evaluation of hyperviscosity in monoclonal gammopathies

Evaluation of Hyperviscosity in Monoclonal Gammopathies

JEFFREY CRAWFORD, M.D.

EDWIN B. COX, M.D.

HARVEY JAY COHEN, M.D.

Durham, North Carolina

From the Department of Medicine, Veterans Ad- ministration Medical Center, and the Compre- hensive Cancer Center and Center for the Study of Aging and Human Development, Duke Univer- sity Medical Center, Durham, North Carolina. This work was supported in part by the Geriatric Fel- lowship Program and the General Medicine Re- search Service of the Veterans Administration, the Mallinckrodt Foundation, and the Southeastern Chemotherapy Study Group, and was presented in part at the 25th Annual Meeting of the American Society of Hematology, San Francisco, California, December 3-6, 1983. Requests for reprints should be addressed to Dr. Jeffrey Crawford, Department of Medicine, Veterans Administration Medical Center, 508 Fulton Street, Durham, North Carolina 27705. Manuscript accepted November 19, 1984.

The serum or plasma hyperviscosity syndrome has been described in both monoclonal and polyclonal immunoglobulin disorders. The usefulness of initial and serial plasma viscosity measurements by an automated viscometer technique was evaluated and compared with serum protein electrophoresis data in 107 patients without monoclonal gammopathies and 153 patients with monoclonal gammopathies. In patients without monoclonal gammopathies, plasma viscosity correlated best with the concentration of gamma globulins. In patients with monoclonal gammopathies, plasma viscosity correlated best with the serum monoclonal protein concentration, but individual patient variations in the ratio of plasma viscosity to monoclonal protein concentration made accurate prediction of plasma viscosity difficult without direct measurement. Six of eight patients with plasma viscosity above 5.0 cp had classic symptoms of hyperviscosity syndrome, and four of the six had recurrent episodes. Six other patients with plasma viscosity above 4.0 cp had more subtle presentations of hyperviscosity but responded equally well to therapeutic lowering of plasma viscosity. These patients are part of a larger subset of 27 patients in whom initial plasma viscosity was above 3.0 cp. No patient with an initial plasma viscosity below 3.0 cp subsequently showed hyperviscosity symptoms. Plasma viscosity measured by this technique is a useful tool in screening patients with dysproteinemias to identify and monitor those with and at risk for the hyperviscosity syndrome.

The “serum hyperviscosity syndrome” has been described clinically as the triad of bleeding, visual signs and symptoms, and neurologic manifestations [I]. This oncologic emergency occurs in patients with IgM, IgG, and IgA monoclonal gammopathies as well as in some patients with polyclonal immunoglobulin disorders [2]. Early recognition is critical so that therapy can be instituted to reverse clinical symptoms and to prevent the evolution to irreversible sequelae of retinal hem- orrhage [3] or stroke [4]. Since these clinical features may have causes other than hyperviscosity in a patient with a dysproteinemia, laboratory confirmation is essential. The hyperviscosity syndrome occurs at a monoclonal or polyclonal protein concentration that differs for each patient; therefore, direct viscosity measurement is the pro- cedure of choice for diagnosis [5].

The ability to manage the hyperviscosity syndrome has been im- proved dramatically by the availability of automated plasmapheresis to achieve short-term reversal of the clinical signs and symptoms [6] and, in some patients, for long-term prophylactic management of the protein disorder [ 71. On the other hand, advances in the monitoring

July 1985 The American Journal of Medicine Volume 79 13

HYPERVISCOSITY IN MONOCLONAL GAMMOPATHIES-CRAWFORD ET AL

Figure 1. Coulter Harkness viscometer. Methylene blue has been added to sample reservoir A to be drawn through capillary 6 to reservoir C by a vacuum pump attached at point D and located behind the viscometer. During normal opera- tion, this viscometer is immersed in a temperature-controlled water bath. To determine viscosity of a plasma sample, the sample is placed in reservoir A and stopcock E is opened to the vacuum pump until the mercury in capillary F falls from the upper reservoir to reservoir G (in progress in this picture). This raises the level of the mercury in reservoir l-l. Stopcock E is then closed and the mercury level rises in capillary F and falls in reservoir H, drawing the plasma sample through capillary B. The transit time of the sample is monitored by the transit time of the mercury between electrodes I and J, recorded in seconds by the electronic timer K. From this transit time, the viscosity of the sample can then be calculated (see text).

of plasma viscosity have not been widely utilized [5]. Although rotational cone-and-plate viscometers provide accurate and reproducible measurements of viscosity [8], they have generally been most useful in research laboratories. The standard clinical tool for plasma or serum viscosity measurement is the manual capillary viscometer, such as the Ostwald viscometer or simply a red cell pipette [9]. This technique compares the flow time of a patient’s serum to the flow time of water through a capillary, with the result expressed as relative viscosity. The Ostwald viscometer requires at least 5 ml of plasma or serum, and the red cell pipette is diffi-

cult to use under temperature-controlled conditions, such as in a water bath. Both manual techniques are cumbersome and require considerable technician time per sample. These factors may contribute to the limited information available concerning the usefulness of viscosity measurements in longitudinal clinical studies. Therefore we have utilized an automated capillary viscometer (Coulter Electronics) [lo] in an effort to learn more about the relationship of plasma viscosity and paraprotein concentrations in individual patients and groups of patients with and without protein disorders.

