Mean corpuscular volume, hematocrit and polycythemia

ABSTRACT Mean corpuscular volume (MCV) as a measure of the size of red blood cells (RBCs) has been pivotal in the diagnosis and morphologic classification of anemias for over a century. Despite its ubiquitous use and time-honored diagnostic value, one essential attribute of MCV has remained under the radar. It has been long underappreciated that the size of RBC correlates with the amount of hemoglobin (Hb) that it accommodates and, therefore, is an important determining factor of the total Hb level. By scrutinizing this basic principle, it has become possible to uncover a hitherto obscured relationship between MCV, hematocrit (Hct) and RBCs described as a dynamic equilibrium. This principle is shown to be invaluable in interpreting RBC parameters, particularly for the evaluation of patients with polycythemia.


Introduction
Hemoglobin (Hb), hematocrit (Hct) and red blood cells (RBCs) are indispensable for diagnosing anemias and polycythemias. The RBC indices, on the other hand, especially mean corpuscular RBC volume (MCV), have been used primarily in the evaluation of anemias. The role of MCV in the diagnosis of polycythemia is not known.
The fundamental relationship between the size of erythrocytes and their Hb content has been recognized for over 100 years [1,2]. The studies showed that larger erythrocytes (macrocytes) accommodate a greater amount of Hb than smaller erythrocytes (microcytes). This principle was later validated by demonstrating that MCV value mirrors the mean RBC Hb (MCH) [3], but its clinical utility remained unrecognized until recently [4]. Herein, this principle is revisited and applied to clinical practice for the evaluation of polycythemias.

Methods
This was an observational study. Patients with various clinical conditions were evaluated. Their routine RBC parameters acquired by using the electronic Hematology Analyzer, Sysmex XN-1000 TM , were analyzed. The formula Hct = MCV × RBC was tested to establish the contribution of the independent variables (MCV and RBC) to the dependent one (Hct). Consequently, a new rule of dynamic equilibrium has been recognized. A few illustrative cases were selected for practical demonstration of the rule and its value in diagnosing polycythemias.

Results and discussion
1. Basic Considerations: Historically, MCV was calculated at the patient's bedside by using a simple arithmetic operation -Hct divided by RBCs. The calculation instantly categorized anemias as normocytic, microcytic or macrocytic [2,5] and pointed to possible anemia etiology. If, for example, anemia is identified as macrocytic (high MCV), the diagnostic process aims at the specific pathologies such as vitamin deficiency, alcohol and drug effects. Thus, the diagnostic value of macrocytosis has been confined traditionally and unvaryingly to identify its cause. In contrast, the effect that macrocytosis exerts on RBC parameters such as Hb and Hct has been scarcely recognized [6]. Because the size of RBCs (MCV) determines the Hb content of RBCs (MCH), the higher the MCV/MCH, the higher the Hb and vice versa. Similarly, MCV is a principal contributor to Hct because Hct is a product of RBCs of certain sizes: Hct = RBC × MCV. This classic formula not only demonstrates how Hct is calculated (manually or by cell analyzers), but it also exposes the fact that MCV is as important in determining Hct as RBCs.  [8,9] that, in aggregate, balances the two counteractive drug effects with a resultant normal Hb level [10,11]. How this mechanism can be leveraged to clinical advantage is described below.  Because MCV elevation is common [12] and frequently occurs without anemia [13,14], the described clinical effect of macrocytosis is more prevalent than generally appreciated. Moreover, the impact of MCV on Hb/Hct is by no means trivial. The observations demonstrate that the effect of a 10 fL-change in the MCV value on the total Hct approximates a change of 0.5 × 10 6 /µL in the RBC count. The recognition of RBC count equivalent of MCV explains the capacity of MCV to force Hb/ Hct beyond the normal levels even in the absence of high RBCs. And, vice versa, it shows how even borderline MCV (<100 fL) can cause abnormally high Hb/Hct. Such cases, if unrecognized, could be incorrectly interpreted as polycythemia vera (Table 1, patients 3 and 4) and trigger unnecessary and costly tests (spleen imaging, erythropoietin and JAK2 mutation analyses) [4]. Figure 2 shows a diagnostic algorithm demonstrating how clinically meaningful 'relative macrocytosis' can be identified. For the rule of dynamic equilibrium to work, accurate RBC and MCV measurements are mandatory. Spurious macrocytosis and spurious erythrocytosis will predictably cause a wrong interpretation.

MCV and Polycythemia Vera Diagnosis
It is customary to refer to high Hb/Hct levels as erythrocytosis. In fact, high Hb/Hct rather than high RBC count fulfill the World Health Organization's major criterion for polycythemia vera [15]. It has been shown previously that Hb cannot be used as a surrogate marker for absolute erythrocytosis [16]. This study corroborates this notion by showing that Hb/Hct is affected not only by RBCs but MCV as well. Therefore, substituting 'erythrocytosis' with 'high Hb/Hct' is not only confusing but also conceptually wrong. Perhaps 'hyperhemoglobinemia' could solve this terminological dilemma.

Conclusion
The clinical value of MCV extends beyond the established merits of guiding anemia work-up as demonstrated here. The recognition that MCV is linked to Hb/ Hct levels and RBC count in a quantifiable way has Figure 2. A simple diagnostic algorithm for identification of relative macrocytosis as a contributing factor to Hb/Hct elevation. Macrocytosis could be borderline (MCV < 100 fL) or relative compared to previous measurements. important practical applications. Whether MCV or RBCs is a principal cause of rising Hct is of profound clinical significance as it provides an important clue to the etiology of the abnormal tests and informs about the plan of further work-up. The approach allows instant narrowing of differential diagnosis thereby sparing costly resources in everyday evaluation of polycythemias.

Ackowledgements
The author received no support from any individual, organization, grant or corporation.

Disclosure statement
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Funding
The author(s) reported there is no funding associated with the work featured in this article.