Mean reticulocyte volume (MRV) as a diagnostic marker for erythropoiesis: results with Mindray BC-6800 Plus

Introduction

Iron deficient erythropoiesis (IDE) is the process of red blood cell production when there is an inadequate supply of iron, leading to defective red blood cells with impaired function. This condition can range from a latent (without anemia) to a full-blown iron deficiency anemia (IDA), where the body cannot produce enough hemoglobin (Hb) (1).

Comprehensive iron status and erythropoiesis evaluation requires a combination of tests and clinical indicators. Certain limitations affect both traditional biochemical markers and cellular markers, leading to diagnostic uncertainty. The former particularly in chronic inflammatory and complex clinical settings, where the values do not accurately reflect iron status and availability. Late response kinetics in case of red cell indices leads to an inadequate sensitivity to early marrow iron depletion (2). These challenges justify the pursuit of new cell-based indicators, which may better capture early marrow iron restriction through morphological evidence independent of inflammation or long erythrocyte lifespan.

The reticulocyte counts are crucial for the differential diagnosis of anemias and the investigation of erythropoiesis, identifying a hypo-regenerative status or an adequate bone marrow response (3). Modern automated instruments provide additional related parameters, such as the reticulocyte Hb content, recognized as a reliable marker for assessing iron restricted erythropoiesis and the monitoring the effectiveness of anemia treatment, or the immature reticulocyte fraction (IRF), useful for diagnosing early erythropoietic activity following chemotherapy or hematopoietic stem cell transplantation (4). The volume ratio reticulocytes/erythrocytes is approximately 1.24; reticulocytes have slightly higher Hb content (approximately +3%) and lower Hb concentration (approximately −16.7%) compared to erythrocytes (5).

Mindray BC-6800 Plus^TM (Mindray, Shenzhen, China) is an automated hematology analyzer that applies flow cytometry principles. In a dedicated channel for reticulocyte analysis, a fluorescent dye (asymmetric cyanine) can bind to cytoplasmic RNA to allow detection of reticulocytes from erythrocytes. The fluorescent signals are proportional to RNA content and the analyzer can divide the reticulocytes into fractions according to maturity. It also provides, derived from a forward light scatter measure the mean “reticulocyte hemoglobin expression” (RHe), which is the mean of the Hb content of the reticulocytes. This system not only measures reticulocyte counts and the aforementioned parameters (6), using a new software version v.2.2.0, but can also report mean reticulocyte volume (MRV). Other automated analyzers reporting reticulocyte counts can determine MRV; nevertheless the current state of harmonization of reticulocyte derived parameters is not as strong as the reticulocyte counts, so in adult population MRV presents differences among those instruments. Therefore, reference ranges should be determined according to the technologies or brands, and these could not be interchangeable in clinical practice (7).

The present study investigates the clinical significance of MRV for assessing the bone marrow activity and its potential diagnostic applications in anemia and related disorders. The values of MRV in different clinical conditions, microcytic anemia, normocytic anemia, macrocytic anemia, latent iron deficiency (LID) and healthy subjects are reported. We also study its reliability for the detection of IDE and as a marker of response to iron therapy. We present this article in accordance with the STARD reporting checklist (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-30/rc).

Methods

Patients

We prospectively selected samples from consecutive outpatients of Hospital Galdakao-Usansolo, in the course of their medical controls, to conduct a cross-sectional study. Only adults aged >18 years were included in the present study; exclusion criteria were a transfusion nor had an acute bleeding in the previous month. The recruitment period was November 2024–January 2025.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of Barrualde-Interior District IHO at Hospital Galdakao Usansolo (Biscay, Spain; No. 1024/24). Informed consent from participants was not required, as residual samples after the requested tests had been completed were used for the present study.

The analyses were requested as part of the routine controls of the outpatients; neither doses nor analysis requests nor visits to the clinicians were changed. The diagnostic, clinical data, comorbidities, treatments and doses of each patient were retrieved from their laboratory and medical records.