PATIENTS AND METHODS

Study Design. Since the summer of 1981, patients being evaluated or treated at Duke Medical Center or the Durham Veterans Administration Medical Center hematology/oncology outpatient clinics or inpatient services for serum protein disorders by serum protein electrophoresis were routinely evaluated with plasma viscosity measurements. For patients subsequently followed longitudinally with serum protein electrophoresis, corresponding plasma viscosity measurements were performed serially. Patients from whom blood was obtained on the same day for serum protein and plasma viscosity measurements were subsequently analyzed in the following groups: (1) no detectable serum monoclonal gammopathy by serum protein electrophoresis, 107 patients; (2) IgG monoclonal gammopathies, 106 patients; (3) IgA monoclonal gammopathies, 24 patients; (4) IgM monoclonal gammopathies, 23 patients; (5) light chain multiple myeloma, 15 patients. In addition to the relationships between class- specific monoclonal immunoglobulin concentrations and plasma viscosity, individual patients’ “M” protein concentrations and plasma viscosity measurements were followed longitudinally and compared with their clinical course. Plasma Viscosity Measurement. Plasma viscosity measurements were made using blood containing potassium EDTA (Vacutainer Systems, Rutherford, New Jersey), generally from the same sample used for blood cell counts. The blood was centrifuged at 750 g X IO minutes, and the plasma was separated and left at room temperature prior to deter- mination. All measurements were made in duplicate using the Coulter Harkness viscometer [ Ill, kindly provided for our investigational use by Coulter Electronics Limited, Luton, England. With this instrument (Figure l), plasma samples (0.5 ml) are placed in a sample reservoir and then drawn through a horizontal capillary tube 20 cm in length with an internal diameter of 0.5 mm. The shear stress remains constant in the system by virtue of 75 mm Hg pressure created by an on-line vacuum pump. An electronic timer measures the transit time of the sample in seconds as a reflection of the shear rate of the sample. By maintaining a constant shear stress, the shear rate, or transit time of the sample, is then proportional to the sample viscosity. To convert the sample transit time in seconds to absolute viscosity in centipoise (cp), a correction factor is used based on the flow time of a fluid of known viscosity (3.6 percent sodium chloride). All measurements are made after standard adjustment to 2!Y’C of the water bath, surrounding the capillary system, because of the marked temperature dependence of viscosity [ 121. In

14 July 1985 The American Journal of Medicine Volume 79

patients with cryoglobulins, plasma viscosity at 37’C was also determined. Plasma rather than serum was used in these studies because of the potential for small particles to plug the narrow capillary tube. Similarly, whole blood is difficult to run through this capillary because of white cell or platelet aggregates. However, plasma with widely varied viscosities could be run easily, with results available in a few minutes. The normal range of plasma viscosity for males and females with this technique is 1.50 to 1.72 cp, with a mean of 1.64 f 0.05 (SD) cp at 25% [ 111. In our laboratory, a group of 12 normal adult volunteers had a plasma viscosity of 1.62 f 0.06 cp. Results were reproducible within the range of 0.05 cp in samples left at room temperature for up to two weeks. Even at viscosities greater than 5.0 cp, the variance in results did not increase. Serum Protein Electrophoresis. Serum protein electrophoresis was performed in the Duke and Durham Veterans Administration Medical Center Clinical Special Hematology Laboratories using standard cellulose acetate electrophoresis (Beckman Instruments, Fullerton, California) [ 131. Total serum protein was determined by the biuret method [14]. Individual protein fractions were calculated by a Beckman CDS 200 or RI 12 densitometer tracing of stained electrophoresis gels. Gel fractions were separated into albumin, alpha,, alpha*, beta, gamma, and M (monoclonal) proteins and expressed as g/dl. Suspected monoclonal gammopathies were confirmed or excluded by standard immunoelectrophoresis techniques with antiserum from Meloy Laboratories (Springfield, Virginia) [ 151. When present, both immunoglobulin heavy and light chain specificity were identified. Analysis. For all patients, identifying clinical information, plasma viscosity measurements, and corresponding serum protein electrophoresis data were entered on the Duke Cancer Center computer. Secondary analysis used the time-oriented record for oncology (TORO) system [ 161. As- sociations between plasma viscosity measurements and various serum protein components were evaluated by linear regression analysis after scatter plots had been constructed revealing approximate linearity of relationships and homo- geneity of variance. The linear regression equation for each relationship of plasma viscosity to protein concentration is described in the figure legends by the equation y = a i- bx where a is the intercept and b is the slope, or the amount of change in plasma viscosity (y) per unit of increase in protein concentration (x).

