Bloodtheology - Journal of Clinical Pathology · Unfortunately, the ESR, like blood viscosity, is dependent on haematocrit and, even in non-anaemic patients, there is a negative correlation

J Clin Pathol 1980;33:417-429

Blood theologyJOHN STUART AND MARTIN W KENNY

From the Department of Haematology, University of Birmingham, Birmingham B15 2TJ, UK

Rheology, the science of the deformation and flowof matter, has become of considerable interest tohaematologists, and now the measurement of bloodand plasma viscosity is a familiar part of the investi-gation of vascular disorders and the paraprotein-aemias. Developments in instrumentation have ledto the measurement of plasma viscosity and the zetasedimentation ratio as practical alternatives to theerythrocyte sedimentation rate, and a variety ofmethods have also been introduced for the study ofred cell deformability. It is therefore an appropriatetime to review these recent developments and toexamine their potential application to the investi-gation and management of clinical disorders.

Determinants of viscosity

All fluids resist, to a greater or lesser extent, attemptsto alter their shape, and this resistance to flow isa measure of a fluid's viscosity. During flow, aslayers of fluid move parallel to one another atdifferent rates, a velocity gradient forms betweenthese layers and is known as the shear rate; it ismeasured in reciprocal seconds (s-1). The forcerequired to produce this velocity gradient is theshear stress and is measured in newtons per squaremetre (NM-2). Viscosity can now be redefined asthe ratio of shear stress to shear rate, the unit ofviscosity being the pascal second (Pa s; conversionfactor - 1 mPa s = 1 centipoise).

Simple fluids, such as plasma and most oils, showa linear relationship between shear stress and shearrate (Newtonian behaviour) so that the viscosityremains constant. Whole blood, however, behavesas a non-Newtonian fluid in that viscosity increasesexponentially at the low shear rates (below 50 s-1)that characterize venous flow. This increase is due tothe larger molecular weight plasma proteins (fibrino-gen and certain globulins) which overcome the zetapotential between erythrocytes and form rouleaux;these large cellular aggregates cause a dispropor-tionate increase in viscosity. At shear rates below1 s51, alterations in plasma fibrinogen around the up-per limit ofthe physiological range have a pronounced

Received for publication 21 January 1980

effect on whole-blood viscosity (Fig. 1). At the highshear rates characteristic of arterial flow (above100 s-1), rouleaux are dispersed, and individualerythrocytes are deformed into ellipsoids with theirlong axes aligned in the direction of flow;' 2 thusviscosity is relatively low and virtually constant athigh shear rates and is independent of the plasmafibrinogen.

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Fig. 1 Disproportionate effect on viscosity at low,compared with high, shear of the addition offibrinogento washed red cells (final haematocrit 045) at 370C.

The appropriate shear-rate range correspondingto blood flow in capillaries is difficult to determinesince flow may be intermittent and, once blood hasbecome stationary, a relatively large force (the yieldstress) is required to restart movement. Thus thereis uncertainty over the shear rates that characterisecapillary blood flow and of the importance ofmeasuring yield stress. For the above reasons,viscosity should always be measured over a widerange of shear rates, but a number of other factorsaffecting viscosity must also be taken into accountwhenever viscosity is measured.Haematocrit is the most important single determi-

nant of whole-blood viscosity. Within the physio-logical range there is a linear relationship betweenhaematocrit and the logarithm of viscosity,3-5 butthis relationship is lost at very high and lowhaematocrits. Since a difference in haematocrit

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between individuals may obscure the effects of otherdeterminants of viscosity, it is customary to adjustthe viscosity (usually to a standard haematocrit of0.45) unless the purpose of the study is to investigatethe effects of polycythaemia or anaemia. Thisadjustment can be made from a semilogarithmicgraph of viscosity plotted against haematocrit.The temperature at which viscosity is measured is

another variable. Within the range 27-37°C there isa linear relationship between fall in temperature andrise in viscosity, with plasma viscosity increasing by2-3% for every degree fall in temperature.6 Below27°C, however, blood viscosity increases dispro-portionately as the temperature falls,7 although thelinear relationship between haematocrit and log-arithm of viscosity at 37°C still applies at temperaturesdown to 22°C (unpublished). Most clinical studies ofwhole-blood viscosity have been performed at 37°Cbut since the temperature of blood in the superficialveins of the leg may fall to 300C,8 and since patientswith vascular disease commonly have cold ex-tremities, it has been of value to study viscosity atlower temperature.9-11 Obviously the temperature(s)selected should be determined by the purpose of thestudy.

