Technological advances in blood rheology.

Critical Reviews in Clinical Laboratory Sciences

ISSN: 1040-8363 (Print) 1549-781X (Online) Journal homepage: http://www.tandfonline.com/loi/ilab20

Technological Advances in Blood Rheology John Stuart & Gerard B. Nash To cite this article: John Stuart & Gerard B. Nash (1990) Technological Advances in Blood Rheology, Critical Reviews in Clinical Laboratory Sciences, 28:1, 61-93 To link to this article: http://dx.doi.org/10.3109/10408369009105898

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Date: 13 September 2015, At: 12:07

Volume 28, Issue 1 (1990)

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Technological Advances in Blood Rheology John Stuart and Gerard €3. Nash

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ABSTRACT The science of blood rheology (study of the flow and deformability of blood) is of increasing practical importance to the investigation of blood disorders. In diagnostic laboratories, rheological tests such as the erythrocyte sedimentation rate, zeta sedimentation ratio, and plasma viscosity are used to monitor patients with an acute-phase response of >24 h duration. In sickle-cell anemia, new methods for measuring erythrocyte deformability can be used to investigate the pathogenesis of vaso-occlusion, to test potential anti-sickling drugs, and to monitor drug efficacy in clinical trials. Genetic defects in the structure of the red cell membrane can have rheological consequences, monitoring of which may be useful for diagnosis. Rheological analysis of red cells infected by Plasmodium falciparum has indicated that their abnormal flow behavior may be an important pathological factor in malaria. Finally, the flow behavior of white blood cells, particularly neutrophils, is also important, as these cells, once activated, have the potential to occlude microvessels. The authors have reviewed the laboratory methodology and clinical applications that have led to recent advances in these aspects of blood rheology . Key Words: blood rheology, erythrocyte, acute-phase response, sickle-cell anemia, and white blood cells.

1. INTRODUCTION Blood rheology (the science of the deformation and flow of blood) has origins that date from before the blood letting of barber surgeons, but its development as a scientific discipline has been relatively recent.’ In this century, the name of Fihraeus is credited with many rheological initiatives* and with the clinical application of what has become the most widely used rheological test - the erythrocyte sedimentation rate (ESR). Clinical blood rheology today covers a wide range of tests, from routine methods used to monitor the acute-phase response, such as the ESR, to new techniques for testing antisickling drugs and for studying the activation of white cells. Its growing importance has been recognized by the International Committee for Standardization in Haematology (ICSH), whose Expert Panel on Blood Rheology has prepared guidelines on rheological method~logy.~,~ This review is a critique of technological advances in three major areas of clinical blood rheology: (1) monitoring the acute-phase response, (2) measurement of red cell rheology , and (3) rheological study of white cells. Platelet rheology is an important area in relation to hemostasis, but does not fall within the scope of this review.

~

J. Stuart (corresponding author), M.D., FRCP, FRCPath,

~~

G. B. Nash, B.Sc., Ph.D., Department of

Haematology, Medical School, University of Birmingham, Vincent Dnve, Birmingham, England B 15 2TT

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II. RHEOLOGY OF THE ACUTE-PHASE RESPONSE The acute-phase response is a systemic response to tissue injury irrespective of its etiology. In addition to fever and a leukocytosis, the response includes a rise in blood concentration of most of the proteins synthesized by hepatocytes. Acute-phase proteins that have a molecule that is either large (a,-macroglobulin) or has a frictional ratio (hydrodynamic radius/geometric radius) that is relatively high (fibrinogen) have the greatest rheological effect. This effect is manifest as a rise in plasma viscosity and whole-blood viscosity, and an increase in red cell aggregation and sedimentation.


