The red blood cell distribution width

The Journal

of Emergency

Medicine,

Vol. 9, pp. 71-74.

Printed

1991

I” the USA.

THE RED BLOOD CELL DISTRIBUTION Timothy C. Evans, Divison

Reprint address: Timothy

MD,

of Emergency Medicine, Allegheny C. Evans, MD, Division of Emergency Pittsburgh,

Copyright

0 1991 Pergamon

Press plc

WIDTH

and Dietrich Jehle, MD General Hospital, Pittsburgh, Medicine, Allegheny General PA 15212

Pennsylvania Hospital, 320

RED CELL DISTRIBUTION

0 Abstract - The availability of automated blood cell analyzers that provide an index of red blood cell distribution width (RDW) has lead to new approaches to patients with anemia. While the emergency physician is primarily responsible for the detection of patients with anemia, the inclusion of the RDW in the complete blood count has made diagnosing certain anemias easier, especially those that are microcytic. The derivation of the RDW and its clinical application to emergency physicians is discussed and a categorization of anemias based on the mean corpuscular volume (MCV) and RDW is included.

E. North

Avenue,

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Heterogeneity of red blood cell size has historically been identified by qualitative inspection of peripheral blood smears. Anisocytosis refers to an increase in heterogeneity above what is considered “normal.” In 1922, Price-Jones reported direct measurements of red cell diameters and calculated coefficients of variation for these diameters (3). From these measurements he developed histograms that revealed that the mean corpuscular volume and the coefficient of variation (analogous to the RDW) distribute into a bell-shaped curve (Gaussian distribution). Price-Jones further discerned that the MCV and the coefficient of variation were elevated in patients with pernicious anemia, but that the MCV decreased following hemorrhage while the coefficient of variation remained elevated. Unfortunately, subtle changes in the red cells’ size (MCV) and in anisocytosis (RDW) are difficult to see on the blood smear, and technical difficulties in quantitation have prevented the use of anisocytosis as a diagnostic aid in the evaluation of anemias. However, the application of particle-sizing technology has now allowed the rapid and precise quantitation of red blood cell heterogeneity. The RDW is calculated from the coefficient of variation of the red cell volume distribution histogram (4). The standard deviation (SD) of the erythrocyte volume distribution is divided by the MCV and the result is multiplied by 100.

0 Keywords - red blood cell distribution width; anemia

INTRODUCTION The usual classification of anemias has been based on the mean corpuscular volume (MCV) and the reticulocyte count (1). Flow cytometric methods have begun to replace chamber counts for routine blood counts. This has not only resulted in improved speed and precision, but has also allowed the measurement of large numbers of single cells. As a result, quantitative measurements of variations in red blood cell size can now be incorporated into automated blood counts. The red blood cell distribution width (RDW) is a measure of the heterogeneity of distribution of red blood cell size and forms the basis of a classification of anemias based on the MCV and the RDW (2). This classification may have diagnostic utility in the emergency department evaluation of anemias in either children or adults and may guide further evaluation, therapy, and referral.

RDW = (SD of red cell volume)(lOO) MCV

w

Emergency Medicine in Review presents comprehensive surveys plus evaluation and critical interpretation of significant management problems in emergency medicine. Ann Harwood-Nuss, MD, of the University Hospital of Jacksonville, Florida, coordinates this section.

RECEIVED: ACCEPTED:

22 October 1990; FINAL SUBMISSION 8 March 1991

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72

Timothy

Table 1. Classification

Jehle

of Anemia Based on the MCV and RDW

RDW

MCV Normal (normocytic)

Low (Microcytic) Chronic disease (10%) Normal infants between 6 weeks and 2-5 years old Heterozygous thalassema

Normal (homogeneous)

C. Evans and Dietrich

Chronic disease (90%) Normal between 6 weeks old and adulthood Nonanemic hemoglobinopathy Chemotherapy Chronic lymphoctyic leukemia Chronic myelocytic leukemia Hemorrhage Hereditary Spherocytosis

High (macroctyic) Aplastic anemia Preleukemia

Normal newborns Iron deficiency High (heterogeneous)

Early iron, folate or B,, deficiency

Hemolytic disease of the newborn

Mixed deficiency

Folate deficiency

Anemic hemoglobinopathy

Vitamin B,, deficiency

Myelofibrosis Acquired sideroblastrc anemia

Immune hemolytic anemia Cold agglutinins Chronic lymphocytic leukemia with high lymphocytic counts

Homozygous thalassemia RBC fragmentation Hereditary sideroblastic

References 2, 5, 8, 8

anemia

10.

The final result is expressed as a percentage and varies from laboratory to laboratory. The RDW ranges from approximately 11% to 15% in normal subjects (4-6). Blacks and Latin Americans have RDW values that are slightly lower on average than whites, but whether this has any clinical significance is unclear (7). The mean value of the RDW is higher and the range of normals broader in children less than 2 years of age than is accepted for adults according to one study (8). Another study reflects this greater RDW only during the first 6 weeks of life (9). The RDW represents an index of heterogeneity analogous to the qualitative anisocytosis observed on the peripheral blood smear (10). Higher values reflect a more heterogeneity population of cells.