Blood, like non-drip thixotropic paints, shows afall in viscosity with time during shearing, and thisshear-thinning effect is particularly noticeable whenreadings are made at low shear. Ideally, a separateblood sample should be used for each shear-ratereading, but when this is impracticable, low-shearreadings should precede high-shear readings on thesame specimen.

Erythrocyte sedimentation

Since Fahraeus' initial investigations on the rateof sedimentation of red cells in plasma,l2 theerythrocyte sedimentation rate (ESR) has been usedas a screening test for alterations in plasma proteinin disease. The ESR is a low-shear (gravity) system inwhich the larger molecular weight plasma proteinscan overcome the red cell zeta potential and exerttheir maximal effect on rouleaux formation and redcell sedimentation.13 Fibrinogen is the plasmaprotein with the greatest influence on the ESR,in both acute and chronic inflammation,'415 andalthough the ESR also correlates with serumgamma globulin15 16 its association with the otherplasma proteins is more tenuous. Other largemolecular weight substances, such as dextran'7and fibrin monomer,'8 19 also increase erythrocytesedimentation and blood viscosity, whereas the lowmolecular weight dextrans20 and the smaller fibrindegradation products2' do not.

Unfortunately, the ESR, like blood viscosity, is

dependent on haematocrit and, even in non-anaemic patients, there is a negative correlationbetween ESR and haemoglobin.22 Correction of theESR for anaemia may be misleading, however, sincethe influence of red cell factors is then ignored.23Also, there is dispute over the normal range of theESR24 which rises with increasing patient age.22These considerations have led to the developmentof alternative screening tests for disease.The effect of asymmetrical macromolecules, such

as fibrinogen, in overcoming the zeta potentialbetween individual red cells in a suspension can alsobe measured as the zeta sedimentation ratio (ZSR).25This technique, using the Zetafugeg (Fig. 2;Coulter Electronics Ltd, Barnstaple), has con-siderable practical advantages over the ESR,including correction for anaemia. The ZSR providesa good assessment of disease activity, including thatof rheumatoid arthritis,26 and correlates well withthe ESR in routine clinical practice.27

Fig. 2 Coulter Zetafuge for measurement of the zetasedimentation ratio.

Plasma viscosity also correlates with the ESR,particularly in non-anaemic patients, but it cor-relates more closely than does the ESR with plasmafibrinogen and gamma globulin.'6 Measurement ofplasma viscosity is another useful screening test fordetecting alterations in plasma proteins in acute andchronic disease28 and has the considerable advantagesof being unaffected by anaemia or by the age andsex of the patient.Whole-blood viscosity has not been adequately

studied as an alternative to the ESR although it isstated that the correlation between them is poor.5

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Further comparison between the ESR, plasmaviscosity, whole-blood viscosity, and ZSR in acuteand chronic diseases is now required.

Measurement of plasma viscosity

Since plasma behaves as a Newtonian fluid, the shearrate at which its viscosity is measured is not critical.Thus a simple capillary viscometer, in which theshear rate is not only unphysiologically high butalso varies across the lumen of the tube, may beused. Viscosity is determined by the time taken for thetest plasma to flow through a capillary tube atcontrolled temperature. The latter must be keptconstant, since viscosity is highly dependent ontemperature, although the actual temperatureselected is not critical.The Harkness29 viscometer (Fig. 3; Coulter

Electronics Ltd, Barnstaple) is the most commonlyused capillary viscometer for the measurement ofplasma viscosity. Measurements are usually madeat 25°C, and this give a normal range of 1.50-1.72mPa s. The instrument is reliable, easy to use, andaccurate30 provided the temperature does not fluc-tuate and partial blockages of the capillary tube arespotted. Measurement of plasma viscosity, reviewedby Harkness,28 has now replaced the ESR in severaldiagnostic laboratories in the United Kingdom.