The scope of the pathology included a variety of diseases representative of our daily workload. The study group was as follows:

• Healthy group: samples from healthy adult subjects with no clinical symptoms of disease complete blood counts (CBCs) and biochemical iron test results were within the reference ranges.
• Those non-anemic patients (Hb >120 g/L in women, Hb >130 g/L in men) with serum ferritin (s-ferritin) <30 µg/L were classified as a LID group.
• IDA: when they presented low Hb (male <130 g/L and female <120 g/L), transferrin saturation (TSAT) <20%, s-ferritin <30 µg/L and no signs of inflammation, C-reactive protein (CRP) <5.0 mg/L.
• Thalassemia carriers were recruited. This group included patients with a previous diagnosis of the disease. β-thalassemia screening is routinely performed in our laboratory by analysis of red cell indices and the concentration of hemoglobin A2 (HbA2). Samples with erythrocytosis (red blood cells, RBC) ≥5.5×10¹²/L and microcytosis [mean cell volume (MCV) <70 fL] are selected for HbA2 quantitation. Those samples with HbA2 >3.8% are considered to be suspicious of β thalassemia trait and send to reference laboratory to confirm the disease.
• Anemia of chronic disease (ACD) group included patients with a variety of diseases: chronic infections, neoplastic disorders (Hodgkin’s disease, breast carcinoma), noninfectious inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, chronic kidney disease). These patients had evidence of chronic inflammation: Hb <130 g/L for males and <120 g/L for females; TSAT <20%, s-ferritin >100 µg/L (8).
• ACD with concomitant IDA (ACD/IDA): Hb <130 g/L for males and <120 g/L for females; TSAT <20%, s-ferritin 30–100 µg/L and chronic inflammation (8).

Patients recruited at diagnosis of anemia before the treatment started were studied after the therapies were applied. The standard doses to treat IDA were oral iron 100–200 mg/day during 3 months; ACD required intravenous (IV) iron (1,000 mg of ferric carboxymaltose). Follow-up of those patients was done in the course of their routine controls (after 4 weeks for oral iron and after 1 week for IV iron), to verify the change in analytical values after replacement therapy (9).

To verify the diagnostic performance of MRV for detecting IDE, a validation group of 150 patients with IDA, ACD with adequate iron supply, ACD/IDA, and LID were selected as a validation group, with the same inclusion criteria. The recruitment period was February 2025. A flow chart of the groups of patients is presented in Figure 1.

Figure 1 Flowchart diagram of the recruited patients, 33 of them were excluded due to transfusion or an acute bleeding in the previous month.

Analytical methods

The samples were obtained in the course of routine analysis and collected in K2-ethylenediaminetetraacetic acid (K2-EDTA) anti-coagulant tubes (Vacutainer^TM Becton-Dickinson, Rutherford, NJ, USA), were run in the Mindray BC-6800 Plus^TM analyser within 4 hours of collection. CRP, s-iron, transferrin, s-ferritin and soluble transferrin receptor (sTfR) were assayed in a Cobas c 8000^TM (Roche Diagnostics, Mannheim, Germany) analyzer. HbA2 is analyzed in a high pressure liquid chromatography device ADAMS A1c HA-8180 T^TM (ARKRAY Inc., Kyoto, Japan).

Metrological aspects: reproducibility and stability

The analyzer was calibrated according to the manufacturer’s instructions and checked once a day using commercial controls (3 levels) provided by the company. Between day imprecision was studied with Mindray quality control materials during 20 working days. The coefficient of variation (CV) of the 3-level controls was calculated. Within run precision was studied with the same controls and peripheral blood samples. The CV of 10 replicates of 4 samples with different reticulocyte concentrations was calculated. To assess changes with time of storage 10 specimens were analyzed within 2 hours of collection (time 0). Analysis was performed after 4, 6 and 8 hours of storage at room temperature and overnight at 4 ℃. This schedule mimics the real situation of the specimens at our laboratory. The percentage change was recorded.

