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Blood Volume in Monoclonal Gammopathy By Raymond Alexanian The plasma volume, red cell volume, or both were measured in 1 70 normal, ane- mic, or polycythemic subjects. For anemic subjects without a serum protein abnor- mality or splenomegaly, the relationship between hematocrit and red cell volume was linear and predictable. In patients with a serum monoclonal globulin on dcc- trophoresis, the plasma volume was sig- nificantly increased for the hematocrit in 30%, and the total blood volume was in- creased in 45%. The frequency of an dc- vated plasma volume was higher in pa- tients with a markedly increased level of monoclonal protein. Reductions of ab- normal proteins with chemotherapy were associated with declines in plasma vol- ume. For a specific concentration, the serum viscosity was highest in patients with 1gM proteins and lowest in patients with lgG globulins. Marked elevations in viscosity were noted only in sera with macroglobulinemia or with more than 5 g/dl of IgG or IgA globulins. N UMEROUS MEASUREMENTS of blood volume have been con- ducted in patients with hematobogic disorders. The relationship between hematocrit and red cell volume has been considered unpredictable, and the necessity of red cell volume assessments for the precise definition of anemia and erythrocytosis has been emphasized.'4 An increased plasma volume has been documented in many patients with splenomegaby, multiple myeboma, or macro- gbobubinemia.57 Yet the relationship ofplasma volume and viscosity to the type and level of the monocbonal globulin has not been fully clarified. This report summarizes results of plasma volume, red cell volume, and serum viscosity determinations the absence in patients with multiple myeboma and macrogbobulinemia. In of serum monoclonab globulins, there is a predictable relationship between the hematocrit and the red cell volume. For patients with abnormal proteins, the plasma volume is greater than expected for the hematocrit in a large fraction of the patients. The serum viscosity is increased primarily in pa- tients with macrogbobulinemia or very high concentrations of IgG or IgA globulins. MATERIALS AND METHODS The red cell volume, plasma volume. or both were measured in 170 human beings summarized in Table I. The control population consisted of 16 healthy volunteers in whom the range, mean, and I SD for red cell volume was 950 1300 ml/sqm (mean 1100 130). The upper limit of the normal range was 1900 ml/sqm for plasma volume and 2800 ml/sqm for total blood volume. Blood volume studies were conducted in 140 consecutive patients with chronic anemia. Forty- two with bone marrow failure had a decreased red cell volume due to aplastic anemia, sidero- blastic anemia, lymphoma, myeloma, or solid tumors, but without splenomegaly or a serum protein abnormality: 98 had serum monoclonal globulins due to myeloma or macroglobulinemia. Irmtz the Department o/ Medicine. The University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, Texas. Submitted Januars' 30, 1 976; accepted September 21 . I 976. Supported by USPHS Grants A M 09155. CA 03195. and CA 05831. Addressfor reprint requests: Raymond Alexanian. M. D. . Department of Medicine. The Universitt' of Texas M. D. Anderson Hospital and Tunor Institute. (C) 1977 by Grune & Stratton, Inc. Houston. Texas 77025. Blood, Vol. 49, No. 2 (February), 1977 301 302 Normal red cell volume Normal volunteers Increased red cell volume Secondary erythrocytosis Decreased red cell volume Myeloma with only Bence Jones protein Other bone marrow diseases without splenomegaly Serum monoclonal gammopathy Multiple myeloma SerumlgGpeak Serum gA peak Macroglobulinemia Table 1 . Patien t Population No. Patients Median Age 16 32 14 51 12 53 30 57 68 64 20 56 10 65 RAYMOND ALEXANIAN Hematocrit Median and Range 47 (42-50) 61 (56-72) Mean 1 SD 47 2 61 5 34 (21-42) 32 (19-45) 34 6 32 7 29(14-46) 30 (20-46) 26 (19-43) 306 32 8 29 6 Studies in the latter patients with abnormal serum globulins, when compared with those in anemic