Measurement of whole-blood viscosity

Capillary viscometers, as designed at present, shouldnot be used to measure whole-blood viscosity owingto the high and inconstant shear rate at which theyoperate. Blood viscosity should be measured ata known and constant shear rate, and the whole ofthe specimen should be exposed to the same shear.The ideal instrument should operate over a widerange of shear rates, and it is the extent of this range,particularly at lower shear, that dictates its cost.

MEASUREMENTS AT HIGHER SHEARAt high shear rates (above 100 s-1), and down toabout 20 s-1, most rotational viscometers operatewith a low coefficient of variation. The Wells-Brookfield microviscometer (Fig. 4; Baird and

Fig. 4 Wells-Brookfield whole-blood viscometer.

Fig. 3 Coulter viscometer for measurement ofplasmaviscosity.

Tatlock Ltd, London) was the first widely availablecommercial viscometer of this type. It consists of arotating cone suspended on, and driven by, aberyllium-copper spring. The cone is located ina stationary cup surrounded by a water jacket andcontaining the blood sample (0.8 ml). The springtransmits its rotational force through the cone to theblood, and the drag applied by the blood is measuredby the same suspension system. The latter is robustand the instrument simple to operate but, although

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the shear rate can be adjusted over the range standardised1-230 s-1, the instrument is not sufficiently sensitive is claimed tcto give accurate readings below 20 s-1. It can be pension systerecommended, however, for viscosity measurements at shear rat(at intermediate and high shear rates. however, and

system is obtaMEASURE-MENTS AT LOWER SHEARThe Low Shear 30 Contraves viscometer (Fig. 5; MEASURE-MEContraves Industrial Products Ltd, Ruislip) consists In the Deelr rof a cylindrical bob suspended inside a water- Leeds) a conjacketed cup containing the blood sample (0 9 ml). either a conThis instrument differs in that the cup, rather than measuring systhe bob, is driven and thus transmits rotational torque (shear rate)across the blood to the bob which is suspended on direct measura wire to which a mirror is attached to reflect from a Contnrrotal tonal movement. The degree of sensitivity is as ostosuch that viscosity can be measured at shear rates yield stressbelow 01 s-1 provided the instrument is mounted patholstresson an anti-vibration table and protected by a wind- pathologicalshield. The operator working at low shear requiresskill to centre the bob after it has been lowered into OSCILLATORthe cup, and if this is done too slowly, particularly Viscosity meawhen the fibrinogen level is high, a false-low reading been made usiis obtained as a result of red cell settling. cone-and-platiThe recently introduced Haake CVI0 viscometer ometer R19;

(Fig. 6; MSE Scientific Instruments, Crawley) was Bognor Regidesigned to overcome some of these operational system (Contrdifficulties. The bob is supported and centred by an application oair bearing and is lowered automatically under also requires i

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conditions into the blood sample; thisD eliminate the problems of wire sus-ims. The instrument does not measurees as low as the Contraves system,lthe increased stability of the suspensionained at the expense of some sensitivity.

NT OF YIELD STRESSheometer (Rheometer Marketing Ltd,stant torque (shear stress) is applied toie-and-plate or a concentric-cylinderstem, and the resulting speed of rotationis recorded. This provides a more*ement of yield stress than extrapolationaves rheometer tracing.3' The clinical,the theoretical, significance of a raisednow requires to be determined inconditions.

LY FLOWsurements during oscillatory flow haveing a capillary viscometer,32 a rotationalte system33 (Weissenberg rheogoni-; Sangamo Weston Controls Ltd,is), and a cylindrical bob-and-cupraves Low Shear 30-sinus). The clinicalf measurements in oscillatory modefurther investigation.