Statistical analysis

Kolmogorov-Smirnoff test was applied to detect skew distributions and analysis of variance (ANOVA) was used to assess differences among groups. Post hoc Scheffe’s test was used for parameters with a significant difference, to verify which values are significantly different from each other; P<0.05 was considered to be statistically significant. Pearson’s correlation coefficient and linear regression between MRV and related parameters. The sample size was calculated using Fisher’s formula. Receiver operating characteristic (ROC) curve analysis was utilized to verify the diagnostic performance of MRV for detecting IDE. The gold standard for iron deficiency (ID) was sTfR >52 nmol/L (10). The homogeneity of the study and the validation cohorts was verified with Fisher’s exact test (demographic and clinical features) and Student’s t-test to compare the means of analytical results. Statistical software package SPSS version 29.0 for Windows was used for statistical analysis (SPSS; Chicago, IL, USA).

Results

Analytical imprecision and stability

Within-day imprecision assessment showed that the CVs for MRV controls (target values: 77.3, 87.5, and 100.8 fL) were 0.8%, 0.4%, and 0.22%, respectively, while CVs for patient samples were 0.38%, 0.34%, 0.53% and 0.3%. Between-day imprecision results demonstrated mean MRV values of 94.6 fL (CV 0.6%), 78.8 fL (CV 0.5%), and 66.8 fL (CV 0.9%). Regarding the stability after venipuncture, there are no significant differences between time 0 and 8 hours, mean difference of 0.6%, but after 24 hours, the deviation ranged around 2.6% on average.

Study population

A total of 736 patients were initially recruited, of whom 33 were excluded based on the criteria; The final study group comprised 553 patients with an additional 150 patients constituting the validation group. The study group included 196 non-anemic (105 were considered healthy and 91 LID), the anemic patients were 357 (135 microcytic, 145 normocytic and 77 macrocytic). In this study group, 189 patients [73 IDA, 61 ID and 55 ACD] were recruited at diagnosis of anemia before the treatment started.

MRV in different anemias and iron status

There were no statistically significant differences between the cohorts, study and validation. The gender distribution were as follows: in the study group, males 34.5%/females 65.5%, validation group, males 36.9%/females 63.1%, P=0.62. Mean age in the study group was 55.1 years, and 58.5 years for the validation group, P=0.32. The analytical data had no statistical differences between the groups (Table 1).

MRV values were normally distributed, with an overall range of 51.8–151.3 fL. In healthy subjects, the mean MRV was 107.8 fL (range, 94.6–121.2 fL). Among anemic patients classified by morphology, mean MRV values were as follows: microcytic anemia, 78.5 fL [standard deviation (SD) 13.5 fL]; normocytic anemia, 105.1 fL (SD 16.9 fL); and macrocytic anemia, 122.5 fL (SD 18.6 fL).

In the microcytic group, MRV values in patients with IDA (mean 78.8 fL, SD 14.3 fL) and thalassemia carries (mean 76.6 fL, SD 10.2 fL) were not significantly different (P=0.07), so patients with restricted erythropoiesis, due to lack of iron or globin, had similar low values.

The results in the IDA group reflected a state of iron depletion: low ferritin, low iron availability (low TSAT) and iron-restricted erythropoiesis (low RHe and MRV). Patients with ACD or ACD/IDA showed the typical pattern with normal or high s-ferritin. Based on sTfR values, the ACD group was divided into those under therapy and adequate iron supply and those with functional ID (FID); the former group had mean MRV 97.7 fL, statistically different from those of the latter group (mean MRV 90.5 fL, P<0.001).

Low values were also found in case of LID (mean 88.4 fL), which reflects iron deficient erythropoiesis and compromised Hb synthesis. Values over the range in healthy subjects in the macrocytic group, due to lack of vitamin B12 or folate and/or myelodysplastic syndromes (MDS), reflect the megaloblastosis.