CLINICAL

APPLICATION

Bessman and colleagues (2) have proposed a classification of anemia based on the MCV and RDW. The MCV may be low (microcytic), normal (normocytic), or high (macrocytic). The RDW may be normal (homogeneous), or high (heterogeneous). No disease states have been identified in which the RDW is decreased (11). Table 1 presents the differential diagnoses for the combination of categories of MCV and RDW.

The Microcytic Anemias

Microcytosis is a common laboratory abnormality that is a classic finding in iron deficiency and thalassemia. As many as 3% of patients admitted to general hospitals will have microcytosis (5,12). The anisocytosis due to iron deficiency apparent on the peripheral blood smear will be reflected in an elevated RDW (3). This increased heterogeneity is the result of abnormal erythropoiesis producing an increased variation in the size and shape of the red blood cells (11). As the anemia progresses, the newly produced cells become progressively smaller. In early iron deficiency anemia, the MCV may be normal, since the measured MCV reflects the volume of cells produced over the preceding 120 days (10). Later the MCV becomes microcytic. In either case, the RDW is elevated. Following adequate iron therapy, both the MCV and the RDW will return to normal. Both homozygous and heterozygous thalassemia syndromes produce microcytosis. The majority of patients with heterozygous thalassemia will have a normal RDW. The RDW may be slightly elevated when a mild anemia is present but will not approach the levels associated with iron deficiency ( 11,12). Patients with homozygous thalassemia will be anemic with an elevated RDW.

Red Blood Cell Distribution

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This diagnosis is usually easily confirmed clinically and by hemoglobin electrophoresis. In cases in which iron deficiency is superimposed on an underlying heterozygous thalassemia, the RDW will be high. With treatment of the iron deficiency, the RDW will return toward normal while the microcytosis will persist. The continued depression of the MCV should prompt an evaluation for heterozygous thalassemia by the consultant. Early studies of the RDW indicate that nearly 100% of patients with iron deficiency anemia have an elevated RDW (11,13-G). More recent reports question this finding in certain populations (16-19). Similarly, early reports reflect only occasional, minimal elevations of the RDW in heterozygous thalassemia (2,l l13). However, other studies have questioned this finding (15). Nonetheless, even in those studies demonstrating an elevated RDW in patients with thalassemia, this elevation is much less impressive than in patients with iron deficiency anemia. Therefore, when discriminating between iron deficiency and thalassemia, the greater the degree of heterogeneity (the higher the RDW), the more likely the diagnosis of iron deficiency. Most authors consider the RDW to be a very sensitive tool for detecting the presence of iron deficiency (2,l l-13,15,18,19). Iron deficiency seldom needs to be a concern when the RDW is not elevated. Therefore, the emergency physician may feel confident in initiating iron therapy in patients with a microcytosis and an elevated RDW. However, the lack of specificity of the RDW indicates that other factors that can elevate the RDW may coexist in iron deficient patients. Accordingly, the patient should be followed to determine whether the abnormalities persist and whether further evaluation is warranted. The Normocytic Anemias The anemia of chronic disease is probably the most common form of anemia in hospitalized patients in the United States (10). This anemia may be either microcytic (10%) or normocytic (90%) (4,ll). In either case the RDW will be normal. An elevated RDW in the patient with chronic disease reflects an additional disease process (for example, iron, folate, or B,, deficiency). Heterogeneous cell size with normal cell volume may be the first evidence of either early nutritional deficiencies or mixed disorders. An elevated RDW in the setting of a normal MCV should prompt a search for an early iron, folate, or vitamin B,, deficiency. The majority of anemic hemoglobinopathies, myelofibrosis, and acquired idiopathic sideroblastic disease produce similar indices.

Bone marrow suppression with chemotherapy will usually result in normocytic cells that are homogeneous. However, patients receiving chemotherapy may have normal or increased MCV and RDW (11). Patients with chronic lymphocytic leukemia (CLL) with lymphocyte counts below 15O,OOO/~L will have a normal MCV and RDW. It is possible in patients with CLL to have an artifactually elevated RDW due to the larger cell volume of the lymphocyte. This occurs when the lymphocyte count exceeds 15O,OOO/~L (2). Chronic myelogenous leukemia, hereditary spherocytosis, and acute hemorrhage result in normocytic cells that are homogeneous.

