Establishing reference intervals for extended red blood cell parameters with the <scp>Mindray BC</scp>‐<scp>6800Plus</scp> hematology analyzer in a <scp>Chinese</scp> population

With the development of haematological analysis techniques, the relationship between the new extended red blood cell parameters provided by them and the associated diseases of the hematologic related is of clinical concern. It has been reported that hyperchromic red blood cell percentage (HYPER%) and mean reticulocyte volume (MRV) can be used as two indexes in the specific screening of hereditary spherocytosis.1, 2 There is a strong correlation between decreased reticulocyte production index (RPI) and severe malarial anemia with high incidence and mortality rates among children.3 Increased mean hemoglobin distribution width of red blood cells (HDW) is commonly observed in various sickle cell anemia.4 Changes in extended red blood cell parameters are not only related to hematological diseases but also related to insufficient iron content in the body. Hypochromic red blood cell percentage (HYPO%), as an index of iron disorder diagnosis, has been included in the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines by the National Kidney Foundation in the United States. Mean corpuscular hemoglobin of reticulocyte (MCHr) has also been reported as a reliable index in detecting iron deficiency.5 Establishing reference intervals for these eight research parameters lays a foundation for relevant clinical research and applications. However, previous reference intervals were mostly established based on research on Western populations.6 Therefore, with the BC-6800Plus analyzer, this study is to establish reference intervals for these parameters based on data from Chinese adults. Research parameters related to those eight red blood cell types mentioned above have been detected in the Cell-Dyn Sapphire, Sysmex XN-2000, and Siemens Advia hematology analyzer. BC-6800Plus hematology analyzer is an ERP channel detection instrument newly introduced by Mindray in Shenzhen. With new channels for detecting red blood cells, platelets, and reticulocytes, this instrument can perform sphericalization treatment of red blood cells with DR diluent, thus avoiding the interference of microcytes and fragmented red blood cells. Furthermore, it utilizes a stronger new fluorescence dye (asymmetric cyanine dye) to bind nucleic acids in reticulocytes and red blood cells together, then collects the forward scatter, fluorescence, and side scatter signals for three-dimensional image analysis. Then, FRC# and FRC% can be obtained through the analysis of algorithm-positioned specific regions in the three-dimensional scatterplot. Also, MRV can be obtained through the centroid analysis of forward scatter signals in the scatterplot, and RPI can be further calculated based on the reticulocyte percentage and red blood cell hematocrit in the scatterplot. In addition to the calculations mentioned above, the three-dimensional scatterplot of the ERP channel can be transformed into a nine-parameter graph of red blood cells with different volumes and hemoglobin concentrations through a Mie scattering model, as shown in Figure 1. Furthermore, the information presented in the nine-parameter graph of red blood cells can be converted into such parameters as MCHr, HDW, HYPER%, and HYPO% with a histogram. A total of 1539 apparently healthy individuals in physical examination at Shenzhen Luohu Hospital Group Luohu People's Hospital from January to June 2021 were used as research subjects in this study. Among these participants, no abnormal values were detected in various parameters. Also, among them, there were 823 males and 716 females, with ages ranging from 18 to 89 years. In this study, 2 mL of venous blood sample was collected and placed in an EDTA-K2 anticoagulant vacuum tube. Then, within 4 h, under the CDR mode, the sample was tested on the BC-6800 Plus analyzer with daily three-level quality control, and then the information was collected. Based on the C28-A3 guidelines of the U.S. Clinical and Laboratory Standards Institute,7 outliers were treated, with the difference value (D) between the test value of a suspected outlier and its adjacent value divided by the whole data range (R). If D/R ≥ 1/3, then the suspected outlier value in question should be viewed as an outlier value, which is subsequently removed from the analysis. After that, according to Harris' proposition in the C28-A3 guidelines, Z-values and Z*-values were calculated to analyze whether reference intervals of those eight blood cell parameters should be divided into groups with gender (Z* = 3(naverage/120)½ = 3[(n1 + n2)/240]½). Analysis results show that only on RPI should a reference interval based on gender be established. Then, a nonparametric method was employed with 2.50% and 97.50% of data distribution used as the upper and lower limits of the reference