Table 2 summarizes the laboratory parameters for the assessment of iron status in the study group, which included healthy subjects, thalassemia carriers, IDA, ACD, ACD/IDA and LID. The groups had MRV values significantly different, P<0.001, except the healthy group and ACD patients with adequate iron supply, P=0.07. MRV in IDA and LID groups presented no statistical difference, P=0.08.

This result shows that MRV detects earlier shifts: MRV changes appear sooner in disease progression. Since reticulocytes precede mature RBCs in the circulation, MRV can identify early bone marrow requirements for iron before anemia is present.

Correlation of MRV with related parameters

A strong positive correlation was observed between MRV and MCH (R²=0.86) [95% confidence interval (CI): 0.8469–0.9067]. The correlation between RHe and MRV R²=0.998 (95% CI: 0.989–1.000). Pearson’s regression equation MRV =4.9+3.0 × RHe, r=1.00. Intercept 95% CI: 3.99–5.81, slope 95% CI: 3.04–3.10 (Figure 2).

Figure 2 Correlation between MRV and RHe. Pearson’s regression equation MRV =4.9+3.0 × RHe, r=1.00. Intercept 95% CI: 3.99–5.81, slope 95% CI: 3.04–3.10. CI, confidence interval; MRV, mean reticulocyte volume; RHe, reticulocyte hemoglobin expression.

MRV in the detection of IDE

The study included the IDA, ACD with adequate iron supply, ACD/IDA and LID groups. At a cut-off MRV 94.6 fL, IDE could be diagnosed with sensitivity 82.9% and specificity 97.6%. Area under the curve (AUC) was 0.929 (95% CI: 0.889–0.949). These values are in agreement with RHe results, AUC 0.939 (95% CI: 0.899–0.959), P=0.27. Those results were confirmed in the validation group AUC 0.909 (95% CI: 0.879–0.929), P=0.06 (Figure 3).

Figure 3 ROC curve analysis was utilized to assess the diagnostic performance of MRV for detecting IDE. The gold standard for iron deficiency was sTfR >52 nmol/L. The study included the IDA, ACD, ACD/IDA and LID groups. At a cut-off MRV 94.6 fL, IDE could be diagnosed with sensitivity 82.9% and specificity 97.6%. AUC was 0.929 (95% CI: 0.889–0.949). ACD, anemia of chronic disease; AUC, area under the curve; CI, confidence interval; CI, confidence interval; IDA, iron deficiency anemia; IDE, iron deficient erythropoiesis; LID, latent iron deficiency; MRV, mean reticulocyte volume; ROC, receiver operating characteristic; sTfR, soluble transferrin receptor.

The effect of iron supplements on MRV

Patients were studied at a second follow-up visit after the start of supplementation to verify the change in analytical values after replacement therapy. The basal values in IDA and LID patients were as follows: IDA mean MRV 77.7 fL (range, 67.9–100.3 fL), LID mean MRV 88.1 fL (range, 70.1–101.3 fL). The control after 1 month from the start with oral iron therapy showed an absolute increase in MRV of, on average, 8.4 fL (4.5%), P<0.001.

Table 3 shows the analytical data of patients with ACD at detection of ID and after the start of supplementation with IV iron. ACD patients at diagnosis had a mean MRV 93.3 fL (range, 82.2–98.6 fL), and after 1 week of IV iron therapy mean MRV 101.7 fL (range, 96.5–106.3 fL), P<0.001. The increase in MRV runs in parallel with that of RHe.

Discussion

Automated analyzers can process large number of specimens improving the efficiency and the quality of the results. Dyes to bind RNA are used for the reticulocyte counts but it is also possible the identify other reticulocyte derived parameters which represent an advantage in the study of the erythropoiesis status.