patients without a protein abnormality, defined the effect of serum monoclonal proteins on the plasma volume and red cell volume. Fourteen patients with secondary erythrocytosis due to pulmonary disease were also evaluated to document the changes associated with a high red cell volume. Only patients previously untreated by chemotherapy, splenectomy, or phlebotomy were included. No patient was included with other causes for an increased plasma volume such as heart failure, pleural effusion, liver disease, or renal disease with a blood urea nitrogen greater than 35 mg/dl. Except for five patients with macroglobulinemia and mild splenomegaly, no patient with an enlarged spleen was included. The age distribution and hematocrit values are presented in Table I. The red cell mass was measured in I 19 human beings with 51Cr-labeled red cells by a gravi- metric technique as previously described;3 microhematocrit determinations on venous blood samples were performed in triplicate. The plasma volume was measured simultaneously with 125l-labeled albumin (Albumotope. W. R. Squibb & Sons): the linear extrapolation of at least three measurements over a 15-mm interval defined the amount of plasma radioactivity immediately after the isotope injection.8 The total blood volume was derived from the sum of the measured red cell and plasma volumes. The serum viscosity was measured at 37'C with an Ostwald capillary viscometer, and the time in seconds was expressed relative to distilled water at the same temperature. Each patient included in this report had at least one of these studies, and all procedures were conducted in 49 of the 98 patients with a serum protein abnormality. RESULTS Control studies. The control ranges for the relationship between the venous hematocrit and the red cell volume, as well as between the hematocrit and the plasma volume, were defined from studies in normal subjects, patients anemic from bone marrow failure without splenomegaby, and patients with secondary erythrocytosis (Fig. I). When the hematocrit was less than 40, there was a linear relationship between the hematocrit and red cell volume in accordance with the following regression line calculated by the least squares method: Red cell volume (mb/sqm) hematocrit = (vol/dl) 7 -9 In anemic patients without an abnormal serum protein or splenomegaby, this curve predicted the red cell mass from the hematocrit to within 20% of the mea- MONOCLONAL GAMMOPAIHY 303 70 -.. 60 / * / .50 `#{149} - Fig. 1 . Relationship between hematocrit and red cell volume, and between hematocrit and plasma volume. Results in nor- mal subjects (#{149p}a)tients anemic from marrow failure without myeloma or splenomegaly (), anemic patients with only Bence Jones proteins (#{149}a)nd patients with secondary erythrocytosis ( a) are compared. Dotted lines define the range for all red cell mass re- suIts and the 90% confidence interval for individual plasma volumes. /. 1,4 1 / `I #{231},"/ 30 / 4./ ,/ / 7 #{149} #{149}. . . ,. . ` ,- 000 2000 000 2000 3000 Red Cell Mass (mi/M2 Plasma Volume (ml/M2) sured value. For hematocrit values greater than 50, there was a progressively greater elevation in red cell volume with serial increments in hematocrit (Fig. 1). Similarly, a linear regression line was calculated for the increasing plasma volume associated with increasing degrees of anemia below a hemato- crit of 40. Plasma volume (mb/sqm) = hematocrit (vob/dI) 018 - 60 The dotted lines in Fig. 1 defined the 90/ confidence limits for individual values of plasma volume for a specific hematocrit.9 The total blood volume did not exceed 2800 ml/sqm in any normal or anemic subject. Multiple myeloma and macroglobulinemia. Myeloma patients producing only Bence Jones protein had a red cell volume and plasma volume appropriate for the hematocrit (Fig. 1). As indicated in Fig. 2A, 26 of myeboma patients with a serum monocbonal globulin had an increased plasma volume with no dif- ference in the frequency of patients with IgG or IgA myeboma proteins (25#{176}4 and 29#{176}r,espectively): the frequency of an elevated plasma volume was higher in patients with an abnormal globulin level above 4 g/dl (29/) than in those with a concentration equal to or less than this level (l3#{176}/), but this difference was not significant (p > 0.2). Of 14 patients with a hematocrit of 40 or more, only one had an elevated plasma volume. The total blood volume exceeded 2800 mI/sq m in 45#{176}o4f patients with IgG or IgA globulin peaks. Six of nine patients (67) with monoclonal macroglobulinemia also showed an increased plasma volume (Fig. 2A), along with a total blood volume greater than 2800 304 RAYMOND ALEXANIAN 4Q4 . 