RESULTS

The relationship between plasma viscosity and serum protein fractions was evaluated in samples from 107 patients who did not have monoclonal serum protein disorders and is shown in Figure 2. This group was heterogeneous and included patients with hypogam- maglobulinemia, polyclonal hyperglobulinemia, malignancies not associated with monoclonal gammopathies, and other nonmalignant disorders. For the group, plasma viscosity correlated positively with total protein concentration (r = 0.63) (Figure 2, top). The correlation with total globulins was even greater (r = 0.78) (Figure 2, bottom). For individual protein fractions,

OLH--++t-+H--t- 0' I 5 30 4 5 6.0 7.5 9.0 10.5 12.0 13.5 I!

Total Proteins (gm%)


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‘igure 2. Top, correlation between plasma viscosity (cp) and total serum proteins (g/d/ /gm %I) in patients without monoclonal gammopathies (n = 107patients): r = 0.633; p < 0.0000 1; plasma viscosity 0.430 + 0.193 X total protein; mean total protein 7.82 f 0.9 16 (SD); mean plasma viscosity 7.744 f 0.280 (SD). Bottom, correlation between plasma viscosity (cp) and total serum globulins (gidl [gm %]) in patients without monoclonal gammopathies (n = 107 patients): r = 0.759; p <O.OOOO 1; plasma viscosity 1.095 + 0.229 X total globulins; mean total globulins 2.828 f 0.927; mean plasma viscosity 1.744 f 0.280.

gamma globulin showed the best correlation (r = 0.76), whereas albumin showed a slight negative correlation (r = -0.30) (data not shown). This apparent negative correlation was largely due to the common association of hypoalbuminemia with hypergammaglobulinemia in many patients.

A patient with rheumatoid arthritis had a history of polyctonal hyperviscosity syndrome two years prior to entry in this study. His plasma viscosity was consistently


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higher than predicted for his level of hyperglobulinemia by the group studies (Figure 2, bottom, value of plasma viscosity 3.l/total globulin 6.6). This suggests that, although a general linear relationship between plasma viscosity and globulin concentration exists for the non-monoclonal protein disorders, plasma viscosity may not be accurately predicted from protein concentration measurements for an individual patient. This point is even better demonstrated in subsequent studies of patients with monoclonal protein disorders.

In patients with monoclonal gammopathies, the correlation of plasma viscosity with total protein and total globulin concentrations persisted, but the over- whelming fraction of importance was the monoclonal protein concentration. Figure 3 demonstrates the relationship of plasma viscosity to IgG, IgA, and IgM monoclonal protein concentrations, utilizing the highest M protein concentration and corresponding plasma viscosity measurement for each patient. For 106 patients with IgG monoclonal gammopathies (Figure 3, top), plasma viscosity was strongly correlated with monoclonal protein concentration (r = 0.79). However, marked individual patient variation in the relationship of plasma viscosity to protein concentration is obvious by the scatter of the data points. In contrast, in the 24 patients with IgA monoclonal gammopathies (Figure 3, middle), the scatter is minimal (r = 0.91). Interestingly,

Figure 3. Top, correlation between plasma viscosity (cp) and monoclonal /gG protein concentration (g/d/ [gm %]) in all patients with IgG monoclonal gammopathies; each patient is represented once using the maximal measured plasma viscosity value and the corresponding monoclonal protein concentration (n = 106 patients): r = 0.789; p < 0.0000 1; plasma viscosity 1.506 + 0.309 X monoclonal protein concentration; mean IgG monoclonal protein concentration 2.694 f 1.792; mean plasma viscosity 2.339 f 0.70. Mid- dle, correlation between plasma viscosity (cp) and monoclonal IgA protein concentration (gldl [gm %I) in all patients with IgA monoclonal gammopathies; each patient is represented once using the maximal measured plasma viscosity and corresponding monoclonal IgA protein concentration (n = 24 patients): r = 0.913; p <O.OOOOl; plasma viscosity 1.45 7 + 0.3 1 I X monoclonal protein concentration; mean IgA monoclonal protein concentration 3.168 f 2.124; mean plasma viscosity 2.437 f 0.724. Bottom, correlation between plasma viscosity (cp) and monoclonal IgM protein concentration (gldl [gm %]) in all patients with IgM monoclonal gammopathies; each patient is represented once using the maximal recorded plasma viscosity and corresponding monoclonal IgM protein concentration (n = 23 patients): r = 0.915; p <0.00007; plasma viscosity 0.969 + 1.066 X monoclonal protein concentration; mean IgM monoclonal protein concentration 2.569 f 1.99 1; mean plasma viscosity 3.708 f 2.320.


