Individuals with macrocytosis or a high RDW are at increased risk of developing haematological malignancies. The mechanisms that mediate this association remain unknown but may involve the presence of clonal haematopoiesis (CH). Here, we performed targeted next-generation sequencing on all individuals ≥60 years with macrocytosis (MCV >100 fL; n = 269) or high RDW (RDW ≥16%; n = 242) and 1:2 age- and sex-matched controls from the population-based Lifelines cohort. Macrocytosis is not associated with CH or peripheral blood count abnormalities. In contrast, individuals with a high RDW were associated with an increased number of mutated genes, larger clone sizes and a high prevalence of blood count abnormalities. Interestingly, individuals with a high RDW and CH display a uniform population of red blood cells in the distribution plots, despite not all cells carrying the respective mutation, suggesting an indirect effect of CH on the red blood cell population. While macrocytosis is not associated with CH in general, SF3B1 mutations associate with an elevated MCV. Individuals with a combination of TET2 and SRSF2 mutations show marked disturbances in platelet morphology. In conclusion, cytometric parameters of peripheral blood cells may serve as early indicators of dysplastic changes and are associated with distinct mutational patterns in CH.
Keywords: acute leukaemia; clinical haematology; clonal evolution; clonal haematopoiesis; epidemiology; genetic analysis.