A. Erythrocyte Sedimentation Rate F&aeus6 and Westergren' developed the ESR as a practical test for monitoring inflammation. It remains one of the most widely used, and misused, laboratory tests. In 1977, ICSH described a standardized version of the Westergren ESR that remains the recommended method for measuring the ESR.' Subsequently, a reference method based on an undiluted Westergren ESR has been described by the National Committee for Clinical Laboratory Standards9 and used as the basis of a quality-control pr~ cedure. ~ Many of the original limitations of ESR technology are being overcome. Improvements in laboratory safety have included the introduction of plastic disposable, rather than glass reusable, ESR tubes, and various automatic suction devices are available for filling the 200mm vertical Westergren ESR tube with the blood sample. A more recent advance in safety is the sealed vacuum aspiration system in which the tube used to draw the blood sample is never opened but is set vertically, as the ESR tube." The labor-intensive nature of the standard Westergren ESR can be overcome by automating both the filling of 200-mm Westergren tubes and subsequent reading of the end-point after 1 h (StaRRsed; R & R Mechatronics, Zwaag, The Netherlands). Automatic tube readers for shorter vacuum aspiration tubes are also now available (Diesse Diagnostica, 53035 Monteriggioni, Italy). Laboratory safety is the driving force behind the trend to closed vacuum aspiration systems for measuring the ESR. Systems based on short vacuum aspiration tubes (Seditainer ESR; Becton Dickinson Vacutainer Sytems, Oxford, U.K.) suffer from the disadvantages of the large volume of drawn blood (5.2 ml) and the 100-mm length of tube that causes the ESR to bottom our above a value of 55 r n d l h. Despite mathematical correction for tube length, ESR values above 55 r n d l h should be regarded as semiquantitative." Proponents of the method argue that this is acceptable in practice, and the test has performed as well as the Westergren ESR in a recent longitudinal study of patients with rheumatoid arthritis." Opponents of the test argue that it combines the disadvantages of the Wintrobe methodI2 (insensitivity to high ESR values owing to the short tube length) with the disadvantages of the Westergren method (insensitivity to low ESR values owing to dilution of the blood with citrate anticoagulant). A vacuum aspiration technique using a tube of 200 mm length has been introduced recently (ESrT-System; LABimport Diagnostics KB, S-43201 Varberg, Sweden) (Plate l).* Sedimentation of aggregated red cells in the ESR tube serves as a useful visual marker of the end-point, but does confer hematocrit dependency on the method. This remains one of the greatest limitations of the ESR, as no satisfactory formula for correction for anemia has been devised. Most ESRs are performed as a screening test for occult disease, and false positive results, arising from coincidental anemia that is not secondary to the disease, lower the specificity of the test. Conversely, in disorders such as rheumatoid arthritis, the anemia of that chronic disease acts together with the acute-phase hyperproteinemia to elevate the ESR. Under this circumstance, the ESR performs better than tests, such 2s plasma viscosity, that depend solely on the acute-phase hyperproteinemia.

* Plate 1 appears following page 68


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6. Plasma Viscosity The hematocrit-independent plasma viscosity is a significant competitor to the ESR. H a r k n e s ~did ~ ~much to publicize the advantages of measuring plasma viscosity, and the selected ICSH methodI4 was based on his in~trument.'~ Now obsolete, the instrument has been replaced by the Coulter Viscometer I1 (Coulter Electronics Ltd., Luton, U.K.), which gives virtually identical results but with automated sampling of the plasma plus a printout of the result.I6 The instrument is semiautomated only and the need for prior centrifugation of anticoagulated whole blood is a significant limitation in comparison with the simplicity of the new vacuum aspiration ESR methods.

C. Measurement of Individual Acute-Phase Proteins Clinical chemists may argue that the dependency of hematologists on rheological methods for monitoring the acute-phase response is obsolete and that a rapid automated assay for Creactive protein (CRP), incorporating the international reference standard,I7 is preferable. Quantitative assay of serum CRP is the test of choice when an acute (5 pm faster than granulocytes, but the difference is lost at apertures of around 3 to 4 prn.I7’Monocytes are said to be the least deformable cells under all conditions. I7’,l8O There is little difference rheologically between eosinophilic and neutrophilic granulocytes,213but B lymphocytes have been shown to be less viscous than T lymphocytes.I8’ To summarize, white cells probably have little effect on arterial blood flow, but are capable of obstructing flow into and through capillaries where they must adapt their normal spherical shape. On the venular side, where flow rates are at their lowest, neutrophils in particular are seen to roll along the wall and to hesitate intermittently.’82This is not directly due to any impaired deformability , but, rather, to adhesive interaction with the endothelium; this can cause white cells to become stationary if they are stimulated.Ig3Such adhesion can increase flow resistance of the blood by restricting the vessel lumen,Is4 but is also the first step necessary physiologically for extravascular migration, enabling neutrophils to cany out their role in the inflammatory response. Such adhesion is therefore seen as a functional property of the cells, but is nevertheless linked to rheological behavior. It should also be noted that microvascular obstruction, mechanical or adhesive, is exacerbated by a reduction in perfusion pressure, which contributes to the important role of white cell rheology in ischemia (see below).