Fig. 5 Contraves Low Shear whole-blood viscometer.



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Fig. 6 Haake CVJOO whole-blood viscometer.

Red cell deformability

The role of red cell deformability at high shear rateshas already been mentioned. In the microcirculation,where the diameter of the blood vessel lumen may be3 ,pm, the deformability of erythrocytes is alsoessential for normal flow, A particularly at points ofcapillary bifurcation.35 Three main factors determinered cell deformability: first, the viscoelasticity of thecell membrane, which in turn is dependent on themolecular structure of the membrane and themetabolic state of the cell; second, the cell geometryor, more specifically, the ratio of surface area to cellvolume; and third, the internal viscosity of the cell,as determined by the physical state of the haemo-globin.A variety of techniques have been devised to

investigate deformability. Red cells suspended ina Ringer-albumin solution have been subjected toboth high and low shear in a rotational viscometer,36the results at high shear reflecting internal viscosityand the low-shear values reflecting cell geometryand membrane elasticity.37 Deformability underconditions of rotational shear can also be measuredby shining a laser beam through a cell suspension inthe Ektacytometer (Technicon, Domont, France) andobserving the resulting pattern of diffraction rings.38The amount of red cell packing following centri-fugation has also been used as a measure ofdeformability.39 A more widely used technique is themeasurement of red cell filtration through a poly-

carbonate membrane, and this method is sensitive toboth the internal viscosity and the geometry of thecell. Erythrocytes may be filtered through 5 ,umpolycarbonate filters under conditions of eitherpositive40-42 or negative43-45 pressure.

Alternatively, the deformability of individual redcells may be studied by aspiration into a micro-pipette, using either partial aspiration into a 1 tzmmicropipette to test membrane elasticity46 or totalaspiration into a 3 [Lm micropipette to test cellgeometry and membrane properties.47 Also, byusing a membrane filter of 0-6 jum pore size, theelasticity of single cells may be studied by takingscanning electron micrograph measurements of thecell membrane protrusions into the filter resultingfrom negative pressure48 49.

These techniques measure different aspects of celldeformability. Although the polycarbonate-mem-brane filtration technique is frequently used becauseof its simplicity, there is a lack of comparativestudies between different methods. The negativepressure system appears less suitable for the study ofrigid (eg, sickled) cells, and dilute cell suspensions,compared with positive-pressure filtration (un-published).

Clinical applications

PERIPHERAL ARTERIAL DISEASEPatients with chronic arterial disease commonlyhave a raised whole-blood viscosity. This has been

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reported in atherosclerotic intermittent claudi-cation,50 idiopathic9 and vibration-induced" Ray-naud's syndrome, and Raynaud's syndrome associ-ated with systemic collagen vascular disease.51 Al-though the hyperviscosity of Raynaud's syndromewas believed to occur at low temperature (27°C)only,9 this finding was not confirmed by others,10 52and patients with various forms of vascular diseaseshow a similar tendency to higher viscosity at lowtemperature."The cause of the hyperviscosity of vascular

disease is poorly understood. Acute-phase proteinsof large molecular size (fibrinogen, haptoglobin, andfactor VIII) are increased in the plasma in peripheralvascular disease and in Raynaud's syndrome" andmay induce rouleaux formation and hyperviscosityat low shear. Although viscosity in intermittentclaudicants has been found to correlate with theplasma fibrinogen level,31 the correlation was poor(r = 0 399), and hyperviscosity was also found athigh shear (230 s-1) when rouleaux are dispersed.Some patients had hyperviscosity despite a normalfibrinogen level but may have had reducederythrocyte deformability.53 Further studies of therelationships between hyperviscosity, hyperfibrino-genaemia, and erythrocyte deformability are

required.Peripheral vascular disease is commonly associated

with a raised serum cholesterol or triglyceride level,and patients with hyperlipoproteinaemia, but withoutovert vascular disease, have shown elevated plasmaviscosity.54 The increase in whole-blood viscosity inperipheral vascular disease does not seem, however,to correlate with the lipid abnormality.3'

