Context.-Polycythemia describes an increased proportion of red blood cells in the peripheral blood. In absolute polycythemia, there is increased red cell mass (RCM) with normal plasma volume, in contrast with apparent polycythemia, in which there is increased or normal RCM and decreased plasma volume. In order to deliver the appropriate treatment it is necessary to differentiate between the two.
Objective.-A retrospective analysis of RCM and plasma volume data are presented, with special attention to different methods of RCM interpretation.
Design.-The measurements of RCM and plasma volume in 64 patients were compared with the venous and wholebody packed cell volume, and the incidence of absolute and apparent polycythemia was determined for increasing hematocrit levels. Measurements of RCM and plasma volume were performed using chromium 51-labeled red cells and iodine 125-labeled albumin, respectively. The measured RCM of each patient was expressed as a percentage of the mean expected RCM and was also defined as being within or outside the range of 2 SD of the mean. The results were also expressed in the traditional manner of mL/kg body weight.
Results.-Twenty-one patients (13 women and 8 men) had absolute polycythemia. None of them had an increased plasma volume beyond 2 SD of the mean. When expressed according to the criteria of mL/kg body weight, 17 of the 21 patients had abnormally increased RCM, but 4 patients (19%) had a normal RCM value. Twenty-eight patients had apparent polycythemia. The remaining 15 patients had normal RCM and plasma volume.
Conclusions.-The measurement of RCM and plasma volume is a simple and necessary procedure in the evaluation of polycythemia. In obese patients, the expression of RCM in mL/kg body weight lacks precision, considering that adipose tissue is hypovascular. The results of RCM are best described as being within or beyond 2 SD of the mean value.
(Arch Pathol Lab Med. 2005;129:89-91)
Polycythemia or erythrocytosis describes an increased proportion of red blood cells in the peripheral blood.1,2 Absolute polycythemia includes primary polycythemia (congenital [due to truncation of the erythropoietin receptor] and acquired [polycythemia vera; PV]) and secondary polycythemia (congenital [high affinity hemoglobin], autonomous [high erythropoietin production], and acquired [hypoxemia, renal disease, and idiopathic polycythemia]). Apparent polycythemia is also known as relative, stress, spurious, pseudopolycythemia, and Gaisböck syndrome. Possible mechanisms include physiological variant, hypertension, renal disease, fluid loss and diuretics, alcohol consumption, obesity, smoking, arterial oxygen desaturation, pheochromocytoma, and the early stage of development of absolute polycythemia.
In absolute polycythemia there is a true increase in the proportion of red blood cells; red cell mass (RCM) is increased, while plasma volume is not lowered. In contrast, the majority of the patients with apparent polycythemia have an increased or normal RCM and a lower plasma volume; one third of them have a plasma volume that is below normal levels. Measuring RCM and plasma volume helps differentiate between absolute and apparent polycythemia.3 It is important to make this differentiation in order to deliver the appropriate treatment.
MATERIALS AND METHODS
A total of 64 consecutive patients were studied: 26 women and 38 men. The mean age was 58 years (range, 23-87 years). Most patients were referred to our department to exclude or confirm the diagnosis of absolute polycythemia or erythrocytosis. No selection of patients was used.
Clinical information was obtained and additional diagnostic criteria for PV, including arterial oxygen saturation, leukocyte and platelet counts, leukocyte alkaline phosphatase level, and serum B12 score, were collected. The size of the spleen was also recorded.
The measurements of RCM and plasma volume were obtained using chromium 51-labeled red cells and iodine 125 (^sup 125^I)-labeled albumin, respectively, following the guidelines proposed by the International Committee for Standardization in Haematology.·1 In general, 10 to 15 mL of whole blood was incubated with a small volume of acid-citrate-dextrose solution and 50 µCi of ^sup 51^Cr for 45 minutes. Five milliliters of whole blood was reserved for background activity. Following the incubation period, ascorbic acid (50-100 mg) was added to reduce the hexavalent chromium to the trivalent state and to stop the binding of ^sup 51^Cr to red cells; 5 µCi of ^sup 125^I-albumin was than added, and aliquots were taken from the tagged blood for preparation of standards. The tagged blood was reinjected into the patient's circulation, and samples were drawn at 10, 20, and 40 minutes postinjection from a different vein. The packed cell volume (PCV) was obtained for all samples using the microhematocrit method, and the mean of the 3 measurements was calculated. Aliquots from the samples, standard, and background were counted.
The mean expected RCM was calculated for each patient using 2 well-established methods: the method based on body surface area proposed by Hurley5 and the method based on height and weight by Nadler et al." A confidence interval of 2 SD was calculated for each mean expected RCM. The measured RCM of each patient was expressed as a percentage of the mean expected RCM and was also defined as being within or outside the range of 2 SD of the mean. A patient was considered as having absolute polycythemia if the measured RCM was above 2 SD of the mean, with either method (Hurley or Nadler). The results were also expressed in the traditional manner of mL/kg body weight. Values above 36 mL/kg in men and above 32 mL/kg in women were considered abnormal. The measured plasma volume of each patient was also expressed as a percentage of the mean expected plasma volume and were defined as being within or outside the range of 2 SD of the mean using the formula of Hurley. The plasma volume was considered abnormal when above or below 2 SD of the mean.
