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INTRODUCTION

Early investigators conceptualized blood as a viscous fluid, assuming that the viscosity controls

its flow properties[1]. But blood is not a fluid in the ordinary sense; it is a fluidized suspension of

elastic cells. In 1972, G. B. Thurston was the first to measure the viscoelastic properties that

control the pulsatile flow of blood[2]. The viscoelasticity reflects the cumulative effects of manyblood parameters such as plasma viscosity, red blood cell deformability, aggregation, and

hematocrit.

Now extensive basic research on blood viscoelasticity and the factors affecting it has provided afirm foundation for the increasing interest in viscoelasticity among researchers in clinical

medicine and physiology. The effects of compositional parameters such as hematocrit, certain

plasma proteins[3], and clinically relevant control fluids like Dextran 40[4], have been studied.

Major shifts in the viscoelasticity of blood have been found to be associated with suchpathologies as myocardial infarction, peripheral vascular disease, cancer and diabetes [5,6,7].

VISCOSITY VS. VISCOELASTICITY

The most common method of determining the consistency of a flowing liquid uses the relation

between shear stress and time rate of shear strain (or shear rate). If the flow is constant in time,then the ratio of shear stress to shear rate is the viscosity. When flows are changing with time,

such as blood flow in the human circulation, the liquid generally demonstrates both a viscous and

an elastic effect, both of which determine the stress-to-strain rate relationship. Such liquids arecalled viscoelastic. Blood plasma normally shows viscosity only[8], while whole blood is both

viscous and elastic.

BLOOD VISCOELASTICITY

The viscoelasticity of blood is traceable to the elastic red blood cells, which occupy about halfthe volume. When the red cells are at rest they tend to aggregate and stack together in a space

efficient manner. In order for blood to flow freely, the size of these aggregates must be reduced,

which in turn provides some freedom of internal motion. The forces that disaggregate the cellsalso produce elastic deformation and orientation of the cells, causing elastic energy to be stored

in the cellular microstructure of the blood. As flow proceeds, the sliding of the internal cellular

structure requires a continuous input of energy, which is dissipated through viscous friction.

These effects make blood a viscoelastic fluid, exhibiting both viscous and elastic properties.


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F igure 1.The shear rate dependence of normal human blood viscoelasticity at 2 Hz and 22 C.

Failure to either disaggregate or deform (or both) results in impaired perfusion of the capillary

beds and failed tissue servicing. Since aggregation[9,10] and deformability[11,12] are key

factors in the viscoelasticity of blood, the structural organization of cells that affects blood flowmust be evaluated in terms of its contribution to the viscoelastic properties of blood, which in

vivodetermine the pressure-to-flow relationships in the vessels.

A scan with increasing oscillatory shear rates can show influences of aggregation,

disaggregation, cell orientation and cell deformation on the viscoelasticity of blood. Figure 1shows an example of normal human blood measured at a frequency near that of the human pulse.In Region 1, the cells are in large aggregates and as the shear rate increases, the size of the

aggregates diminish. In this range of shear rates, the viscoelasticity is strongly influenced by the

aggregation tendency of the red blood cells. In Region 2, the cells are disaggregated and the

applied forces are forcing the cells to orient. As the shear rate increases, the applied forcesdeform the cells. In Region 3, increasing stress deforms the cells, and if the cells have normal

deformability they will form layers[13] that slide on layers of plasma. In this region, the

viscoelasticity is strongly influenced by the deformability of red blood cells. Cells with impaireddeformability produce dilatant viscoelasticity marked by elevated viscosity and elasticity in the

high shear rate region[14].

