Extreme erythrocyte macrocytic and microcytic percentages are highly predictive of morbidity and mortality

BACKGROUND. The red cell distribution width (RDW) is associated with health outcomes. Whether non-RDW risk information is contained in RBC sizes is unknown. This study evaluated the association of the percentage of extreme macrocytic RBCs (%Macro, RBC volume > 120 fl) and microcytic RBCs (%Micro, RBC volume < 60 fl) and the RDW-size distribution (RDW-sd) with mortality and morbidity. METHODS. Patients (females, n = 165,770; males, n = 100,210) at Intermountain Healthcare were studied if they had a hematology panel between May 2014 and September 2016. Adjusted sex-specific associations of %Macro/%Micro and RDW-sd with mortality and 33 morbidities were evaluated. RESULTS. Among females with fourth-quartile values of %Macro quartile and %Micro (referred to throughout as 4/4), there was an average of 7.2 morbidities versus 2.9 in the lowest risk (LR1) categories, 1/1, 1/2, 2/1, and 2/2 (P < 0.001). Among males, those in the 4/4 category had 8.0 morbidities, while those in the LR1 had 3.4 (P < 0.001). Cox regressions found %Macro/%Micro (4/4 vs. LR1, females: hazard ratio [HR] = 1.97 [95%CI = 1.53, 2.54]; males: HR = 2.17 [CI = 1.72, 2.73]), RDW-sd (quartile 4 vs. 1, females: HR = 1.33 [CI = 1.04, 1.69]; males: HR = 1.41 [CI = 1.10, 1.80]), and RDW (quartile 4 vs. 1, females: HR = 1.59 [CI = 1.26, 2.00]; males: HR = 1.23 [CI = 0.99, 1.52]) independently predicted mortality. Limitations include that the observational design did not reveal causality and unknown confounders may be unmeasured. CONCLUSIONS. Concomitantly elevated %Macro and %Micro predicted the highest mortality risk and the greatest number of morbidities, revealing predictive ability of RBC volume beyond what is measured clinically. Mechanistic investigations are needed to explain the biological basis of these observations.