The total body hematocrit was obtained directly from the ratio RCM/RCM+plasma volume. The ratio of total body to venous hematocrit (TBHF) was calculated for all patients. The results obtained in patients with absolute polycythemia were compared with the results obtained in patients with no polycythemia, and statistical analysis was performed using the 2-tailed Student t test.
RESULTS
Twenty-one patients (13 women and 8 men) had absolute polycythemia or erythrocytosis according to the SD criteria using the formulas of Nadler and/or Hurley (Tables 1 and 2). None of these patients had an increased plasma volume beyond 2 SD of the mean. However, the plasma volume of 4 patients was elevated 12% to 18% above the mean. The mean venous PCV for men with absolute polycythemia was 58.3 ± 7.6, and for men with no polycythemia, this value was 51.6 ± 3.2 (P = .04). The mean venous PCV for women with absolute polycythemia was 56.7 ± 3.9, and for women with no polycythemia, this value was 48.1 ± 4.9 (P
Absolute polycythemia was observed in men at a minimum venous PCV value of 51.4 and was always present when the PCV was above 59.4. It was observed in women at a minimum venous PCV value of 51.1 and was always present when the PCV was above 58.1. Tables 1 and 2 correlate the distribution of absolute and apparent polycythemia compared to PCV values in men and women, respectively. A peculiar case involved a 47-year-old woman with a venous PCV of 56.9 who actually had a diminished RCM (80% of the mean). However, her high PCV was explained by a markedly diminished plasma volume (only 52% of the mean). Excluding this case, absolute polycythemia occurred in all women at a PCV of greater than 52.0. When expressed according to the criteria of mL/kg body weight, 17 of the 21 patients had abnormally increased RCM, but 4 patients (19%) had a normal RCM.
Twenty-eight patients had apparent polycythemia (20 men and 8 women) and the remaining 15 patients had normal RCM and plasma volume values. Regarding plasma volume, it was significantly diminished in 19 patients: 16 patients had normal RCM, but 3 patients had increased RCM (16%). Forty-four patients had a normal plasma volume: there were 18 patients with increased RCM and 26 patients with normal or decreased RCM. Only 1 patient had an increased plasma volume with a normal RCM.
The calculated TBHF for all the patients was 0.86 ± 0.05 (0.54-0.96), for patients with absolute polycythemia this value was 0.87 ± 0.04 (0.79-0.96), and for patients with apparent polycythemia this value measured 0.85 ± 0.06 (0.54-0.92) (P = .23).
Complete agreement between Hurley and Nadler's estimations was observed in 45 of the 64 patients. Nineteen patients showed a discrepancy between the methods: in 14 patients, the discrepancy was between normal or low RCM, but this difference did not change the diagnosis. Four patients were more than 2 SD above the mean according to Hurley but were within 2 SD according to Nadler, although their percent deviation from the mean was almost identical (1% discrepancy). When considering only patients with increased RCM, the agreement between the methods is 74% (14/19).
DISCUSSION
The laboratory parameters used for evaluation of blood volume, including hemoglobin, red cell count, and PCV, may not always reflect the total RCM because of variations in plasma volume.7
Traditionally, the results of RCM measurements were interpreted using the formula of mL/kg body weight. This approach was also adapted by the polycythemia study group for the diagnosis of PV and in the report made by the International Committee for Standardization in Haematology.4 Values above 36 mL/kg in men and above 32 mL/kg in women are commonly considered abnormal. However, since adipose tissue is hypovascular, a more accurate assessment of RCM should refer to the lean body mass. The measurements of lean body mass are inconvenient and time consuming and, therefore, several estimates were proposed that take into consideration the lean body mass.
In our study we applied 2 commonly used predictions: those based on height and weight, proposed by Nadler et al6 in 1962, and those based on body surface area, proposed by Hurley5 in 1975. Four of the patients with elevated RCM using the predictions of Nadler and Hurley had a normal RCM/kg but were 2 SD above the mean expected RCM (eg, a patient who weighed 81 kg with a surface area of 2.01 m^sup 2^ had 33.8 mL/kg RCM and another patient who weighed 103.8 kg with a surface area of 2.30 m^sup 2^ had 32.7 mL/kg RCM). These findings confirm the observation that mL/kg values of RCM may be inaccurate in the individual patient and may be used only for screening of large populations.
In normal subjects the total blood volume (body) hematocrit is consistently lower than the peripheral venous hematocrit, and the mean ratio (TBHF) is approximately 0.89 to 0.92.8,9 This ratio, however, was found to rise in direct proportion to the size of the spleen, indicating an increased concentration of erythrocytes in the enlarged spleen.9,10 In our patients, the calculated TBHF for patients with polycythemia was 0.87 ± 0.04, a value that was not significantly different from those of the rest of the patients (0.85 ± 0.06). This ratio is utilized in some laboratories when using only one radioisotope to calculate the volume of one compartment when measuring the other. However, the wide range of values obtained for the TBHF makes this approach unreliable. In addition, 3 patients with increased RCM had decreased plasma volume below 2 SD of the mean, and 3 additional patients had plasma volumes less than 85% of the mean. Consequently, measurements of plasma volume alone cannot be used to predict relative polycythemia.