Modification of plasma such as changes in osmotic pressure, pH, concentration of fibrinogen and

other plasma proteins, and clinically introduced blood volume expanders, can have major effects

on blood viscoelasticity.[2,3,9,11] For example, changing the plasma composition by addition ofblood volume expanders can affect aggregation and deformability of the cells, resulting in a

shear rate-dependent viscoelasticity that deviates from that of normal blood. Figure 2 shows the

effect of dilution of three samples of blood from the same donor from a hematocrit of 0.46 to a

hematocrit of 0.31 by the addition of autogenous plasma, lactated Ringer's, and Dextran 40,


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providing a 50% dilution of the original plasma[4].

F igure 2. The viscoelasticity for normal 0.46 hematocrit blood diluted to 0.31 hematocrit by the

addition of Dextran 40 (D), autogenous plasma (P), and lactated Ringer's solution (L).

easurements were made at 2 Hz and 22 C.

Variation in blood viscoelasticity among normals is very small. Thus, changes due to disease or

surgical intervention can be readily identified, making blood viscoelasticity a useful clinical

parameter. For example, the viscoelasticity of an individual's blood changes significantly as theresult of cardiopulmonary bypass surgery (Figure 3).

Examination of a group of patients undergoing CPB found that the changes seen in Figure 3 arenot solely due to changes in hematocrit but also may be a due to the combined effects of 1)

dilution of plasma proteins by the priming solution, 2) changes in plasma viscosity and 3) the

effects of the priming solution on aggregation and deformability of the red blood cells [15].


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F igure 3.Changes in the viscoelasticity of blood from a male patient undergoing

cardiopulmonary bypass surgery. The pump priming solution was Normosol-R.

CRITERIA FOR MEASUREMENT OF VISCOSITY AND VISCOELASTICITY

A suitable system for the measurement of blood viscoelasticity or plasma viscosity must haveseveral features for clinical applications:

Rapid, reproducible and precise measurements

Small blood or plasma sample volume

Simulate in vivotime-varying flow conditions usingoscillatory flow in a tube

Precise thermal control

Simple operation

Minimal exposure of operator to blood borne pathogens

TheBioProfilerprecisely measures viscosity of plasma and both the viscous and elasticproperties of blood and other biofluids under controlled conditions of frequency, temperature andtime. The Vilastic-3 can measure the viscosity and elasticity of blood under oscillatory flow in

cylindrical tubes that mimic a range of blood vessels (1 mm to 20 micron i.d.) and in stenotic

tubes and porous media, mimicking the complex geometries encountered by flowing blood in the

human circulation. Blood or plasma samples as small as 0.25 ml can be measured repeatedlywith reliable results and minimal user exposure to the sample. Computer controlled measurement

protocols allow for ease of operation and reproducible measurement conditions. In addition to
http://www.vilastic.com/BioProfiler.htmhttp://www.vilastic.com/BioProfiler.htmhttp://www.vilastic.com/BioProfiler.htmhttp://www.vilastic.com/BioProfiler.htm


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measuring the viscoelastic character of blood, the Vilastic-3 also can monitor dynamic changesin the viscoelasticity during blood or plasma clotting.

References[1] Lowe, G. D. O. Nature and clinical importance of blood rheology, Clinical Blood Rheology, Vol.1, ed. by G. D.

O. Lowe, CRC Press, Boca Ration Florida, 1-10 (1988).

[2] Thurston, G. B., The viscoelasticity of human blood, Biophysical Journal, 12, 1205-1217 (1972).

[3] Kasser, U.; Heimburge, P; Walitza. Viscoelasticity of whole blood and its dependence on laboratory parameters,

Clinical Hemorheology, 9, 307-312 (1989).

[4] Thurston, G. B., Viscoelastic properties of blood and blood analogs, Advances in Hemodynamics and

Hemorheology, ed. by T. C. Howe, JAI Press, 1-30 (1996).

[5] Chmiel, H.; Anadere, I.; Walitza, E. The determination of blood viscoelasticity in clinical hemorheology,

Clinical Hemorheology, 10, 363-374 (1990).

[6] Anadere, I.; Chmiel, H.; Hess, H.; Thurston, G. B. Clinical blood rheology , Biorheology, 16, 171-178 (1979).