00 8 16 24 3 2 40 48 56 64 72 80 IgG Monoclonal Protein Concentration (gm %I

Figure 4. Correlation of plasma viscosity in monoclonal IgG protein concentration in two patients with IgG multiple myeloma. Open circles represent Patient 1 with IgG lambda multiple myeloma who had 20 different sample measurements of plasma viscosity and corresponding monoclonal protein concentration: r = 0.857; p <O.OOOO 1; plasma viscosity 0.959 + 0.4 17 X monoclonal protein concentration. Solid circles represent Patient 2 with IgG kappa multiple myeloma who also had 20 different plasma viscosity sample measurements with corresponding monoclonal protein concentration determinations: r = 0.866; p <O.OOOO 1; plasma viscosity 1.444 + 0.175 X monoclonal protein concentration.

the slope of the linear regression equations for both the IgG and IgA plasma viscosity to protein concentrations is similar (0.309 versus 0.31 l), whereas the slope for the IgM plasma viscosity to protein concentration is 1.066 (Figure 3, bottom). Even in this IgM curve, however, the outlying data points suggest individual patient variation in ratio of plasma viscosity to protein concentration that differs from the group relationship. The outlying value of a plasma viscosity of 10.0 cp and an M protein of 5.2 g/d1 in Figure 3, bottom, was found in a patient presenting with the hyperviscosity syndrome. Plasmapheresis lowered his plasma viscosity to 5.2 cp after the first run and 2.7 cp after the second, and he has since been followed elsewhere. The 15 patients with light chain myeloma had no measurable serum monoclonal components. The relationship of plasma viscosity to globulin concentrations in this group was similar to that in the non-monoclonal gammopathy group (data not shown).

Figures 4 and 5 demonstrate the differences in relationships of plasma viscosity to protein concentration between individual patients with monoclonal gammo-

/ + I / I 00 8 16 24 32 40 48 56 64 7.2 80 IgM Monoclonal Protein Concentration (gm %) 1

Figure 5. Correlation of plasma viscosity with monocional IgM protein concentration in two patients with IgM monoclonal gammopathies. Open circles represent Patient 3 with IgM kappa Waldensttim’s rnacroglobulinem~ who had 76 plasma viscosity measurements with corresponding monoclonal protein concentration determinations: r = 0.890; p <O.OOOO 1; plasma viscosity 0.698 + 1.275 X monoclonal protein concentration. Solid circles represent Patient 4 with IgM lambda multiple myeloma who had 79 plasma viscosity measurements with corresponding monoclonal concentration determinations: r = 0.485; p < 0.03; plasma viscosity 2.521 + 0.403 X monoclonal protein concentration.

pathies of the same immunoglobulin class. For each patient, plasma viscosity with corresponding M protein concentrations were determined at multiple intervals during the clinical course. Figure 4 shows these data for two patients with IgG multiple myeloma, both of whom had 20 different measurements with good correlation between plasma viscosity and protein concentration (r = 0.86 and 0.87). However, the slope of the linear regression equation for the two patients is distinctly different (b = 0.175 versus b = 0.417). Figure 5 shows a similar comparison of plasma viscosity to monoclonal protein concentration in two patients with IgM disorders, again showing the marked contrast in slopes of 1.28 and 0.40 for the two patients. (The lower correlation coefficient of plasma viscosity and protein concentration in the second patient will be discussed later).

During the time course of these studies, 35 patients of the total of 153 patients with monoclonal gammopathies had a maximal plasma viscosity measurement greater than 3.0 cp (Table I). Fourteen of these patients had a plasma viscosity greater than 4.0 cp, and all but



TABLE I Maximal Plasma Viscosity Measurements for All Patients with Monoclonal Gammopathies

Maximal Viscosity (cp) (3.0 3.0-4.0 4.0-5.0 >5.0

IgG a4 12 2 3 @A 17 4 1 0 ICIM 7 5 3 5 Total 118 21 6 a Symptoms secondary 0 1 6 6

to viscosity

Figures given are numbers of patients.

two were symptomatic. Both asymptomatic patients had plasma viscosity measurements greater that 5.0 cp without any overt signs of the hyperviscosity syndrome or cryoglobulinemia. The other six patients with plasma viscosity values greater than 5.0 cp had the classic manifestations of the serum hyperviscosity syndrome with retinal changes, neurologic signs or symptoms, and/or mucosal bleeding.