B. Methods of Rheological Analysis and Relationship to White Cell Function Methods used to study white cell rheology are similar in principle to those described earlier for red cells, but, to date, they are less well developed and standardized. Filtration analysis of white cell suspensions, using 5- and 8-pm pore diameter filters, has proven popular. 180.185-187The effects on filtration of different preparative and different cell subpopulations have been studied.”’ White cell suspensions need to be prepared at a fixed concentration and may then be analyzed by measuring changes in flow rate through filter pores at constant pressure’8oor by measuring the changing pressure at a constant flow rate.186It is then possible to carry out analysis of the filtration curves generated by either method and to calculate pore transit time or cellular resistance. 185.188 Simpified parameters have also been used, either characterizing the various stages of flowLpoor using a single flow rate or pressure measurement.187 The rheological behavior of different white cell subpopulations should ideally be evaluated separately. Filtration techniques typically yield parameters that are averaged over a large number of cells and, clearly, this information cannot fully characterize a mixed population of cells. Since the differential white cell count may vary from person to person, differences


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Critical Reviews in Clinical Laborutory Sciences

FIGURE 6. Sequential photomicrographs showing progressive entry of a neutrophil into a micropipette of 4.0 km diameter. Each panel shows (upper right comer) voltage-time curve for automated recording of cell entry. The final curve is computer analyzed to determine cell entry time.

in the proportion of white cells will not be separable from changes in the characteristics of individual cell types. Subpopulation analysis requires a cell separation procedure such as density fractionation. Standardized procedures for sample preparation and cell filtration are needed, but, as yet, there is no consensus on preferred methodology. In theory, analysis of the transit time of single white cells would be advantageous, yielding distributions of cell flow times. This has been carried out using micropipettes, morphologically recognizable cell types being compared. 177 Their entry times into 5-pm pipettes were in the order of seconds for pressures similar to those used in filtration studies (Figure 6). These times agree quite well with averaged transit times computed from filtration flow curves.18oThe number of cells analyzable by pipette entry in this way is in the order of hundreds, but the measurement could be extended to thousands of cells, and made much quicker, using a Cell Transit Analyser (see Section 1II.C for description). Use of this device for white cells is in its infancy and only preliminary reports on granulocytes have so far appeared, mainly using 8-pm pores.189Results show a positively skewed distribution of and are sensitive to intentional flow times, which agrees with pipette entry cell a c t i ~ a t i o n ,as ' ~ expected ~ from previous pipette entry177and filtrationlS5studies. Rheological studies such as these, showing that activation of white cells reduces their deformability , are likely to be biologically significant. Clinical studies have shown that, on a patient by patient basis, white cell filterability is inversely related to the number of morphologically active granulocytes. IW.l9' The decrease in cell deformability is apparently linked directly to stiffening of the region of the cell where a pseudopod p r 0 j e ~ t s . IThis ~~ was demonstrated by using a small micropipette to specifically test the viscoelastic behavior of this region of the cell. Stiffening is probably due to polymerization of internal proteins, particularly actin, since it is prevented by cytochalasin B, which inhibits actin polymer formation. ' 9 3


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If rheological changes in white cells stem largely from their activation, then flow behavior can be expected to be related to their functional status. Thus, cell stimulation in vivo may adversely affect the deformabilty and transit of white cells through microvessels as well as lead to their adhesion to venular walls. This suggests that white cell rheology and function should be examined in parallel when possible. For example, analysis of cell morphology” or the nitroblue tetrazolium reduction could be used to assess activation in parallel with a measurement of flow resistance. In studies of ischemic patients, we have included analysis of cell adhesion to protein-coated glass (method of Boghossian et a1.195)and of neutrophil-neutrophil aggregation using the whole blood technique of Fisher et al.196It remains to be seen how closely the results of such functional measurements correlate with rheological measurements.