[7] Isogai, Y.; Ikemoto, S.; Kuchiba, K.; Ogawa, J.; Yokose, T. Abnormal blood viscoelasticity in diabetic

microangiopathy, Clinical Hemorheology, 11, 175-182 (1991).

[8] Lowe, G. D. O.; Barbenel, J. C. Plasma and blood viscosity, Clinical Blood Rheology, Vol.1, ed. by G. D. O.

Lowe, CRC Press, Boca Ration Florida, 11-44 (1988).

[9] Chien, S.; Usami, S.; Dellenback, R. J.; Gregersen, M. I. Shear-dependent interaction of plasma proteins with

erythrocytes in blood rheology, Amer. J. Physiology, 219, 143-153 (1970).[10] Rampling, M. W. Red cell aggregation and yield stress, Clinical Blood Rheology, Vol.1, ed. by G. D. O. Lowe,

CRC Press, Boca Ration Florida, 65-86 (1988).

[11] Dormandy, J., Ed. Proceedings of the Second Workshop Held in London, Marinus Nijhoff Publisher, The

Hague, (1983).

[12] Stuart, J. Erythrocyte deformability, Clinical Blood Rheology, Vol.1, ed. by G. D. O. Lowe, CRC Press, Boca

Ration Florida, 65-86 (1988).

[13] Thurston, G. B. Plasma release-cell layering theory for blood flow, Biorheology, 26, 199-214 (1989).

[14] Thurston, G. B. Erythrocyte rigidity as a factor in blood rheology: viscoelastic dilatancy, J. Rheology, 23, 703-

719 (1979).

[15] Thurston, G. B.; Henderson, N.; Undar, A.; Calhoon, J. H. Blood viscoelasticity changes in cardiac surgery,

17th Biomedical Engineering Conference, February 1998, San Antonio, Texas.

Have any questions? Vi sitBlood Viscoelasticity :FAQAddit ional references can be found atBlood and Biofluid Bibli ography.

Thank you for visiti ng our technical note page.

Contact usif you would l ike to discuss thi s or any other rheological topic.

Vi lastic Scientif ic, I nc (01)512-327-4134www.vilastic.com
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http://www.sciencedirect.com/science/article/pii/002191509390188Z

A recent prospective study has suggested that increased plasma viscosity may be associated with higher

risk of coronary heart disease. A longitudinal approach was used to investigate associations between

plasma viscosity and conventional risk factors in an apparently healthy French population aged 4556

years (637 men and 431 women) over a 2-year follow-up period. In univariate analysis, change in plasma

viscosity was significantly related to changes in smoking status, systolic and diastolic blood pressure,

gamma glutamyl transferase (GT), body mass index and triglycerides only in men, and to changes in

total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B in both sexes.

Change in plasma viscosity was also significantly associated with changes in fibrinogen and hemoglobin

levels in both sexes. No association was found with age, high-density lipoprotein (HDL) cholesterol or apo

A1 in both sexes, or with changes in smoking and menopausal status in women. In multiple stepwise

regression analysis, independent determinants of change in plasma viscosity were changes in smoking

status, systolic blood pressure, GT, total cholesterol, fibrinogen and hemoglobin in men, and changes in

fibrinogen and apo B in women. These results strengthen the hypothesis that increased plasma viscosity

may be one of the mechanisms linking conventional risk factors to the risk of cardiovascular disease and

suggest that its decrease may be obtained by appropriate life-style changes.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92207-1/abstract

Summary

Plasma viscosity is reported to be predictive of coronary heart disease (CHD) and stroke. To find out

whether regional differences in CHD event rates correlate with differences in plasma viscosity, we

compared plasma viscosity in a high-risk area for CHD (Glasgow Multinational Monitoring of Trends and

Determinants in Cardiovascular Disease [MONICA] and Scottish Heart Health Study population surveys,

