AimsRed blood cell (RBC) lysis resistance interferes with white blood cell (WBC) count and differential; still, its detection relies on the identification of an abnormal scattergram, and this is not clearly adverted by specific flags in the Beckman-Coulter DXH-800. The aims were to analyse precisely the effect of RBC lysis resistance interference in WBC counts, differentials and cell population data (CPD) and then to design, develop and implement a novel diagnostic machine learning (ML) model to optimise the detection of samples presenting this phenomenon.MethodsWBC counts, differentials and CPD from 232 patients (anaemia or liver disease) were compared with 100 healthy controls (HC) using analysis of variance. The data were analysed after a corrective action, and the analyser differentials were also compared with the digital leucocyte differentials. The ML support vector machine (SVM) algorithm was trained with 70% of the samples (n=233) and the 30% remaining (n=99) were employed exclusively during the validation phase.ResultsWe identified that impedance WBC was not affected by the RBC lysis resistance interference while the DXH-800 differentials overestimated lymphoid subpopulations (17.6%), sometimes even yielding spurious lymphocytosis, and the latter were corrected when sample dilution was performed. The ML-SVM algorithm allowed the classification of the pathological groups when compared with HC with validation accuracies corresponding to 97.98%, 100% and 88.78% for the global, anaemia and liver disease groups, respectively.ConclusionsThe proposed algorithm has an impressive discriminatory potential and its application would be a valuable support system to detect spurious results due to RBC lysis resistance.