Figure 4. Single-cell model provides a mechanistic link between dynamics of the (v,h) distribution and the balance between increased RBC production and delayed RBC clearance in response to blood loss.

(A) Schematic of the single-cell volume-hemoglobin distribution for RBCs. The major axis of the distribution (u) corresponds to the mean single-RBC hemoglobin concentration (MCHC). An RBC’s position when projected onto u corresponds roughly to its age, with younger RBCs generally appearing in the upper right, and aging along the u axis toward the origin in the bottom left. We can compare changes in the fraction of older RBCs by integrating density along u as shown in the inset in the top left. We can compare changes in the fraction of newly produced RBCs by conditioning on higher u and integrating density along the [Hb] axis as show in the inset in the top right of panel (A). (B) The top panel shows a typical (v,h) distribution that has been transformed onto the u-[Hb] plane in the bottom panel. (C) The typical blood loss response after 1–3 days includes an increase in the fraction of newly produced cells which will have [Hb] more than one standard deviation below the median and u more than one standard deviation above the median (p<1e-3), corresponding to the top right inset in panel (A) and consistent with increased production. (D) 1–3 days following blood loss, the typical response also involves an increase in the fraction of older RBCs, located more than one standard deviation (15%) below the median u (p<1e-3), corresponding to the top left inset in panel (A) and consistent with a delayed clearance. (E) The mean RBC age (M_RBC), as estimated by the glycated hemoglobin fraction, has decreased on average by about 4% after 21 days, but there is significant variation, with some subjects seeing an increase in M_RBC. (F) The model characterizes the relative balance between increased production and delayed clearance in each subject’s blood response by the dimensionless parameter ratio $\left(D_v\bullet v_c\right)/\alpha$. The time-weighted average of this ratio after blood loss for each subject is significantly correlated with the estimated change in M_RBC (ρ = −0.59), suggesting that the model of (v,h) dynamics has accurately captured the $\left(production/clearance\right)$ balance of the typical subject’s blood loss response. The red line is a least-squares linear fit. (G) The dimensionless parameter ratio distinguishes subjects whose M_RBC becomes shorter (production-dominated) during response to blood loss from those whose M_RBC becomes longer (clearance-dominated). (See Figure 2 caption for boxplot description.)