blood flow in the big capillary loops, and
hemorheological abnormalities in viscosity and thixotropy at moderate shear rates
.[13] Diabetes mellitus is accompanied by increased blood viscosity, due to
endothelial dysfunction leading to disorders in blood viscosity regulatory feedback
mechanisms; due to increased generation of active oxygen species in erythrocytes and
endothelial cells leading to decreased RBC deformability; due to increased RBC aggregation
and fibrinogen levels.[47] Mishra and Singh investigated the effect of glycemic control on
blood viscosity, lipid profile, and lipid peroxidation in Type-1 diabetic subjects and reported
that monitoring of blood viscosity and oxidative stress in persistent hyperglycemia and poor
glycemic control in Type-1 diabetes serves as an indicator of diabetic complications by
causing disturbances in lipid profiles, especially an increased production of oxygen free
radicals.[48] Several hemorheological abnormalities in blood viscosity and blood
viscoelasticity may impair the oxygen transport efficiency of blood in Alzheimer's disease
patients caused by oxidative stress-induced damage of erythrocyte membranes and elevation
of fibrinogen concentration leading to decreased erythrocyte deformability and accelerated
erythrocyte aggregation respectively.[49] Meighan et al (2009) reported abnormalities in
hemorheologic parameters, including vessel diameter, flow velocity, and whole blood
viscosity, present in AD correlated with microvascular abnormalities (vasculopathy).
[50]
Increased diastolic blood viscosity that differed according to apolipoprotein 4 genotype (a
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known risk factor for vascular and parenchymal amyloid) was reported to be responsible for
the progression of subcortical vascular mild cognitive impairment without cerebral amyloid
deposition detected by [11C] Pittsburgh compound B positron emission tomography.
[51]
Metabolic syndrome, whose major components are diabetes mellitus, hypertension,
dyslipidemia and obesity, is the state of oxidative stress and systemic inflammation, and it
can independently affect blood vessels and microcirculation through pro-oxidant and
inflammatory cytokines induced endothelial dysfunction altogether leading to increased
whole blood viscosity.[52] Syringe method was used to measure relative blood viscosity and
relative plasma viscosity; significant difference in relative blood viscosity not for relative
plasma viscosity between control and anemia was obtained with high direct correlation
between relative blood viscosity and other blood parameters in both control and anemia.[53]
Irace et al. showed a direct relationship between blood viscosity and blood glucose in
nondiabetic subjects; within normal glucose values, higher blood glucose levels had increased
blood viscosity comparable with prediabetic blood glucose levels.[54] Not only in diseased
states but also under stressful conditions alterations of blood rheological parameters have
been found. In lead poisoning pathogenesis, lead-induced oxidative stress in erythrocytes has
been identified as the essential factor with association in a dose-effect relationship between
lead levels and blood rheological parameters with respect to malondialdehyde (a lipid
peroxidation product), lipofuscin, and glutathione concentrations in erythrocytes that elevates
whole blood viscosity and disrupts erythrocyte aggregation and deformation.[55] During
chemotherapy, measurement of blood rheological parameters is beneficial in assessing the
response to therapy and drug compliance. Paclitaxel and Cremophor-EL induced oxidative
stress through increased malondialdehyde, protein carbonyl content and reduced glutathione
associated with an increase of whole blood viscosity.[56]
TREATMENT FOR THE ABNORMAL BLOOD VISCOSITY: PHARMACOLOGIC
THERAPY
Now a days several treatment options are available for reducing blood viscosity directly
which are applied in cardio-cerebrovascular diseases and diabetes mellitus. Plasma exchange;
phlebotomy; and rheopheresis are used for instance, in hypercholesterolemia and
hypertriglyceridemia; polycythemia vera and hemochromatosis; microvascular diseases
respectively; combination of phlebotomy and fluid therapy has been used to treat diseases
such as ischemic stroke and myocardial infarction.[57] Dual effects of vinpocetine derived
from Vinca minor and periwinkle leaves, and pyritinol, a pyridoxine analogue with nootropic
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effect, at low shear rates significantly improved blood and plasma viscosity in
cerebrovascular disorders.[58] Improved hydration status was found to normalize the blood
hyperviscosity in exercising sickle cell trait carriers obtained by measuring, blood viscosity
and haematocrit per blood viscosity ratio as an index of red blood cell oxygen transport
effectiveness, before and at the end of each game.[59] Participation in aerobic physical fitness
program, conducted using a cycle ergometer, 3 times per week on alternate days, with an
intensity corresponding to ventilatory threshold 1 was found to significantly decrease blood
viscosity, improve memory, and increase aerobic capacity, indicating the same as a
nonmedication alternative to improve physical and cognitive function.
[60]
Besides certain
antioxidant therapy, nitroglycerin, Chinese herbal medicines, are also used as an indirect
therapy for reducing blood viscosity. On the contrary, transfusion increases blood viscosity
and oxygen carrying capacity thus maintaining the shear stress on the endothelium and
microvascular perfusion. Hyperviscous plasma expanders are superior to oxygen therapeutics
that function by increasing the oxygen delivery capacity; in anemia they increase tissue
perfusion while polyethylene glycol conjugate albumin achieves this by increasing shear
thinning behavior of diluted blood, which enhances endothelial stress, causes vasodilation
and decreases peripheral resistance thus improving cardiac activity.[61] Not only for treatment
purpose, should blood viscosity also be maintained during preparation of blood substitutes to
avoid vasoconstriction and increasing total peripheral vascular resistance caused by increased
endothelial shear stress.[62]
CONCLUSIONS
The biophysical aspects of blood viscosity in various physiological function and pathological
conditions renders viscosity investigation a matter of particular importance at the clinical
level. Assessment of blood viscosity both for its monitoring and control involves minimal
invasion and is amendable using pharmacologic therapy as well as by hemodilution.
[63]
Viscosity assessment in clinical practice may serve in the investigation of diseases and
mechanisms affecting the cerebro-cardiovascular system and the vascular endothelium.
Understanding and development of the existing techniques and methods for viscosity
measurement may contribute greatly towards this goal. At the same time it is important to
include blood viscosity in treatment interventions and explore into their mechanism of action
for its close association with the pathogenesis, development, and prognosis of several lifethreating diseases including cardio-cerebrovascular diseases, diabetes and others.
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Source of Support: Nil
Conflict of interest: None
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