C. Methodological Limitations There are certain problems inherent in analysis of the rheology of white cells as opposed to red cells. As mentioned above, the white cell population is highly heterogeneous. This heterogeneity is increased when activation is taken into account, some cells responding to stimulation but not others. Density gradient procedures may separate the major subpopulations, but, because of the ease of activation of white cells, there is concern over the rheological effect of the separation procedure itself. In one study, it was found that the process of density separation had little effect on white cell filterability, but filterability subsequently decreased rapidly on storage of the cells. Considering the highly reactive nature of white cells, it is interesting to speculate to what extent in vitro properties relate to in vivo behavior. Sample withdrawal and preparation may be equivalent to “mild” activation, and the rheological measurement may test white cell responsiveness rather than in vivo flow properties. Such problems have not prevented white cell functional assays - for example, of phagocytic capability19’ - from being carried out in the past, but very careful quality control is clearly required. Interdonor rheological variability, and intrasample variability between cells, is much higher for white cells than for red cells. For clinical studies of white cell rheology, the relatively rapid and simple filtration method seems most applicable. More detailed pipette analysis is useful for studying mechanisms of cellular change,I9’ but the time required and complexity of the method are forbidding. Automated cell transit analysis could be a good compromise, giving information on the effects of subpopulations. This might resolve whether variability in filtration data arises from the reactivity of a small number of cells, as might be expected. D. Clinical Aspects Evidence that changes in white cell rheology may be relevant to disturbances of blood flow was first derived from animal models. In experimental hemorrhagic shock, a decrease in perfusion pressure occurs, and this is followed by maldistribution of microcirculatory flow attributable to capillary plugging by white cells.’99During perfusion of isolated skeletal muscle2” and kidney,20’ injection of a bolus of white cells increases flow resistance, particularly when the pressure is lowered. Not all the white cells can then be washed out of the area on elevation of the perfusion pressure. This is analogous to the situation found in experimental, temporary occlusion of coronary arteries. Here, numerous capillaries are found to become blocked by neutrophils that cannot be removed on reperfusion.202 Reperfusion after such occlusions was dramatically improved if the circulating blood was first depleted of neutrophils. 203 The process of tissue infarction may thus be strongly influenced by white cell trapping. The basic mechanism could in part be rheological, but also related to stimulation of aniving cells so that their adhesiveness increases. Again, it is hard to separate mechanical and


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functional changes in the cells. Trapped neutrophils will cause tissue damage as a result of their extreme reactivity and ability to release oxygen-free radicals and proteolytic enzymes. 204 This is probably as important, or more important, than their mechanical ability to restrict flow. However, rheological factors are likely to affect the initial trapping of white cells in the tissue. From the above, it can be seen that white cell rheology will have the most clinical influence in conditions of reduced perfusion such as chronic peripheral vascular disease, in acute ischemia such as myocardial infarction or stroke, and in shock. White cell-mediated damage has been implicated in all of these, and rheological analysis may be relevant to an understanding of the pathogenesis. 190.191,199~205Marked loss of filterability of all types of white cells has been found in patients with severe ischemia of the leg requiring amputation.190 After myocardial infarction and stroke, filterability is again reduced. 191205 Milder ischemia, such as in intermittent claudication, does not appear to affect rheological properties of circulating white cells,213but there is evidence that acute worsening of ischemia induced by exercise induces white cell activation and alters flow .’06 In severe peripheral ischemia190 and myocardial infarction,’” changes in granulocyte filterability have correlated well with changes in activation assessed by cell morphology. Analysis of white cell rheology could therefore be useful in several ways. First, evidence may be obtained concerning the pathogenetic role of white cells in a disease process. Second, measurements might be used to study the progress of a disease or assess its prognosis. Rheological changes might also be useful for monitoring the effects of therapy. In addition to vascular disease, changes in white cell function and rheology may be implicated in conditions as diverse as diabetes, hemolytic uremic syndrome, and postsurgical complicat i o n ~ .The ~ ~tissue ~ - ~insult ~ ~of surgery or acute ischemia may stimulate neutrophils locally and thereby affect their circulation in other regions of the body. Secondary complications could occur, for instance, in the Thus, several areas of clinical interest require rheological analysis of white cells, particularly granulocytes.