3O :;> .. ..` . :20 ..#{149} _8 #{149} * L ... ` .c #{149}#{149}#{149} \ N ......,... 10 1000 2000 . 3000 000 2000 Plasma Volume (mI./M2) 3000 500 000 Red Cell Volume (ml/M2) Fig. 2. (A,B) Relationship between hematocrit and plasma volume in anemic patients with serum monoclonal gammopathy, in comparison with the control range for plasma volume defined in Fig. 1. Results in patients with increased lgG globulins (.), IgA proteins (H), and lgM globulins ( D) are compared. Changes in the increased plasma volume after chemotherapy are indicated for nine patients in whom the pretreatment serum monoclonal globulin ranged from 5.7 to 8.0 g/dl and posttreatment values ranged from 0.6 to 3.1 g/dl. (C) Increased red cell volume for the hematocrit in most patients with an abnormal serum globulin in comparison with the control range defined in Fig. 1. mb/sq m. Of 16 patients with an increased plasma volume and a serum mono- cbonal globulin, 15 had a red cell volume measured simultaneously that was higher than the upper limit of the range predicted for the hematocrit: of 34 patierfts with a normal plasma volume, only 12 had an increased red cell volume (Fig. 2C). In two patients, the hematocrit was as much as 6 less than the lower limit predicted for the red cell volume. In 9 patients with monoclonal globulins greater than 5.5 g/dl and an increased plasma volume, serial measurements were repeated after chemotherapy had reduced the concentration by at least 50#{176}cA. s indicated in Fig. 2B. reductions in abnormal protein bevel were as- sociated with marked declines in plasma volume. Serum viscosity. The serum viscosity was evaluated in 72 consecutive, pre- viousby untreated patients with serum monocbonab gammopathy due to myeboma (63 patients) or macrogbobubinemia (9 patients). Results were corn- pared with studies in normal volunteers, myeboma patients with only Bence Jones protein, and patients with anemia from other causes in whom the serum viscosity ranged from 1 .4 to 2.0. An elevated serum viscosity was confirmed in 78#{176}o(f, the patients with multiple rnyeboma. Only 14 myeboma patients (22#{176}) had a viscosity index greater than 3.0, and only three (5#{176})showed an index greater than 4.0 (two of lgG type, one of IgA type). No patient had symptoms of hyperviscosity. For a specific concentration of myeboma globulin, the mean serum viscosity was highest in patients with 1gM globulins and lowest in pa- tients with abnormal IgG proteins. While the viscosity for sera with monocbonab 1gM proteins of a specific concentration was significantly higher than that for sera with IgG or IgA globulins (p < 0.01), the difference between sera with in- creased IgA and IgG proteins was not significant (p > 0.3). In no patient with macrogbobulinemia did the calculated whole blood viscosity exceed 6.5 centi- poises using the formula proposed by Mannik.'#{176} An increased serum viscosity was usually associated with an increased concentration of myeboma globulin so MONOCLONAL GAMMOPAIHY 305 6 (I) E - cD4 E a) Ct) Fig. 3. Correlation between the magnitude of the serum monoclonal component and relative serum vis- cosity. Data from patients with ab- normal globulins of lgG (.), IgA (i ;), and lgM () types are compared. Dotted lines include the ranges for all measurements except for two pa- tients with macroglobulinemia. 