DIABETIC MICROANGIOPATHY

Similarities between the retinopathy of diabetesmellitus and that of the hyperviscosity syndromesuggested that diabetic microangiopathy mightresult from abnormal blood flow. Diabetics, com-pared with healthy controls, show elevated bloodviscosity at both high55 56 and low57 58 shear rates,the latter being particularly so in patients withmicroangiopathy. Hyperviscosity, as in intermittentclaudicants, may again be a consequence of theincreased plasma level of large molecular weightproteins (fibrinogen, haptoglobin, and x2-macro-globulin)56 59 which enhance red cell aggregation.60 61

A reduction in erythrocyte deformability, as

measured by membrane filtration5658 and micro-pipette elastimetry,62 has also been found, however,particularly in patients with diabetic complications.58Poor metabolic control reduces erythrocyte de-formability,56 and this may be causally related to thecell level of -glycolysated haemoglobin (Hb Al,)which is hyperviscous62 and binds to the cell

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membrane so that elasticity is reduced.63 In addition,since 2,3-diphosphoglycerate binds less readily toHb Aie,64 there is a consequential increase inhaemoglobin oxygen affinity and thus in haematocritand whole-blood viscosity.

ISCHAEMIC HEART DISEASEAn increase in blood viscosity has been reportedafter myocardial infarction65-67 although this prob-ably reflects the acute-phase hyperfibrinogenaemiaof the immediate post-infarction period. Hyper-fibrinogenaemia has also been reported, however, inpatients with angina68 and extensive coronaryartery stenosis69 and, as in peripheral vasculardisease, this would seem to be a furtherexample of thehyperfibrinogenaemia of generalised atherosclerosis.The raised fibrinogen level, together with an increasein haematocrit,70 result in hyperviscosity in some ofthese patients with ischaemic heart disease.68-69

VENOUS THROMBOSISSurgical patients may be at increased risk of post-operative deep vein thrombosis when there is a pre-operative increase in either plasma fibrinogen,71blood viscosity,72 or blood yield stress.73 Hyper-fibrinogenaemia may again be the common factor.

PRE-ECLAMPSIANormal pregnancy is associated with a rise inplasma fibrinogen and factor VIII antigen and a fallin albumin.74 75 When pre-eclampsia or eclampsiadevelops there is a further decrease in plasmaproteins of small and intermediate molecular sizeand an increase in larger proteins, including fibrino-gen, factor VIII antigen, and OC2-macroglobulin.76-78Plasma viscosity may increase slightly in the third

trimester of normal pregnancy,28 but patients withpre-eclampsia have been reported to show a dis-proportionate increase.79 Further studies are requiredto determine whether the increase in large molecularweight proteins in pregnancy is sufficient to increasewhole-blood viscosity at low shear or whether this iscounteracted by the haemodilution of pregnancy.Such information is important in relation to theplacental insufficiency of pre-eclampsia.

NEONATAL HYPERVISCOSITYNeonatal, like adult, blood shows a disproportionateincrease in viscosity at haematocrit levels above0.65.80 Overtransfusion of placental blood, as a resultof late clamping of the cord, may therefore causea substantial increase in blood viscosity.8' 82Neonatal polycythaemia and hyperviscosity havebeen implicated in the pathogenesis of digitalgangrene,83 inferior vena caval thrombosis,84 cardiacfailure,85 neurological signs,86 necrotising entero-



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colitis,87 and possibly the respiratory distresssyndrome.88 High-risk infants are those with Down'ssyndrome, a diabetic mother, or placental in-sufficiency and intrauterine hypoxia.89

Decreased erythrocyte deformability has also beenreported in neonates with neurological signs,86 butthe contribution of deformability to viscosity in theneonatal period has not been adequately studied.