All six patients whose maximal plasma viscosity measurement was between 4.0 and 5.0 cp had symp-

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Figure 6. Comparison of serial monoclonal IgM protein concentration determinations (s/d/ [gm %I), plasma viscosity (P. V.) measurements (cp), and total serum protein (T. P.) determinations (gldl [gm %]) in Patient 4 with IgM lambda multiple myeloma. Symptoms referable to hyperviscosity are listed along with therapeutic interventions (see text for further description of clinical course).

toms responsive to lowering of the monoclonal protein concentration and plasma viscosity, although some of the patients did not have all the classic features of the serum hyperviscosity syndrome. For example, one patient with IgA multiple myeloma presented with iso- lated gross hematuria (without a documented coagu- lopathy) with a plasma viscosity of 4.6 cp and a monoclonal protein concentration of 8.8 g/dl. His symptoms dramatically responded when his protein concentration and viscosity were lowered with plasmapheresis. Two patients with IgM disorders and plasma viscosity measurements of 4.9 and 4.6 cp, respectively, had head- aches, without any other features of the hyperviscosity syndrome, that responded to lowering of plasma viscosity by plasmapheresis in one patient and chemotherapy in the other.

Two additional patients, one with a plasma viscosity of 4.3 cp and one with a plasma viscosity of 3.6 cp, showed altered mental status that was responsive to plasmapheresis. The first patient had Waldenstrom’s macroglobulinenemia, congestive heart failure, and renal insufficiency and had undergone transfusion im- mediately prior to the development of symptoms. The second patient had chronic lymphocytic leukemia with an IgM monoclonal gammopathy and had previously been asymptomatic with a similar plasma viscosity measurement. Altered mental status developed in the hospital after she received four units of packed red blood cells, which precipitated congestive heart failure subsequently treated with diuretics. In these two patients, blood transfusion and altered volume status may have influenced the level of plasma velocity at which symptoms developed. However, in the other symptomatic patients in our series, individual differences in the “symptomatic threshold” of plasma viscosity could not clearly be attributed to differences in the immunoglobulin class, presence of cytoglobulins, or age (one 80-year-old man was asymptomatic with a plasma viscosity of 5.6 cp).

Among the 12 patients with hyperviscosity symptoms, five patients have had recurrent episodes ne- cessitating repeated plasmapheresis and/or change in systemic therapy. Routine plasma viscosity measurements were useful in these patients as an adjunct to monitoring of the clinical course and M protein concentration as shown in the case study in Figure 6. This patient with IgM lambda multiple myeloma, with overt bone disease since 1979, had an initial plasma viscosity of 3.4 cp in 1981 with a corresponding monoclonal protein concentration of 2.0 g/dl. Despite therapy, the M protein slowly increased to 5.8 g/d1 and plasma viscosity rose to nearly 5.0 cp by June 1982. The patient remained asymptomatic until July when he presented with nausea and vomiting, retinal changes, and central nervous system symptoms of lethargy and confusion


consistent with hyperviscosity syndrome. At this time, a plasma viscosity was greater than 6.0 cp, without any measurable change in M protein by serum protein electrophoresis. Subsequent plasmapheresis resulted in a disproportionate decrease in plasma viscosity relative to the monoclonal protein concentration. When symptoms recurred, long-term plasmapheresis was reinstituted over several months to control the symptoms. Subsequent treatment with high-dose cyclo- phosphamide stabilized the monoclonal protein concentration and plasma viscosity without the need for subsequent plasmapheresis. However, the patient’s course was complicated by multiple episodes of sepsis and finally death.

All 12 patients who initially or subsequently showed hyperviscosity symptoms were part of a subgroup of 27 patients with an initial plasma viscosity above 3.0 cp. In contrast, none of the 126 patients with an initial plasma viscosity less than 3.0 cp subsequently had signs or symptoms referable to hyperviscosity, and only eight of these patients showed plasma viscosity above 3.0 cp with disease progression over the two years of the study.

COMMENTS

The first laboratory and clinical observations of increased serum or plasma viscosity were made in the 1930s in patients with multiple myeloma [ 17,181. Subsequently, Waldenstrom [ 191 described a group of patients with macroglobulinemia and increased blood viscosity. The clinical triad of bleeding, ocular disorders, and neurologic signs has been recognized as the serum hyperviscosity syndrome since Fahey et al’s [l] description in 1965. Further studies in selected patients with the hyperviscosity syndrome have identified a variety of factors that influence plasma viscosity, apart from globulin concentration [2], limiting the usefulness of monoclonal protein concentration in predicting viscosity in an individual patient. Currently, major centers vary widely in the means by which viscosity is measured, but the most common measurement still involves manual capillary viscometry [5]. Although such a technique may be able to confirm clinically recognized hyperviscosity syndrome, it has limitations in the identification of patients in the pre-symptomatic stage or in long-term monitoring of such patients. The inad- equacy of current manual methods of diagnosis is in marked contrast to our enhanced ability to manage the complications of hyperviscosity syndrome. The advent and wide availability of automated plasmapheresis [6,7], as well as a broader armentarium of chemo- therapeutic drugs, provide the clinician with multiple therapeutic options, if patients with a high risk for the hyperviscosity syndrome can be identified and accurately monitored. In addition, in patients with symptoms

HYPERvlscoslTY IN MoNOcLot4AL GAMM~PATHIES-CRAWFORD ET AL

mimicking features of the hyperviscosity syndrome, confidence in a plasma viscosity measurement below the symptomatic threshold can be helpful in redirecting attention toward other causes of the patient’s symptoms and in avoiding unnecessary plamapheresis, sometimes utilized as a “therapeutic trial.”