2 0 0 . /...:. : j% .0,, 00 S0 i... i 0#{149}. i#{1490}#{1409}#{/149} i i #{1490Os} / 0 #{149} 0 iI #{149}:#{149} lo I 2 34 5 Relative Serum Viscosity 6 that a viscosity index greater than 3.0 was confirmed in 14 patients with an IgG or IgA level greater than 4 g/db, but in none with a lower serum concentra- tion (Fig. 3). Two patients with 1gM globulins had a viscosity index greater than 5.0, despite a serum concentration less than 4.0 g/dl. DISCUSSION Numerous hematobogic disorders have been associated with abnormalities in red cell volume, plasma volume, or both. This report presents the results of blood volume studies in a large number of patients with chronic anemia and monocbonab gamrnopathies. Individuals with splenomegaly or other known causes for an increased plasma volume were excluded. Standard isotope pro- cedures were used: results were expressed in terms of the body surface area: and both men and women were combined in the analyses. Since an elevated plasma volume may occur with anemia from any cause, increased values were defined by elevations greater than expected for a specific hematocrit; an elevated total blood volume was confirmed when the combined red cell and plasma volumes exceeded the highest value identified in our control population. In the anemic patients without serum monocbonal globulins or splenomegaly who were studied, there was a linear and predictable relationship between the hematocrit and red cell volume. For patients with a hematocrit less than 40, the red cell volume was predictable within 20#{176}o,,f the measured value. Huber et ab. defined the close relationship between venous hematocrit and red cell volume in normal and anemic subjects and found that only patients with a disproportionate increase in plasma volume due to certain medical disorders showed any deviation.4 Thus the red cell volume can be deduced from the 306 RAYMOND ALEXANIAN hematocrit in the absence of clinical disorders known to affect plasma vol- ume.'7 With erythrocytosis, the red cell volume increased more markedly than predicted from increments in the venous hematocrit. This observation was also noted by others,4'5 and was attributed to the normal plasma volume in most pa- tients with a high hematocrit.6 The total body hematocrit is the ratio of the red cell mass to the sum of the red cell mass and plasma volume: thus, a specific increase in a high red cell volume would elevate the hematocrit less than the same number of red cells added to a bow red cell volume. A large fraction of patients with serum monocbonab proteins due to myeboma or macrogbobulinemia had an increased plasma volume and total blood vol- ume. A falsely elevated plasma volume may have resulted from a rapid loss of radioactive albumin to the extravascular space during the isotope procedure because of increased capillary permeability or a decreased serum albumin pool. Since the measured red cell volume was also higher than predicted for the hematocrit in the same patients considered to have an increased plasma vol- ume, this possibility was unlikely. An increased plasma volume has been well documented in patients with macrogbobulinemia, where the danger of transfusing patients with hyper- volemia has been emphasized.7" Similar observations have been described in isolated patients with myeboma."2 This report documents that a large fraction of myeloma patients with a serum protein abnormality have an increased plasma volume and total blood volume. Thus, some of the apparent "anemia" in many patients with serum monoclonal gammopathy results from an ex- panded plasma volume, which produces a measured venous hematocrit as much as 6 lower than that predicted from the red cell volume. Direct measurements of the red cell volume in patients with serum protein abnormalities, and a low hematocrit will spare many the need for unnecessary and potentially hazardous red cell transfusions. Demonstration of an increased plasma volume, using more rapid and convenient isotope procedures, may also explain a low hemato- crit. In patients with macrogbobulinemia, assessments of plasma volume also provide a more rational basis for plasmapheresis. The hyperviscosity