REVIEW JORI E. MAY, MD MARISA B. MARQUES, MD VISHNU V.B. REDDY, MD RADHIKA GANGARAJU, MD Department of Medicine, Department of Pathology, Department of Pathology, Department of Medicine, University of University of Alabama, University of Alabama, Birmingham University of Alabama, Birmingham Alabama, Birmingham Birmingham Three neglected numbers in the CBC: The RDW, MPV, and NRBC count ABSTRACT he complete blood cell count (CBC) T is one of the most frequently ordered lab- The complete blood cell count (CBC) is one of the most oratory tests in both the inpatient and outpa- frequently ordered laboratory tests, but some values tient settings. Not long ago, the CBC required included in the test may be overlooked. This brief re- peering through a microscope and counting view discusses 3 potentially underutilized components the red blood cells, white blood cells, and of the CBC: the red blood cell distribution width (RDW), platelets. These 3 numbers are still the primary the mean platelet volume (MPV), and the nucleated purpose of the test. red blood cell (NRBC) count. These results have unique Now, with automated counters, the CBC diagnostic applications and prognostic implications that report also contains other numbers that delin- can be incorporated into clinical practice. By understand- eate characteristics of each cell type. For ex- ing all components of the CBC, providers can learn more ample: about the patient’s condition. The mean corpuscular volume is the aver- age volume of red blood cells. Providers use it KEY POINTS to classify anemia as either microcytic, normo- The RDW can help differentiate the cause of anemia: eg, cytic, or macrocytic, each with its own differ- a high RDW suggests iron-defi ciency anemia, while a nor- ential diagnosis. mal RDW suggests thalassemia. Studies also suggest that The differential white blood cell count a high RDW may be associated with an increased rate of provides absolute counts and relative percent- all-cause mortality and may predict a poor prognosis in ages of each type of leukocyte. For example, several cardiac diseases. the absolute neutrophil count is an important measure of immunocompetence. But other values in the CBC may be over- The MPV can be used in the evaluation of thrombocy- looked, even though they can provide im- topenia. Furthermore, emerging evidence suggests that portant information. Here, we highlight 3 of high MPV is associated with worse outcomes in cardio- them: vascular disorders. • The red blood cell distribution width (RDW) An elevated NRBC count may predict poor outcomes in • The mean platelet volume (MPV) a number of critical care settings. It can also indicate a • The nucleated red blood cell (NRBC) serious underlying hematologic disorder. count. In addition to describing their diagnostic utility, we also discuss emerging evidence of their potential prognostic signifi cance in he- matologic and nonhematologic disorders. By incorporating an awareness of their value in clinical practice, providers can maximize the doi:10.3949/ccjm.86a.18072 usefulness of the CBC. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 3 MARCH 2019 167 INTERPRETING THE CBC Figure 1. A: Example of a normal red blood cell distribution width (RDW) of 13.5% (red line) in a patient with a normal complete blood cell count. B: Example of an increased RDW of 28.8% in a patient with iron defi ciency shortly after initiation of iron supplemen- tation. ■ RED BLOOD CELL DISTRIBUTION WIDTH hemorrhage or rapid hemolysis, as the acute The RDW is a measure of variation (anisocy- drop in hemoglobin results in increased pro- tosis) in the size of the circulating red cells. duction of reticulocytes, which are larger than The RDW The term “width” is misleading, as the value mature erythrocytes. Because a range of disorders can elevate is not derived from the width of the red blood measures the RDW, reviewing the peripheral blood cell, but rather from the width of the distribu- smear is an important next step in the di- variation tion curve of the corpuscular volume (Figure agnostic evaluation, specifi cally looking for in size, 1). Therefore, a normal RDW means that the reticulocytes, microspherocytes, and other not size itself cells are all about the same size, while a high abnormal red blood cells contributing to the RDW means they vary widely in size. RDW elevation. The RDW can be calculated either as a A normal RDW is less diagnostically use- coeffi cient of variation, with a reference range ful. It indicates the red blood cells are of uni- of 11% to 16% depending on the laboratory, form size, but they may be uniformly small or or, less often, as a standard deviation, with a large depending on how long the anemia has reference range of 39 to 46 fL. persisted. Since red cells circulate for only The RDW can differentiate about 120 days, patients who have severe between causes of anemia iron-defi ciency anemia for months to years are A high RDW is often found in nutritional de- expected to have a normal rather than a high RDW, as their