1985/86; n=1166) and in a lower-risk area (MONICA Augsburg survey, 1984/85; n=3258) in men and

women aged 25-64 years. Mean plasma viscosity (37C) was 1261 (SD 0067) mPa s in Augsburg and

1327 (0093) mPa s in the west of Scotland for men, and 1248 (0066) mPa s and 1 318 (0087) mPa s,

respectively, for women. The unadjusted difference of the means between the west of Scotland and

Augsburg was 0066 (95% Cl from weighted regression 0058-0 073) mPa s for men and 0070 (0062-

0078) mPa s for women. Adjustment for age, smoking behaviour, total and high-density-lipoprotein

cholesterol, systolic and diastolic blood pressure, and body-mass index had no effect on these

differences. Age-standardised coronary event rates in 1985-87 were at least two times higher among

men, and four times higher among women, in MONICA Glasgow than in MONICA Augsburg.

This large geographical difference in plasma viscosity might partly explain the differences in CHD event

rates between these populations. Further studies are needed on the determinants of plasma viscosity,

and on its potential roles in atherosclerosis, thrombosis, and ischaemia.
http://www.sciencedirect.com/science/article/pii/002191509390188Zhttp://www.sciencedirect.com/science/article/pii/002191509390188Zhttp://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92207-1/abstracthttp://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92207-1/abstracthttp://www.thelancet.com/journals/lancet/article/PIIS0140-6736(94)92207-1/abstracthttp://www.sciencedirect.com/science/article/pii/002191509390188Z


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http://www.sciencedirect.com/science/article/pii/S1389945705003151

Abstract

Background and purpose

In patients with severe obstructive sleep apnea syndrome (OSAS), diurnal changes of plasma viscosity

and erythrocyte deformability were measured to elucidate the possible mechanism of cardiovascular

diseases in OSAS patients.

Patients and methods

Plasma viscosity and erythrocyte deformability was determined in 11 OSAS patients and 11 healthy

subjects matched by sex and age. Plasma viscosity was measured by a cone-plate viscometer, and

erythrocyte deformability was determined by filtration technique. Whole blood counts were performed and

oxidative status of the patients' plasma and erythrocytes were evaluated.

Results

OSAS patients had higher plasma viscosity than controls, both in the morning (1.74 0.3 vs.

1.360.2 mPa s, P


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contrast, the percentage of patients without stenosis of the coronary vessels decreased with higher levels of plasma

viscosity (from 10.6% within the lower tertile to 3.2% within the upper tertile) (Figure 1 ).

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Figure 1.Percentages of MI patients without any and with three stenosed vessels referring to the total number of MI

patients within tertiles of plasma viscosity.

Mean plasma viscosity was 1.1350.042/1.1410.035 mPa s (adjusted for age/age, fibrinogen, and use of diuretics)

in MI patients without stenosed vessels (n=72), 1.1450.041/1.1470.038 mPa s with one stenosed vessel (n=467),

1.1530.040/1.1510.032 mPa s with two stenosed vessels (n=341), and 1.1640.054/1.1620.044 mPa s with three

stenosed vessels (n=262).

With the exception of no versus one stenosed vessel, differences between the age-adjusted groups were significant

(P


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Discussion

This study is the first showing plasma viscosity to be related to the severity of CHD. Plasma viscosity showed a

significant increase according to a higher number of stenosed coronary vessels in male MI patients.

In 1980, Lowe et al13suggested that blood viscosity is related to the extension of CHD. However, in the study

proposing this suggestion, no significant relationship was found between plasma viscosity and the extension ofCHD. The contrast to our results may be due to the fact that we investigated a larger collective. Geographical

differences in plasma viscosity as described by Koenig et al11may also have contributed to different findings.