POLYCYTHAEMIAThrombosis is a relatively common and majorcomplication of polycythaemia vera.90 Althoughpolycythaemic patients often show platelet activationor coagulation hyperactivity, these abnormalitieshave not correlated with thromboembolic com-plications.9' 92 It has recently been shown, however,that the incidence of vascular occlusive episodescorrelates with the haematocrit, not only at high butalso at moderately elevated levels.93 When thehaematocrit was lowered from a mean of 0-536 to0-455, there was a 73% increase in cerebral bloodflow, as measured by xenon-133 clearance,94 andwhen lowered from 0 493 to 0-426 there was a 50%increase in flow.95

Iron-deficient red cells, however, may have re-duced deformability96 and cause an increase inwhole-blood viscosity in polycythaemia.97 Thus careshould be taken to ensure that iron deficiency,induced by repeated venesection, does not causeparadoxical hyperviscosity.

SICKLE-CELL DISEASEPatients in the asymptomatic steady state of homo-zygous sickle-cell disease have a raised plasmaviscosity, and this rises further during the first weekof a painful, vaso-occlusive crisis. These increasesare related to the raised total serum globulin level ofthe steady state98 and to the hyperfibrinogenaemiaof painful crisis,42 99 respectively.Whole-blood viscosity is also increased in the

steady state,37 98 however, and a further rise occursduring crisis.99 In the steady state, the increasedviscosity is partly a consequence of circulatingirreversibly sickled cells but hyperviscosity persistsafter their removal by centrifugation.36 Thus theremaining cells, although morphologically normalwhen oxygenated, presumably have reduced de-formability, and this may be a consequence of theirincreased calcium content.100 101The cause of the increased whole-blood viscosity

during vaso-occlusive crisis is not clear although thisincrease seems to be important in relation to theaetiology of crises. Although the older literaturestates that the percentage of irreversibly sickled cellsdoes not change during crisis,'02 if the percentage offormaldehyde-fixed sickled cells is studied daily

during crisis there is a progressive fall over the firstthree days.42 103 This fall probably results fromtrapping and destruction of sickled cells in themicrovasculature. A study of the percentage offixed sickled cells, and of the deformability andviscosity of the remaining non-sickled cells, over thefew days immediately preceding the onset of painwould be of great value since the relative importanceof intra- as opposed to extra-erythrocytic factors ininitiating crisis is unknown.

OTHER HAEMOLYTIC ANAEMIASWhereas the erythrocytes of hereditary spherocytosiscause a slight increase in whole-blood viscosity,'04the more sensitive deformability techniques arerequired to demonstrate the abnormal rheology ofmost other haemolytic anaemias. A reduction inerythrocyte deformability has now been demon-strated in patients with unstable Hb Koin,'05pyruvate kinase deficiency,106 glucosephosphateisomerase deficiency,'07 glucose-6-phosphate de-hydrogenase deficiency,108 autoimmune haemolyticanaemia,109 and heterozygous and homozygous 9thalassaemia."10111 Suggested causes for the reductionin deformability have included the presence ofinclusion bodies (Heinz bodies or precipitatedot globin chains), an altered ratio of cell surface areato cell volume, increased viscosity of haemoglobin,and increased rigidity of the cytoplasmic membraneas a result of polypeptide aggregates or the attach-ment of haemoglobin. Reduced deformability of asubpopulation of red cells is clearly relevant to theirselective sequestration and destruction in the spleen.The relationship between red cell deformability andhaemolysis has recently been reviewed."12

THE HYPERVISCOSITY SYNDROMEThe combination of raised plasma viscosity withvisual disturbance and retinopathy, bleeding frommucous membranes or into the skin, neurologicalsymptoms, or cardiorespiratory failure is known asthe hyperviscosity syndrome (HVS)."13-1"5 Anexpanded plasma volume has recently been added tothis symptom complex."16The HVS occurs most frequently in Waldenstrom's

macroglobulinaemia"5 and less commonly in myelo-matosis, although IgA and IgG3 paraproteins havea particular tendency to form large molecularaggregates."7 118 Occasionally the HVS has resultedfrom circulating rheumatoid factor complexes."9 120Measurement of plasma, or serum, viscosity is

a more reliable guide to the diagnosis of HVS thanis the ESR, which may be normal, or even low, inthe presence of highly viscous plasma. An increasingconcentration of the abnormal protein produces anexponential increase in viscosity,28 but large asym-