The extreme sensitivity of the viscometer used in the current studies is suggested by previous studies utilizing this instrument in the United Kingdom to measure plasma protein changes associated with inflammation [20]. The normal range is well established at 1.62 f 0.05 cp, and patients with inflammatory disorders generally have plasma viscosities in the range of 1.75 to 2.25 cp. In fact, it has been suggested that plasma viscosity may be a better monitor of inflammatory disease activity than the erythrocyte sedimentation rate [21,22]. In contrast, multiple myeloma and monoclonal gammopathies generally result in an asymptomatic elevation of plasma viscosity to 2 to 3 cp. Studies using this instrument have been carried out in selected patients with the hyperviscosity syndrome, correlated to protein concentration [23] and blood volume [24]. This report is the first study of the utility of routine screening plasma viscosity measurements in the initial evaluation and longitudinal follow-up of a large population of patients with monoclonal gammopathies. For this purpose, this automated viscometer was ideally suited, being reliable, reproducible, and easily adaptable to use in a clinical hematology laboratory.

Several conclusions can be drawn from the study of plasma viscosity and protein concentration in the population studied. First, in patients without monoclonal gammopathies, total globulin concentration-and gamma globulin concentration, in particular-correlated with plasma viscosity. Albumin, a smaller and more globular molecule, had little effect compared with the larger linear globulin molecules [25]. Fibrinogen, the other major plasma protein that influences viscosity [2], was not measured in these studies. Thus, variation in fibrinogen concentrations independently of globulins may explain some of the scatter in the relationship of plasma viscosity to total globulin concentration shown in Figure 2, bottom. However, elevation in plasma fibrinogen alone rarely causes a plasma viscosity greater than 2.0 cp [26]. It may, however, have contributed to some of the discrepant values, such as the patient with a plasma viscosity of 2.5 cp and globulin value of 2.4 g/dl. This patient had widely metastatic carcinoma of the prostate, and this measurement was days prior to his death.

In the subset with polyclonal gammopathies, differences in plasma viscosity for similar protein concentrations were observed, suggesting intrinsic differences in immunoglobulin viscosity. In patients with a polyclonal hyperviscosity syndrome previously studied,



immunoglobulin interaction between Fc and Fab sites was suggested as one explanation [27]. Although the polyclonal hyperviscosity syndrome is a relatively rare disorder, the variation in plasma viscosity observed for similar elevation in globulin concentration shown in Figure 2 suggests that intrinsic differences in viscosity in polyclonal gammopathy disorders may be a more common phenomenon than previously recognized.

Previous studies in individual patients have suggested distinct class-specific differences in intrinsic viscosity due to IgM versus IgG and IgA monoclonal protein concentration, presumably based on differences in molecular size and configuration [28]. In our study, groups of patients with IgM, IgG, and IgA monoclonal gammopathies were analyzed as shown in Figures 3, and this same relationship was validated. As a group, the relationship of IgM monoclonal protein concentration to plasma viscosity suggests a much higher intrinsic viscosity for IgM than for IgG and IgA, both of which have strikingly similar curves.

The relationship of plasma viscosity to class-specific monoclonal protein concentration was generally well described by linear regression analyses. However Figures 4 and 5 graphically demonstrate that the com- posite relationships of class-specific plasma viscosity to protein concentration are composed of widely di- vergent individual relationships of monoclonal protein concentration to plasma viscosity. Therefore, class- specific plasma viscosity/protein concentration relationships are only a crude guide. Knowledge of the relationship of the individual patient’s monoclonal protein concentration to plasma viscosity is a better predictor of the presence of, or risk of, hyperviscosity syndrome in an individual patient.

In Figures 4 and 5, we emphasized the linear relationship of plasma viscosity to protein concentration for individual patients with IgG and IgM monoclonal gammopathies. This apparent discrepancy with some previously published curvilinear relationships [ 1,2] may be due to several factors. First, individual curvilinear relationships are generally seen only in M proteins that display concentration-dependent aggregation or a similar phenomenon [2]. In these protein disorders, the plasma viscosity to protein concentration is linear below a critical threshold that often heralds a rapid increase in viscosity and symptoms, as shown by the highest data point for Patient 4 in Figure 5 and his corresponding symptoms in Figure 6. In several of our other patients with symptomatic hyperviscosity syndrome, a disproportionate increase in plasma viscosity relative to protein concentration was also seen at the time symptoms developed. By the longitudinal nature of the study, however, most of our patient samples were obtained below these critical threshold levels.