E. Development of Rheological Therapy If white cells, particularly neutrophils, are involved in ischemic damage to tissue, then rheologically active compounds may be of therapeutic value. Such agents might prevent the inappropriate activation of white cells, as this is the most likely cause of rheological changes in vivo. A rheological test, such as filtration, could therefore be used to evaluate putative, rheologically active drugs. For example, pentoxifylline has been shown to improve the flow of a mixture of red cells and white cells taken from patients with intermittent claudication,2” although our own studies have revealed only a minor effect of pentoxifylline infusion on the filterability of white cells from patients with critical ischemia.214 Such ex vivo studies may be supplemented by in vitro testing, particularly in the early stages of drug development. It is likely that white cell stress models will be needed to test the ability of compounds to inhibit both cell activation and rheological change. As with red cells, this approach seems more profitable than attempting to test the ability of a compound to improve the flow properties of normal cells. Stress models should include exposure to mechanical stress, hypoxic conditions, or interaction with platelets, as well as direct stimulation by chemotactic agents or cytokines. In vivo stress, such as exercise (as noted above for claudicants) or experimental acute or chronic ischemia in animals, may also be useful.

VIII. CONCLUSION The technological advances described in this review illustrate the increasing application of blood rheology to clinical medicine. While the importance of determining the molecular basis of disease is undeniable, the expression of a molecular defect at the cellular level



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determines the deformability and in vivo survival time of the human red blood cell. Hence, the importance of rheological techniques that measure the consequences for the intact cell of, for example, molecular defects of hemoglobin or a membrane protein. Rheological techniques are now replacing morphology and gelation of hemoglobin as the basis for testing anti-sickling drugs in vitro and for monitoring their effects in vivo in clinical trials. Red cell rheology is also influenced by the composition of the plasma in which it is suspended. Thus, a rise in the plasma concentration of acute-phase proteins in either acute or chronic vascular disease will enhance cell aggregation and may adversely affect blood rheology . In acute and chronic inflammatory disease, similar increases in acute-phase proteins influence red cell aggregation and sedimentation, which provide the basis of laboratory tests for monitoring the inflammatory response. White cell rheology is a relatively new development of blood rheology, but is likely to improve fundamental knowledge of the pathophysiological consequences of activation of this cell in the acute phase of inflammatory disease. In vascular disease and shock, the adhesive interaction of white cells with vascular endothelium and the plugging of capillaries as perfusion pressure drops may strongly influence the process of tissue infarction. In addition to these functional and mechanical properties, the activated white cell has the potential to release oxidant radicals and proteolytic enzymes, which further compound the cell’s contribution to ischemic damage. Thus, rheological methods are likely to become part of the repertoire of tests for studying white cell activation in disease. The scientific future of blood rheology is clearly dependent on technological advances in laboratory procedures. Although much has been done to improve the sensitivity, specificity, and standardization of rheological method^,^.^ rheological standards are needed to improve quality assurance and better methods are required for the study of subpopulations of red cells and white cells. Such developments can be expected to improve our understanding not only of the humoral factors that influence blood flow, but also of the cellular consequences of molecular defects in blood cells.

ACKNOWLEDGMENTS We are indebted to Action Research for the Crippled Child, The Wellcome Trust, and United Birmingham Hospitals Trust Funds for financial support for sickle cell research, and the British Heart Foundation for support for research on white cell rheology. Investigation of malaria received the financial support of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

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