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metrical molecules, including molecular aggregates,have the greatest effect. Accordingly, IgM hasa greater effect, molecule for molecule, than IgG,thus explaining the higher incidence of HVS inWaldenstrom's macroglobulinaemia. Plasma vis-cosity, conventionally measured at 25°C, may givea false high reading in the presence of a cryoglobulin,however, and additional measurements should bemade at 37°C.The degree of hyperviscosity required to produce

the clinical HVS varies from patient to patient,although it is relatively constant for each individual.Retinopathy and neurological symptoms are rarelyseen, however, below a serum viscosity of 4 mPa S.116

Studies of whole-blood viscosity in the HVS haveshown substantial increases at a variety of shearrates,121-123 and this may reflect increased cellaggregation.124 125 The measured viscosity may, how-ever, be normal if not corrected for the anaemia thatfrequently co-exists.125126 Coating of the red cellmembrane with paraprotein could account for theone report of decreased red cell deformability inthe HVS,125 but this observation requires con-firmation.

LEUCOCYTES AND VISCOSITY

Leucocytes normally contribute little to bloodviscosity but patients with a leucocytosis above200 x 109/1127 or a leukaemic blast cell count above100 x 109/1128 may develop symptoms and signs ofhyperviscosity; both neurological and pulmonarysymptoms have been associated with leucostasis inthe smaller blood vessels.129-131

Deformability of the polynucleated mature granu-locyte is dependent on surface irregularities of itscytoplasmic membrane. These provide a membranereserve that can be stretched smooth during de-formation in the microvasculature.132 In contrast,the immature myeloid cell, having a relatively largenucleus, is less deformable and thus contributesdisproportionately to hyperviscosity.'32 133 Theleukaemic patient is, however, usually protectedfrom the theological effects of leucocytosis byco-existing anaemia, until he is transfused to above10 g/dl when cerebral leucostasis and death mayfollow.128 Leucapheresis can be of dramatic clinicalbenefit,'27 and a blast cell count of 100 x 109/1 shouldfirst be reduced by leucapheresis, or chemotherapy,before the haematocrit is fully corrected.

Treatment of hyperviscosity

PLASMAPHERESIS

Since the first report of successful treatment of theHVS in Waldenstrom's macroglobulinaemia byplasmapheresis,134 this procedure has been widely

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applied, and it has also been used, with transientbenefit, in myelomatosis.135 Large volumes of para-protein can be removed by the continuous-flow cellseparator.'36 137The procedure has also been used to lower the

plasma fibrinogen level, and thus whole-bloodviscosity, in patients with Raynaud's syndrome138-140and atherosclerosis'4l and it may also cause animprovement in red cell deformability in Raynaud'ssyndrome.140 Although the resulting clinical improve-ment may be a short-term one, this can be ofsignificant benefit to the patient with severe tissueischaemia.

HAEMODILUTIONThere is evidence that blood viscosity in the capillariesis largely determined by plasma viscosity and byerythrocyte deformability, haematocrit exerting littleor no effect on flow resistance.142 Although it isunlikely, therefore, that a reduction in arterial orvenous haematocrit will exert an equivalent effect onthe viscosity of capillary blood, there is evidencefrom clinical studies that haemodilution can improveregional blood flow. Venesection in patients witha high normal haematocrit increases cerebral bloodflow,95 and diabetics with limb ischaemia, buta haemoglobin level below 12 g/dl, are more likelyto achieve satisfactory wound healing after ampu-tation than diabetics with a haemoglobin above13 g/dl.143 Beneficial effects of lowering the haemato-crit have also been described after myocardialinfarction,70 before elective surgery,144 and inintermittent claudication.145 Further studies of theeffects of isovolaemic haemodilution on tissueoxygen delivery are required.