20 July 1985 The American Journal of Medlclne Volume 79

Several studies of IgA myeloma have suggested that individual monoclonal protein vary greatly in the percent of polymer formation [29,30]. In those studies, at a given level of monoclonal protein concentration, the plasma viscosity was proportional to the degree of IgA polymer formation. However, in our series of 20 patients, the correlation of plasma viscosity and monoclonal protein concentration was remarkably linear, with a slope similar to the IgG curve. This would suggest that none of the patients with IgA gammopathies in our series had high degrees of polymer formation. Recently, another group of patients with IgA-related hyperviscosity has been described in which hydrophobic inter- actions of IgA with other proteins contributed more to viscosity than did polymer formation [31].

In our series of IgG monoclonal gammopathies, the correlation of plasma viscosity and paraprotein concentration was more variable, with paraproteins in several patients showing significant deviation of their individual plasma viscosity/protein concentration curves from that of the total IgG group. These differences may be due to differences in aggregation commonly seen with lgGa [32], and also described with IgG, [33], linear molecular configuration [34], or other factors in- fluencing intrinsic globulin viscosity such as interaction with other plasma proteins or immune complex formation [2,31,35].

This individual variability in intrinsic globulin viscosity was also seen in the IgM paraproteins. Previous studies had suggested that plasma viscosity in IgM is predictable on the basis of concentration-dependent aggregation [36]. However, as demonstrated in Figure 5, other intrinsic differences must exist to account for the differences in the relationships of IgM paraprotein concentration to plasma viscosity. Whether this is due to intrinsic differences in structural configuration, polymer formation secondary to excess J chain, aggregability, or interaction with other plasma proteins are subjects for future investigation.

Despite these general correlations of class-specific immunoglobulin concentration with plasma viscosity, individual paraprotein concentrations were of limited value in the prediction of plasma viscosity. In contrast, plasma viscosity measurements by the technique used in this study reliably identified symptomatic patients as well as high-risk patients and excluded others whose symptoms may otherwise have been misconstrued to be related to hyperviscosity. In many patients, relationships of protein concentration to plasma viscosity tended to follow a predictable and reproducible course in longitudinal studies. However, in complex patients with recurrent hyperviscosity syndrome and changing volume status due to plasmapheresis, sepsis, transfusions, and/or diuretics, plasma viscosity often changed


significantly while changes in monoclonal protein concentrations were minimal or difficult to detect by serum protein electrophoresis. This may, in part, reflect the difficulties inherent in measuring relatively small differences in monoclonal protein concentrations by serum protein electrophoresis in patients with large monoclonal components [37]. Thus, in these patients, monitoring of plasma viscosity was of major importance in decisions to institute plasmapheresis or change systemic chemotherapy, and in questions of management with regard to hydration and the safety of red cell transfusions.

Clinical hyperviscosity syndrome remains relatively uncommon in most patients with monoclonal gammopathies. In our series, 12 patients among a total population of 153 patients were identified with symptoms referrable to the hyperviscosity syndrome. Twenty-

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seven of these patients initially and eight others subsequently had elevations of plasma viscosity greater than 3.0 cp, identifying them as a potential group at risk for subsequent hyperviscosity syndrome with disease progression and/or change in volume status by dehy- dration and rapid blood transfusion. The intelligent management of patients with the hyperviscosity syndrome and those at high risk, as well as the exclusion of others whose symptoms have causes other than the hyper-viscosity syndrome, requires a reliable longitudinal test of plasma viscosity. Our results would suggest that plasma viscosity measurement by this technique can serve these functions.

ACKNOWLEDGMENT

We thank Jane Davis and Judy Robertson for their technical assistance.

REFERENCES

Fahey JL, Barth WF, Solomon A: Serum hyperviscosity syndrome. JAMA 1965; 192: 120-123.

Crawford J, Cohen HI: Disorders of hyperviscosity. In: Ritzman SE, ed. Pathology of immunoglobulins: diagnostic and clinical aspects. New York: Alan Liss, 1962; 237-259.

Thomas EL, Olk RJ, Markman M, Braine H, Patz A: Irre- versible visual loss in Waldenstrom’s macroglobulinemia. Br J Ophthalmol 1963; 67: 102-106.

Pavy MD, Murphy PL, Virella G: Paraprotein-induced hyperviscosity. A reversible cause of stroke. Postgrad Med 1960; 68; 109-112.

Crawford J, Cohen HJ: The measurement of viscosity. In: Ritzman SE, ed. Pathology of immunglobulins: diagnostic and clinical aspects. New York: Alan Liss, 1962; 13-19.

Russell JA, Toy JL, Powles RL: Plasma exchange in malignant paraproteinemias. Exp Hematol 1977; 5: 105-l 15.

lsbister JP, Biggs JC, Penny R: Experience with large volume plasmapheresis in malignant paraproteinemias and immune disorders. Aust NZ J Med 1976; 6:154-164.

Wells RE: Measurement of viscosity of biological fluids by a cone plate viscometer. J Lab Clin Med 1961; 57: 646- 656.