Different brands apply diverse technologies to obtain the MRV. The Beckman Coulter^TM analyzers (Beckman Coulter, Fullerton, California, USA) utilize volume-conductivity-scatter (VCS) technology for CBC and reticulocyte analysis. Sphered and fixed cells are submitted to the VCS to obtain measurements related to cell volume and cytoplasmic density. The reticulocyte volume generated with impedance technology provides insights into erythropoietic activity in healthy individuals and those with different types of anemia (11). MRV is also crucial for monitoring health and performance of elite athletes, with reference intervals established for various sports (12). MCV/MRV ratio can enhance diagnostic accuracy in cases of hemolytic anemias, when differences in those volumes are significant (13). As a screening tool for hereditary spherocytosis, MRV exhibits high sensitivity and specificity and could be used as a general and new specific index for screening of this inherited disease (14-16). Beckman Coulter also reports red blood cell size factor (Rsf), which relates MCV and MRV, to assess erythropoietic activity and ID (17-21).

Other counters, such as ADVIA^TM (Siemens Healthcare Diagnostics, Tarrytown, NY, USA), Cell Dyn^TM or Alinity^TM analyzers (Abbott Diagnostics, Santa Clara, CA, USA), apply the optical principles of the Mie theory for the implementation of red cell analysis. The volume and Hb concentration of individual reticulocytes are independently determined from measurement of light scatter at 2 different angles (high angle, 5–15° and low angle, 2–3°), after isovolumetric sphering of stained reticulocytes; from those values, the reticulocyte Hb content can be calculated. Articles referring to MRV reported by those analyzers focus more on technical and metrological aspects than on clinical utility (22,23).

The reticulocyte channel in Sysmex^TM (Kobe, Japan) and Mindray^TM analyzers share several similarities. Both systems use fluorescent dyes to label nucleic acids in reticulocytes, allowing differentiation based on RNA content and categorization into maturity stages according to fluorescence intensity (24-26). Both analyzers provide reticulocyte Hb content (Reticulocyte Hb equivalent Ret-He in Sysmex, reticulocyte Hb expression RHe in Mindray), which can be mathematically derived from the intensity of forward scattered light (27).

Mindray reports MRV

The clinical utility of the MRV counters reported by Mindray should be studied to confirm the optimal cut-offs with the highest sensitivity and specificity in identifying different clinical situations. Few data have been reported: a recent study reports that the MRV (BC-7500^TM counter) can be used as a reliable and sensitive parameter for the early diagnosis of cancer-related anemia, suggesting that decreased MRV could be strong predictor of overt anemia in cancer patients (28). Our results are in good agreement: MRV and RHe showed a complete correlation (r=1.000, P<0.001) and similar AUC values for the detection of anemia. The discrepancy in the optimal cut-off may relate to patient selection, technical differences between counters, or the algorithm applied to translate the optical signals into MRV.

The capability of MRV (BC-6900^TM counter) for enhancing the diagnostic accuracy for ID in pregnant women has been recently evaluated. The authors report that MRV is a reliable marker of ID and also useful for monitoring the effectiveness of iron treatment during pregnancy, with advantages of being minimally invasive, cost-effective, and fast (29). Our study confirms good analytical performance for reticulocyte parameters, with good imprecision (CV <1.0%), indicating this is a highly precise test with low CV, which is crucial for diagnostic efficiency and reliability for assessing erythropoiesis status.

A strong correlation between RHe and MRV has also been demonstrated. The reliability of the former parameter as a real-time indicator of erythropoiesis status, bone marrow iron requirements and response to therapy has been extensively studied (30). Reticulocyte Hb content has been recognized as a superior biomarker for the early detection of ID compared to traditional methods, such as s-ferritin and TSAT, providing a more sensitive and specific measure of iron status, an earlier diagnosis and suggesting that reticulocyte Hb and MRV share these advantages.