red cells of normal size have all fi ciencies of iron, vitamin B12, and folate. This information is helpful in differentiating the been replaced by microcytes. A low RDW is not consistently associated cause of microcytic anemia, as a high RDW with any hematologic disorder. suggests iron-defi ciency anemia while a nor- mal RDW suggests thalassemia.1 In iron defi - RDW may have prognostic value ciency, the RDW often rises before the mean Emerging data suggest that the RDW may also corpuscular volume falls, serving as an early have prognostic value in nonhematologic dis- diagnostic clue. eases. In a retrospective study of 15,852 adult The RDW can also be high after recent participants in the Third National Health and 168 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 3 MARCH 2019 MAY AND COLLEAGUES Nutrition Examination Survey (1988–1994), a higher RDW was associated with a higher risk of death, with the all-cause mortality rate increasing by 23% for every 1% increment in RDW.2 This correlation is particularly prominent in cardiac disorders. In 2 large retrospective studies of patients with symptomatic heart failure, a higher RDW was a strong predictor of morbidity and death (hazard ratio 1.17 per 1-standard deviation increase, P < .001), even stronger than more commonly used variables such as ejection fraction, New York Heart As- sociation functional class, and renal function.3 In a retrospective analysis of 4,111 pa- Figure 2. Giant platelets (thin arrows), nor- tients with myocardial infarction, the degree mal sized platelets (dotted arrows), and a of RDW elevation correlated with the risk of nucleated red blood cell (thick arrow) in a repeat nonfatal myocardial infarction, coro- patient with myelofi brosis and extensive extramedullary hematopoiesis. nary death, new symptomatic heart failure, and stroke.4 It is hypothesized that high RDW may In contrast, the MPV is low in patients refl ect poor cell membrane integrity from al- with thrombocytopenia due to megakaryocyte tered cholesterol content, which in turn has hypoplasia, as malfunctioning megakaryocytes deleterious effects on multiple organ systems cannot maintain the total platelet mass, and and is therefore associated with adverse out- any platelets produced remain small. This dis- comes.5 tinction can be obscured in the setting of sple- Currently, using the RDW to assess prog- nomegaly, as larger platelets are more easily nosis remains investigational, and how best to sequestered in the spleen and the MPV may In anemia, interpret it in daily practice requires further therefore be low or normal. a high RDW study. The MPV can also be used to differenti- ate congenital thrombocytopenic disorders, suggests iron ■ MEAN PLATELET VOLUME which can be characterized by either a high defi ciency, The MPV, ie, the average size of platelets, is MPV (eg, gray platelet syndrome, Bernard- while a normal reported in femtoliters (fL). Because the MPV Soulier syndrome) or a low MPV (eg, Wis- varies depending on the instrument used, kott-Aldrich syndrome) (Figure 2). RDW suggests each laboratory has a unique reference range, MPV may have prognostic value thalassemia usually about 8 to 12 fL. The MPV must be Evidence suggests that the MPV also has po- interpreted in conjunction with the platelet tential prognostic value, particularly in vascu- count; the product of the MPV and platelet lar disease, as larger platelets are hypothesized count is called the total platelet mass. to have increased hemostatic potential. Using the MPV to fi nd the cause In a large meta-analysis of patients with of thrombocytopenia coronary artery disease, a high MPV was asso- The MPV can be used to help narrow the ciated with worse outcomes; the risk of death differential diagnosis of thrombocytopenia. or myocardial infarction was 17% higher in For example, it is high in thrombocytopenia those with a high MPV (the threshold ranged resulting from peripheral destruction, as in from 8.4 to 11.7 fL in the different studies) immune thrombocytopenic purpura. This is than in those with a low MPV.6 because as platelets are lost, thrombopoietin In a study of 213 patients with non-ST- production increases and new, larger platelets segment elevation myocardial infarction, the are released from healthy megakaryocytes in risk of signifi cant coronary artery disease was an attempt to increase the total platelet mass. 4.18 times higher in patients with a high MPV CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 86 • NUMBER 3 MARCH 2019 169 INTERPRETING THE CBC and a high troponin level than in patients adults. During erythropoiesis, the common with a normal MPV and a high troponin.7 The myeloid progenitor cell fi rst differentiates into authors suggested that a high MPV may help a proerythroblast; subsequently, the chromatin identify patients at highest risk of signifi cant in the nucleus of the proerythroblast gradually coronary artery disease who would benefi t from condenses until it becomes an orthochromatic invasive studies (ie, coronary angiography).