Wright DJ, Jenkins DE: Simplified method for estimation of serum and plasma viscosity in multiple myeloma and related disorders. Blood 1970; 36: 516-522.

Harkness J: A new instrument for the measurement of plasma viscosity. Lancet 1963; II: 260-261.

Coulter Harkness Viscometer Instruction Manual. Luton, En- gland; Coulter Electronics Limited, Issue B, March 1962.

Whittington RB, Harkness J: Viscosity-temperature variations in human blood-plasma (abstr). Biorheology 1966; 5: 252.

Ritzman SE, Daniels JC: Serum electrophoresis and total serum proteins. In: Ritzman SE, Daniels JC, eds. Serum protein abnormalities: diagnostic and clinical aspects. Boston: Little Brown, 1975; 3.

Henry JB: Clinical diagnosis and management by laboratory methods, vol I. Philadelphia: WB Saunders, 1979; 646.

Ritzman SE, Lawrence M: Qualitative immunoelectrophoresis. In: Ritzman SE, Daniels JC, eds. Serum protein abnormalities: diagnostic and clinical aspects. Boston: Little Brown, 1975; 27.

16.

17.

ia.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

Cox EB, Stanley WE: Schema-driven time-oriented record system on a minicomputer. Comput Biomed Res 1979; 12: 503-515.

Reimann HA: Hyperproteinemia as a cause of autohem- agglutination. Observation in a case of myeloma. JAMA 1932; 99: 1411-1416.

Wintrobe MM, Buell MV: Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 1933; 52: 156-160.

Waldenstrom J: Incipient myelomatosis or “essential” hyperglobulinemia with fibrinogenopenia: a new syndrome? Acta Med Stand 1944; 117: 216-223.

Harkness J: The viscosity of human blood plasma: its measurement in health and disease. Biorheology 1971; 6: 171-196.

Hutchinson RM, Eastham RD: A comparison of the erythrocyte sedimentation rate and plasma viscosity in detecting changes in plasma proteins. J Clin Pathol 1977; 30: 345-351.

Bradlow BA, Haggan JM: A comparison of the plasma viscosity and erythrocyte sedimentation rate as screening tests. S Afr Med J 1979; 55: 415-419.

Preston FE, Cooke KB, Foster MD, Winfield DA, Lee A: Mye- lomatosis and the hyperviscosity syndrome. Br J Haematol 1978; 38: 517-530.

Russel JA, Powles RC: The relationship between serum viscosity, hypervolemia and clinical manifestations associated with circulating paraprotein. Br J Haematol 1976; 39: 163-175.

DuPont PA, Sirs JA: The relationship of plasma fibrinogen, erythrocyte flexibility, and blood viscosity. Thromb Haemost 1977; 36: 660-667.

Harkness J, Whittington RB: Variations of human plasma and serum viscosities with their protein content. Bibl Anat 1966; 9: 226-231.

Hadler NM, Gabriel D, Chung K Su, Teague P, Napier MD: Polyclonal hyperviscosity syndrome. Arthritis Rheum 1977; 20: 1388-1394.

Somer T: Hyperviscosity syndrome in plasma cell dyscrasia. Adv Microcirc 1975; 6: l-55.

Roberts-Thompsom PJ, Mason DY, MacLennan ICM: Rela- tionship between paraprotein polymerization and clinical



features in IgA myeloma. Br J Haematol 1976; 33: 117- 130.

30. Virella G, Preto RV, Graca F: Polymerized monoclonal IgA in two patients with myelomatosis and hyperviscosity syndrome. Br J Haematol 1979; 30: 479-487.

31. Alkner V, Hansson VB, Lindstrom FD: Factors affecting IgA related hyperviscosity. Clin Exp lmmunol 1983; 51: 617-623:

32. Capra JD, Kunkel HG: Aggregation of yGs proteins: reference to the hyperviscosity syndrome. J Clin Invest 1970; 49: 610-621.

33. Lindsley H, Teller D, Noonan B, Peterson M, Mannik M: Hyp- erviscosity syndrome in multiple myeloma. Am J Med 1973; 54: 682-688.

34. MacKenzie MR, Fudenberg HH, O’Reilly RA: The hyperviscosity syndrome. I. IgG myeloma. The role of protein concentration and molecular shape. J Clin Invest 1970; 49: 15-20.

35. Kosaka M, Soloman A: Hyperviscosity syndrome associated with an idiopathic monoclonal IgA-rheumatoid factor. Am J Med 1980; 69: 145-154.

36. Mackenzie M, Babcock J: Studies of the hyperviscosity syndrome. II. Macroglobulinemia. J Lab Clin Med 1975; 85: 227-234.

37. Austin GE, Check IJ, Hunter RL: Analysis of the reliability of serial paraprotein determinations in patients with plasma cell dyscrasias. Am J Clin Pathol 1983; 79: 227-232.


evaluation of hyperviscosity in monoclonal gammopathies

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