Intervention in IDA across various populations (31,32). The results of the present study suggest that reticulocyte Hb and MRV share these advantages. The most interesting items are:

• Independence from inflammation: s-ferritin is an acute-phase reactant which can be elevated despite low iron storage and/or low availability; its value could be therefore misleading in complex clinical contexts, such as chronic inflammation, cancer and chronic renal disease. This is termed FID, a state in which there is insufficient iron availability and paradoxically apparently adequate body iron stores, with normal s-ferritin values (8). Unlike s-ferritin, reticulocyte Hb levels are not significantly affected by inflammatory states, providing a clearer and more reliable picture of iron status.
• Early detection of ID: reticulocyte Hb can identify ID before the onset of anemia making it crucial for the timely start of treatment. It is important to detect not just evident anemia but also LID, which is ID without anemia, when only minor changes on CBC are present. MRV and MCV are both measures of cell size, but they represent different populations and have distinct clinical implications. Since MCV is based on mature RBCs, MCV alterations typically signal changes that have already occurred in circulating red cells. Due to the long life span of RBC, it may lag behind the earliest bone marrow changes, while MRV detects earlier shifts in the bone marrow activity. MRV changes appear sooner in disease progression. Since reticulocytes precede mature RBCs in the circulation, MRV can identify early bone marrow responses before MCV shifts are detectable. The low values of MRV in case of LID (mean 88.4 fL) suggest its potential role as a marker for detecting ID in early stages, before anemia is established. People with LID are more likely to develop IDA in next weeks or months if LID is not suspected: its detection could provide a chance to make appropriate interventions such as dietetic changes or iron therapy (33).
• Monitoring therapy: a rise in reticulocyte Hb can indicate a positive response to iron therapy, facilitating better management of ID. Due to the short life of reticulocytes, the response to iron therapy can be detected earlier, so it is advantageous over other hematological parameters, for which it takes several weeks or months to show the response (34,35). The early detection of patients who do not respond to oral iron (due to chronic blood loss or malabsorption) is crucial to shift them to different diagnostic and/or treatment trainings, such as IV iron therapy (36).

The fact that reticulocyte indices can allow for real-time assessment of IDE, as well as the efficacy of replacement therapies, has been recognised.

MRV may be an accurate indicator of iron availability in non-macrocytic individuals than conventional markers of iron status (37). But it must be considered that the interplay among other parameters can enhance diagnostic accuracy in clinical settings; MRV is a valuable marker of the quality of erythropoiesis, but it is essential to consider other factors and parameters to ensure a comprehensive assessment and management of patients.

Our results highlight the good diagnostic performance of MRV for the detection of IDE in anemic and non-anemic patients, with the same performance as RHe; its reliability as a marker of response to iron therapy has also been proven. Nevertheless, the study has some weaknesses. First, this is a single-center study, so multicenter evaluations should be conducted to confirm the optimal cut-offs in diverse populations and clinical settings. Second, only adults have been enrolled; studies on children and groups at risk of ID, i.e., pregnant could be of interest.

Reticulocyte-derived parameters have become critical tools for assessing the quality of erythropoiesis, offering real-time insights into iron availability and Hb production efficiency. These biomarkers provide advantages over traditional mature erythrocyte indices by reflecting recent bone marrow activity and iron utilization. However, the lack of standardization and the quality control of inter-laboratory performance remains a concern and a significant barrier for these parameters to be widely used in clinical settings (7). The standardization of reticulocyte parameters is essential for ensuring reliable diagnostics and effective patient management. This requires collaborative efforts among laboratories, manufacturers, and regulatory bodies to develop harmonized methodologies, reference materials, and reporting standards.

Conclusions

MRV provides a sensitive method for quantifying hemoglobinization of reticulocytes. A reliable marker for identifying IDE, MRV can make it possible to quickly identify the full extent of iron metabolism disorders and manage them accordingly. It is a reliable parameter with enhanced diagnostic accuracy, allowing for personalized treatment plans, improving the management of anemia and thus the patients’ outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-30/rc

Data Sharing Statement: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-30/dss

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-30/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-30/coif). E.U. serves as an unpaid editorial board member of Journal of Laboratory and Precision Medicine from December 2025 to November 2027. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of Barrualde-Interior District IHO at Hospital Galdakao Usansolo (Biscay, Spain; No. 1024/24). Informed consent from participants was not required, as residual samples after the requested tests had been completed were used for the present study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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