syndrome has been described in many patients with Wald- enstr#{246}m's macrogbobulinemia, as well as in some with multiple myeloma. Mac- Kenzie et al. have demonstrated that serum viscosity values greater than 6.0, and 1gM concentrations greater than 4 g/dl are usually necessary before symptoms occur.7"3 Marked increases in serum viscosity may occur with low 1gM levels, and only slight increases in viscosity may occur with high 1gM levels. The absence of clinical evidence of hyperviscosity in our study was attributed to the low concentration of 1gM globulin present in most of our pa- tients who usually had been referred for the evaluation of an overt lymphoma or chronic lymphocytic leukemia. Since hyperviscosity complications may occur with low concentrations of 1gM globulins, the serum viscosity and plasma volume should be determined in all patients with 1gM peaks. Serum hyperviscosity of slight degree occurred in most of our myeloma pa- tients with monoclonal serum globulins, but none showed any clinical mani- festations from this abnormality. Similar magnitudes of hyperviscosity have been described in other patients with multiple In one series, pro- MONOCLONAL GAMMOPATHY 307 teins with an IgG3 subclass were present in about one-half of the IgG patients with hyperviscosity.'5 For similar protein levels, the serum viscosity was higher when IgA, rather than IgG, globulins, were present; this was attributed to the higher molecular weight and the greater tendency of IgA molecules to form polymers. Since serum hyperviscosity has been reported only when abnormal IgG or IgA proteins exceeded 5.0 g/db,'4'7 serum viscosity measurements are indicated in myeboma patients only when monocbonal globulins are greater than this bevel. The authors are indebted ACKNOWLEDGMENT to Brenda Doherty and Eloise Smith for their technical assistance. REFERENCES I. Berlin NI, Lawrence JH, Elmlinger PJ: Recent advances in the knowledge of total red cell volume, production and destruction. Blood 12:147 164. 1957 2. Nathan DG: Comments on the interpreta- tion of measurements of total red cell volume in the diagnosis of polycythemia vera. Semin Hematol 3:216-219. 1966 3. Donohue DM. Motulsky AG. Giblett ER, et al: 5tCr as a red cell tag. Br J Haematol I: 249 263. 1955 4. Huber H, Lewis SM, Szur L: The in- fluence of anaemia, polycythaemia and splenomegaly on the relationship between venous hamatocrit and red cell volume. Br J Haematol 10:567-575, 1964 5. Bowdler AJ: Blood volume studies patients with splenomegaly. Transfusion 171-181, 1970 in 10: 6. Bowdler AJ: Plasma volume and splenomegaly in polycythaemia vera. Br J Haematol 22:331-340, 1972 7. MacKenzie MR. Brown E, Fudenberg H I-I. et al: Waldenstr#{246}m's macroglobulinemia: Correlation between expanded plasma volume and increased serum viscosity. Blood 35:394- 408. 1970 8. Crispell KR. Porter ofplasma volume using tagged with radioactive 29:513 516, 1950 B. Nieset RT: Studies human serum albumin iodine. J Clin Invest 9. Snedecor GW. Cochran WG: Statistical Methods (ed 6). Ames, low" State Univ Pr. 1967, pp 153 157 10. Mannik M: Blood viscosity in Walden- strom's macroglobulinemia. Blood 44:87-98, I 974 II. Kopp WL, MacKinney AA. Wasson G: Blood volume and hematocrit value. Arch In- tern Med 123:394 396.1969 12. Kopp WL, Beirne GJ. Burns RO: viscosity syndrome in multiple myeloma. HyperAm J Med43:141-l46, 1967 13. MacKenzie M, Babcock J: Studies of the hyperviscosity syndrome. I 1 . Macroglobuli- nemia. J Lab Clin Med 85:227 234. 1975 14. Smith E. Kochwa 5, Wasserman L: Ag- gregation of lgG globulin in vivo. Am J Med 39:35 48. 1965 IS. Capra JD. Kunkel HG: Aggregation o gamma-G3 proteins: Relevance to the hyper viscosity syndrome. J Clin Invest 49:610621. I 970 16. MacKenzie MR. Fudenberg HH. O'Reilly RA: The hyperviscosity syndrome. I. In lgG myeloma. The role of protein con- centration and molecular shape. J Clin Invest 49:15 20. 1970 17. Benninger GW. Kreps SI: Aggregation phenomenon in an lgG multiple myeloma re- suIting in the hyperviscosity MedSl:287 293. 1971 syndrome. Am J