The strong positive correlation between plasma viscosity and fibrinogen found by other authors21319202122was

confirmed by our results (Table 2 ). Because fibrinogen is the major determinant of plasma viscosity,23patient

groups were adjusted not only for age but also for levels of fibrinogen. Additionally, groups were adjusted for

current use of diuretics to exclude an influence of such drugs. After this, the significant relationship between plasma

viscosity and the severity of CHD remained and thus cannot be due to increased levels of fibrinogen or use of

diuretics (Figure 2 ). Plasma viscosity was similar in patients using lipid-lowering drugs (until 2 weeks before

blood collection) and patients not using these drugs (data not shown).

In our study, the relative number of men with three stenosed vessels (referring to the total number of MI patients

within tertiles of plasma viscosity) showed an increase according to higher levels of plasma viscosity, while the

opposite was found for MI patients without stenosis of the coronary vessels (Figure 1 ). Elevated plasma viscosity

has been shown to have a deleterious effect on oxygen delivery to the ischemic myocardium.

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An unfavorableblood flow may also lead to an increase in aggregation of blood cells, especially in the presence of high levels of

fibrinogen.2627We therefore suggest that ischemia and a tendency to thrombosis in stenosed vessels due to a

decreased blood flow with increasing viscosity contributes on the one hand to the progress of atherosclerosis. On the

other hand, an increased cardiovascular risk through an elevated plasma viscosity may be of greater relevance in

already stenosed coronary vessels. Effects of rheological properties of blood on thrombogenesis and atherosclerosis

have been summarized by several authors.12282930

Most of our findings concerning the relationship between plasma viscosity and other parameters were consistent

with the results of other authors. The positive bivariate correlation between plasma viscosity and the acute-phase

protein CRP remained significant in the MLRA. Acute-phase reactions are associated with the release of molecules

of high molecular mass, which increase plasma viscosity. Hence, our findings support the assumption that

atherosclerosis is a mild chronic inflammatory disease.31

A positive relationship between plasma viscosity and LDL cholesterol, as well as between plasma viscosity and

triglycerides, which may be explained by rheological effects of molecules of high molecular mass, are consistent

with the results of other studies.19323334353637The negative bivariate correlation between plasma viscosity and HDL

cholesterol seems to be equivocal but is nevertheless consistent with the findings of other authors.363738However,

the relationship remained no longer significant after performing the MLRA.

Positive bivariate correlations between plasma viscosity and fibrinogen, as well as between plasma viscosity and

plasminogen, remained significant in the MLRA, indicating an elevated hemostatic balance according to an

increased plasma viscosity. No bivariate correlation was found between plasma viscosity and F1+2, whereas in the

MLRA, significance was lost for the bivariate correlation between plasma viscosity and D-dimer. The latter results

partly contrast the findings of Lowe et al,13who suggested an imbalance of coagulation and fibrinolysis toward

coagulation, but in their study fibrinopeptide A and fibrin B 1542were used as markers for coagulation and

fibrinolysis. Fibrin B1542is a degradation product of fibrinogen and noncross-linked fibrin, whereas D-dimer

results from plasmin-mediated fibrinolysis of cross-linked fibrin. As cross-linking is dependent on coagulation

factor XIIIa, one may speculate that on the one hand, an increased plasma viscosity may increase factor XIII

activity. On the other hand, cross-linking may be enhanced by an increased plasma viscosity. Fibrinopeptide A

represents fibrin generation from fibrinogen, whereas F1+2 is a marker for thrombin generation. Levels offibrinogen (and therefore nonadjusted levels of plasma viscosity) may be more closely related to fibrin generation

than levels of thrombin, which might explain the differences in our findings.19

A causal relationship between BP and plasma viscosity may be suggested, but so far evidence has not been found.

We can confirm a positive bivariate correlation as previously described,21920213940but no significant relationship

between BP and plasma viscosity was found in the MLRA.

