(A) Routine complete blood counts (CBC) measure the single-cell volume and hemoglobin for young RBCs (b(v,h,t), blue contours showing ‘reticulocytes’ that are <~3 days old) as well as for all circulating RBCs (P(v,h,t), red contours showing RBCs of all ages from 0 up to 90–120 days, with RBC lifespan well-controlled in each person but varying from one person to the next). The black line through the origin shows the mean hemoglobin concentration (mean corpuscular hemoglobin concentration, MCHC) for the sampled population and this major axis of the distribution (u) provides a very rough estimate of RBC age, with higher u corresponding to younger age. (B) Schematic of the model of single-RBC volume-hemoglobin dynamics. Individual RBCs are produced as reticulocytes (RET) in the top right and lose about 30% of their volume and about 20% of their hemoglobin during their 90–120 day lifespan, with volume and hemoglobin reductions occurring during an early fast phase parameterized by βv and βh and a later slow phase parameterized by α, with fluctuations in rates of single-RBC volume and hemoglobin change quantified by Dv and Dh. As the single-RBC volume and hemoglobin continue to fall, the probability of clearance increases dramatically as the RBC’s trajectory approaches the boundary region shown as vc. (C) Four measurements were made to establish each subject’s baseline before controlled blood loss. Additional measurements were made 1–3 days and 21 days later. (D) The modeling integrated serial CBCs into the parameter estimation process in a piecewise manner. The first CBC (left) is assumed to be at steady state, and the model is used to estimate dynamic parameters which produce RBC1 given RET1. These model parameters and RET1 are then used to estimate the initial condition leading to timepoint t2, and the model estimates the dynamics between timepoints t1 and t2. These steps for timepoint t2 are then repeated to estimate the transient dynamics between each successive timepoint. LS refers to the lifespan of RBCs. Panels (E–F) are frames from Video 1 that shows a simulation of the evolution of P(v,h,t) from t = 0 to t = 105 days for a typical study subject. Equal-probability contours for P(v,h) are shown at the bottom, with the empirical measurement as blue lines, and the simulation in solid red. The surface plot also shows the simulated P(v,h,t). The plot of the empirical measurement in dashed blue is serially updated during the movie to the measurement subsequent to the value of t. Marginal P(v,t) and P(h,t) are shown on the left and right.