The Macrocytic Anemias All three common deficiency states (iron, folic acid, and vitamin Bi2) are characterized by an elevation in the RDW reflecting the heterogeneous population of red cells that result from ineffective erythropoiesis (2). The increase in the RDW precedes the macrocytosis associated with folate and B,, deficiencies. This elevation is corrected with appropriate therapy and may be followed to evaluate the efficacy of treatment. The presence of a normal RDW has been asserted to effectively eliminate these deficiency states as a cause of anemia (11). Others have questioned this assertion (20). Patients with longstanding aplastic anemia will have a homogeneous red blood cell population and a normal RDW. In these, and in other patients who have been repeatedly transfused, an elevated RDW reflects the heterogeneity of the donor and the recipient red blood cell populations (2). In patients with cold agglutinin disease, the RBC agglutinates will be visualized as a single cell with a large volume. This increases both the MCV and the RDW. This artifactual elevation of the RDW (as well as the artifactual elevations resulting from transfusions and CLL with lymphocyte counts greater than 150,000/ pL) may increase the RDW far out of proportion to changes present in the MCV or red blood cell count (2). SUMMARY The RDW appears to be particularly useful in guiding the evaluation of microcytic anemias. A normal RDW effectively eliminates iron deficiency as a cause of anemia in this population. Unfortunately, an anemia that is frequently present in patients in the emergency department - the anemia of chronic liver disease - is not easily classified by this system. This difficulty re-

Timothy

sults from the multiple factors that may coexist with, and contribute to, this anemia (for example, nutritional deficiencies, bone marrow suppression, hemolysis, and splenic sequestration) (9). The red blood cell distribution width is now widely reported with the complete blood count. Its sensitivity in detecting deficiency states (in particular, iron defi-

C. Evans and Dietrich

Jehle

ciency) is well accepted. Unfortunately, the specificity of this index is imperfect. Nonetheless, the RDW compliments the MCV and, when used in conjunction with it, allows the emergency physician to accurately define the possible cause(s) of anemia and to efficiently proteed with a diagnostic evaluation, therapeutic intervention, and referral.

REFERENCES 1. Wallerstein RO. Laboratory evaluation of anemia. West J Med. 1987;146:443-51. 2. Bessman JD, Gilmer PR, Gardner FH. Improved classification of anemias by MCV and RDW. Am J Clin Pathol. 1983;80: 322-6. 3. Price-Jones C. The diameters of red cells in pernicious anemia and anemia following haemoxrhage. J Pathol. 1922:25:487-504. 4. Williams WJ, Nelson DA, Morris MW. Examination of the blood in hematology. Williams WJ, Beutler E, Erslew AJ, Litman MA, eds. New York: McGraw-Hill; 1990:10-15. 5. Bessman JD. Heterogeneity of red cell volume: quantitation, clinical correlations, and possible mechanisms. Johns Hopkins Med J. 1980;146:226-30. 6. Savage RA. More on RDWs [letter to the editor]. Am J Clin Pathol. 1987;87:293-4. 7. Novak RW. Red blood cell distribution width in pediatric microcytic anemia. Pediatrics. 1987;80:2514. 8. Monzon CM, Beaver BD, Dillon TD. Evaluation of erythrocyte disorders with mean corpuscular volume (MCV) and red cell distribution width (RDW). Clin Pediatr. 1987;26:632-8. 9. Kamad A, Poskitt TR. The automated complete blood cell count. Arch Intern Med. 1985;145:1270-2. 10. Bergin JJ. Evaluation of anemia. Postgrad Med. 1985;77: 253-69. 11. Johnson CS, Tegos C, Beutler E. Thalassemia minor: routine erythrocyte measurements and differentiation from iron de% ciency. Am J Clin Pathol. 1983;80(1):31-6.

12. Bessman JD, Feinstein DI. Quantitative anisocytosis as a discriminant between iron deficiency and thalassemia minor. Blood. 1979;53:288-93. 13. McClure S, Custer E, Bessman JD. Improved detection of early iron deficiency in nonanemic patients. JAMA. 1985;253:270914. 14. Flynn MM, Reppun TS, Bhagavan NV. Limitations of red blood cell distribution width (RDW) in evaluation of microcytosis. Am J Clin Pathol. 1986;85:445-9. 15. Thompson WG, Meola T, Lipkin M, Freedman ML. Red blood cell distribution width, mean corpuscular volume, and transferrin saturation in the diagnosis of heterogeneity. Arch Intern Med. 1988;148:2128-30. 16. Osborne PT, Burkitt LL, Ryan GM, Lane M. An evaluation of red blood cell heterogeneity (increased red blood cell distribution width) in iron deficiency of pregnancy. Obstet Gynecol. 1989;160: 336-9. 17. McDonald ME, Smyrk TC, Payne BA, Pierre RV. Evaluation of the concept of the classification of anemias by the use of RDW/ MCV. Blood. 1984;644(suppl 1):45a. 18. Morgan DL, Peck SD. The use of red blood cell distribution width in the detection of iron deficiency in chronic hemodialysis patients. Am J Clin Pathol. 1988;89:513-15. 19. Saxena S, Weiner JM, Carmel R. Red blood cell distribution width in untreated pernicious anemia. Am J Clin Pathol. 1988;89: 660-3.