The incidence of relative polycythemia in men was 52% in the PCV range of 50.5 to 59.5 and in 25% of women in the PCV range of 48.0 to 52.0. These values are higher than those found by Pearson et al11 (18% of male patients in the PCV range 0.500-0.599). However, Davies et al12 found relative polycythemia in all 25 patients referred for RCM measurements, although in that study, mL/kg values were used. Our results indicate that both PV and RCM should be measured in all men with PCV values of greater than 50.5 and in all women with PCV values of greater than 48.0 (although in our series no woman was found with true polycythemia when the PCV was less than 51.1), since a large proportion of these patients may have a relative polycythemia.
Twelve patients in our study (7 men and 5 women) had an apparent polycythemia with PV and RCM values in the normal range. The mechanisms responsible for apparent polycythemia (with or without diminished PV) are poorly understood. An association was made with obesity, hypertension, cardiovascular disease, smoking, alcohol consumption, renal disease, stress, and diuretic therapy.11
Pearson et al11 proposed that the measured RCM must exceed the predicted mean normal value by 25% to be consistent with absolute polycythemia, based on 95% confidence limits of the predictions made by Nadler et al. However, using this criterion in our patients would result in 19% false positives (4/21) and 9.5% false negatives (2/ 21). Consequently, we prefer to use the SD as the discriminator. The measurements based on SD as proposed by Hurley were more closely associated with increased RCM of 25% above the mean.
COMMENT
The measurement of RCM and plasma volume is a simple and necessary procedure in the evaluation of polycythemia. With the appropriate prediction methods (eg, Nadler or Hurley), it is more accurate than PCV for the differential diagnosis between PV and other types of polycythemia. The results of RCM are best described as being within or beyond 2 SD of the mean value, rather than expressing the results in terms of mL/kg body weight.
Measurement of plasma volume alone cannot be used to predict the RCM. In addition, the ratio of TBHF is not changed significantly in patients with absolute polycythemia.
References
1. Pearson TC, Messinezy M, Westwood N, et al. A polycythemia vera update: diagnosis, pathobiology, and treatment. In: Hematology 2000, The American Society ot Hematology Education Book. Washington, DC: American Society of Hematology: 2000:51-68.
2. Murphy S. Polycythaemia vera. Dis Monthly. 1992;38:157-212.
3. Eridani S. Polycythemia: from clones to clinic. Haematologica. 1993;78: 345-352.
4. International Committee for Standardization in Haematology. Recommended methods for measurement of red-cell and plasma volume. J Nucl Med. 1980; 21:793-800.
5. Hurley PJ. Red cell and plasma volumes in normal adults. J Nucl Med. 1975:16:46-52.
6. Nadler SB, Hidalgo JU, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962:51:224-232.
7. Berlin NI. Diagnosis and classification of the polycythemias. Semin Hematol. 1975;12:339-351.
8. Gregersen Ml, Rawson RA. Blood volume. Physiol Rev. 1959:39:307-342.
9. Fudenberg H, Baldini M, Mahoney JP, Dameshek W. The body hematocrit/ venous hematocrit ratio and the "splenic reservoir." Blood. 1961:17:71-82.
10. Toghill PJ. Red-cell pooling in enlarged spleens. Br J Haematol 1964;10: 347-357.
11. Pearson TC, Botterill CA, Class UH, Wetherley-Mein G. Interpretation of measured red cell mass and plasma volume in males with elevated venous PCV values. Scand J Haematol. 1984:33:68-74.
12. Davies SW, Clynne-|ones E, Lewis EP. Red face and reduced plasma volume. ; Clin Pathol. 1974:27:109-112.
13. Messinezy M, Pearson TC. Apparent polycythaemia: diagnosis, pathogenesis and management, Eur J Haematol. 1993;51:125-131.
Mordechai Lorberboym, MD; Naomi Rahimi-Levene, MD; Helena Lipszyc, CNMT; Chun K. Kim, MD
Accepted for publication August 10, 2004.
From the Division of Nuclear Medicine of the Department of Radiology, The Mount Sinai Medical Center, The Mount Sinai School of Medicine, New York, NY (Dr Lorberboym, Ms Lipszyc, and Dr Kim); and the Blood Bank and Hematology Institute, Assaf Harofeh Medical Center, Zerifin, Israel (Dr Rahimi-Levene).
The authors have no relevant financial interest in the products or companies described in this article.
Corresponding author: Mordechai Lorberboym, MD, Department of Nuclear Medicine, Edith Wolfson Medical Center, Holon, 58100, Israel (e-mail: mvlorber@zahav.net.il).
Copyright College of American Pathologists Jan 2005
Provided by ProQuest Information and Learning Company. All rights Reserved
Contact
Home
A
Arthritis