DRUGS THAT LOWER VISCOSITY

AnticoagulantsThe fibrinogen-lowering effect of ancrod results ina marked decrease in whole-blood viscosity,146-'48but the evidence that other anticoagulants owe anyof their antithrombotic action to a reduction inviscosity is unconvincing. Low-dose subcutaneousheparin was shown to reduce low-shear viscosity inhealthy volunteers and in patients undergoingsurgery,'49 although this was not confirmed ina subsequent study of subcutaneous and intravenousheparin;150 nor does in vitro anticoagulation withheparin alter viscosity.7 31 It was claimed15' thatcoumarin anticoagulants reduce plasma and whole-blood viscosity, but the latter values were notcorrected for an accompanying fall in haematocrit,and viscosity readings were made at unphysiologic-ally high shear using a capillary viscometer.



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Other drugsA variety of drugs have been claimed to influenceviscosity by either reducing the plasma fibrinogen orincreasing red cell deformability. Clofibrate, forexample, lowers plasma fibrinogen'12 and reducesthe hyperviscosity of patients with intermittentclaudication.153 Isoxsuprine is also stated to lowerplasma fibrinogen and viscosity,l54 155 while cin-narizine may reduce hyperviscosity in peripheralvascular disease by its effect on erythrocyte calciummetabolism and thus membrane flexibility.156Oxpentifylline was reported to increase erythrocyteflexibility under hyperosmolar conditions, byincreasing cellular ATP,157 158 and troxerutin mayaffect red cell aggregation and deformability.159fl-blockers are also stated to increase red cellflexibility and reduce viscosity.160 The majority ofthese observations require confirmation, however,before clinical studies and therapeutic trials areundertaken.Low molecular weight dextran can be used effec-

tively for haemodilution,161 but there is little evidencethat any of the dextrans have an effect other thandilution in lowering blood viscosity.

Conclusion

In recent years, a variety of new methods have beenintroduced for the study of blood viscosity and redcell deformability, and a period of consolidation isnow required. Clinical studies are needed to allowevaluation of, and comparison between, these newtechniques so that some degree of standardisation ofshear rate, temperature, and other instrumentvariables can be achieved.

Hyperviscosity is, of course, the result of aninteraction between several different plasma and redcell components, and the contribution of eachcomponent in different clinical situations requires tobe carefully defined. Hyperfibrinogenaemia is oneof the more important factors affecting viscosity butthe cause of the increase in fibrinogen, and otherlarge molecular weight acute-phase proteins, inchronic vascular disease is unknown. Yet thisinformation must be of fundamental importance tolong-term control of the hyperfibrinogenaemia andhyperviscosity. Similarly, since there is no satisfactorydrug for the correction of increased red cell rigidity,the in vivo factors that adversely affect deformability(hypoxia, low temperature, low pH, and reducederythrocyte ATP) should be studied in parallel withdeformability to establish the cause of the increasedcell rigidity. While the cause of the hyperviscosity ofpolycythaemia and paraproteinaemia is obvious, themechanism is not at all clear in arterial disease, andthis area requires urgent investigation.

References

Schmid-Schonbein H, Wells R. Quantification of thedynamics of red cell aggregation. Bibi Anat 1969;10:45-51.

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161 Dormandy JA. Influence of blood viscosity on blood flowand the effect of low molecular weight dextran. .Br MedJ 1971 ;4:716-9.

Requests for reprints to: Professor J Stuart, The QueenElizabeth Hospital, Department of Haematology, QueenElizabeth Medical Centre, Edgbaston, BirminghamB15 2TH, UK.



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Bloodtheology - Journal of Clinical Pathology · Unfortunately, the ESR, like blood viscosity, is dependent on haematocrit and, even in non-anaemic patients, there is a negative correlation