interval, as shown in Table 1. In this study, Analyse-it (v5.11) software and Excel 2013 software were used for statistical analysis. FRC count provided by the hematology analyzer is a potentially useful screening tool, presenting a value indicating whether a blood smear should be prepared to reexamine fragmented red cells. In 2021, the International Council for Standardization in Hematology (ICSH) updated its recommendations on fragmented red cell detection.8 In the recommendations, the council pointed out that thrombotic microangiopathy, as a life-threatening disease, can only be treated through early and accurate diagnosis and cure. Also, it is an important method to detect fragmented red cells in peripheral blood smears for early detection of thrombotic microangiopathy. The reference interval of FRC previously settled with Sysmex is 0.00–0.06 (%).6 However, a reference interval of 0.12–0.53 (%) was settled in this study with BC-6800 Plus. Although these two instruments have an identical parameter name on FRC with only slight differences, they employ different principles in detecting FRC; that is, the threshold of FRC indicating blood smear reexamination should be settled in accordance with a specific instrument. In addition, at present, different manufacturers use different names for parameters with identical meanings. For example, the distribution width of hemoglobin concentration is displayed as HDW in Abbott CELL-DYN Sapphire system and BC-6800 Plus, while it is displayed as HC VAR in Siemens Advia. Such discrepancies have posed challenges for future clinical research and applications. Reference intervals of HDW settled in the Korean Abbott CELL-DYN Sapphire system are 5.98–9.07 g/L (male) and 5.71–8.71 g/L (female).9 However, in this study, an HDW reference interval of 18.8–37.6 g/L was settled. Because there is a lack of traceability and standardization, it is not possible to compare the huge differences between these two intervals that were settled. Feasibility studies have been previously carried out by the International Council for Standardization in Hematology (ICSH) regarding MPV standardization.10 Nevertheless, currently, there is no research exploring the standardization of related parameters of these red blood cells. Future clinical applications of these parameters are not possible unless this problem is tackled. Recently, with BC-6800 Plus, Bohn established reference intervals of 79 parameters for the child and adolescent population in Canada. This research has analyzed hematological parameters among specific age and gender groups and emphasized the complexity of hematological parameters of children.11 RPI is an index that helps identify elevated reticulocyte counts caused by red cell depletion in children with anemia.12 RPI reference intervals previously settled for female and male adolescents aged 14–19 years in Canada were 0.60–2.10 and 0.70–3.10, respectively. In this study, the RPI reference intervals settled for Chinese female and male adults are 0.60–2.50 and 1.00–4.74, respectively. There is a slightly big difference between the RPI reference intervals settled for males in these two studies. One major possible reason is that this parameter is influenced by factors of age and region. This study has certain limitations. Reference individuals within an age range of 18–89 years were selected in this study, but no analysis has been performed on various age groups separately. Furthermore, in view of the increasing number of innovative parameters in blood cell analysis, biological variations have not been fully covered in this study. Future studies should further investigate the biological variation of each parameter to lay a foundation for clinical applications. It is worth noting that the reference intervals of those eight red blood cell expansion parameters established for Chinese adults in this study are applicable to the Mindray BC-6800Plus analyzer. Further research should be conducted to investigate the applicability of these reference intervals to other instruments or such special populations as pregnant women, infants, children, and adolescents. In addition, the reference intervals of these research parameters established in this study are only intended for clinical research, with their clinical implications to be further verified. Also, the purpose of this study is to lay a foundation for future clinical practice and research. Yanping Luo, contribution to the work: design, data analysis and writing. Shuaiyan Wang, contribution to the work: experiment and data analysis. Zhuocheng Chen, contribution to the work: experiment and data analysis. Shan Lin, contribution to the work: experiment. Sanping Guo, contribution to the work: experiment and interpretation of data. Hongmei Mo, contribution to the work: design, drafts and revisions. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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