One of the linking mechanisms between smoking and CHD may be the increase in fibrinogen and white blood cell

count in smokers and therefore an increase in plasma viscosity related to cigarette consumption.192028404142In our

study, the proportion of smokers decreased according to the number of stenosed vessels (from 80.5% in patients
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without stenosed vessels to 51.7% in patients with three stenosed vessels). Hence, the relationship between smoking

and CHD could neither be confirmed nor rejected.

Compared with the relevant literature, plasma viscosity values were low in our study (eg, Lowe et al ,131.380.10 to

1.430.10 mPa s; Yarnell et al,21.6880.096 to 1.7350.099 mPa s; versus our results, 1.1300.042 to 1.1680.057

mPa s). Instead of the conventionally used EDTA-plasma, we used 1:10 diluted citrated plasma for measuring

plasma viscosity. Therefore, this finding may be attributable to the dilution effect. Another aspect contributing to

low plasma viscosity levels may be the storage of frozen plasma, which could lead to a breakdown of molecules of

high molecular weight. Furthermore differences in methodology have to be taken into account when comparing

results of different studies. However, as the above-mentioned aspects would lead to a systematic shift in the

viscosity values, the conclusions of our study are not influenced by them.

On the whole, with our recent findings, we can give further support to the hypothesis that an increased plasma

viscosity may be a linking mechanism between cardiovascular risk factors and CHD. Clinical studies will be

required to investigate the therapeutic benefit of reducing plasma viscosity in the clinical management of CHD.

Selected Abbreviations and Acronyms

BMI = body mass indexBP = blood pressure

CHD = coronary heart diseaseCRP = C-reactive protein

ELISA = enzyme-linked immunosorbent assayF1+2 = prothrombin fragment 1+2

Lp(a) = lipoprotein(a)

MI = myocardial infarctionMLRA= multiple logistic regression analysis

Acknowledgments

This study was supported by the Bundesministerium fr Forschung und Technologie, the Ministerium fr

Wissenschaft und Forschung NRW, the Deutsche Forschungsgemeinschaft, the Landesversicherungsanstalt

Westfalen, and the Landesversicherungsanstalt Rheinprovinz. The excellent technical cooperation of R. Bumer, M.

Kse, and R. Kokott is gratefully acknowledged. We thank F. Stuhldreher for English editing.

Footnotes1Hans Ulbrich died April 25, 1996.

Received July 18, 1997; accepted November 17, 1997.

http://www.sciencedirect.com/science/article/pii/S0950353687800215

Summary

The proper understanding of the causes, pathophysiology, diagnosis and management of the plasma

hyperviscosity syndrome is based on good knowledge of malignant paraproteinaemias, properties of

immunoglobulins, rheology of blood in the microcirculation, and modern plasma separation techniques.
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This multifaceted syndrome complicates less than ten per cent of IgA and IgG myelomas, and up to one-

third of Waldenstrm's macroglobulinaemias. A few cases of HVS have also been reported in association

with polyclonal hypergammaglobulinaemias. Excessive paraproteinaemia may cause the plasma HVS,

especially when paraproteins are extraordinarily large, asymmetrical or cryosensitive, or if they aggregate

into hyperviscous macroaggregates. The resultant severe microcirculatory impairment is mainly due to

the combined effects of plasma hyperviscosity, significant plasma volume expansion and intense red cell

aggregation. The individually variable general symptoms, bleeding tendency, ocular, neurological,

cardiovascular, and renal manifestations and laboratory parameters of the HVS are summarized briefly.

The majority of patients present hyperviscosity manifestations when the plasma viscosity exceeds 56

mPas.

Plasmapheresis or plasma exchange have established themselves as efficient and safe modes of therapy

of hyperviscosity and hypervolaemia. The therapeutic guidelines for the plasma HVS are briefly discussed

with regard to recent experience with developing plasma separation techniques. Diagnostic and

therapeutic advances combined with increasing haemorheological knowledge have greatly improved the

proper management of this potentially lethal complication of paraproteinaemias.

plasma viscosity and

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