Morphology of depletant-induced erythrocyte aggregates

Red blood cells suspended in quiescent plasma tend to aggregate into multicellular assemblages, including linearly stacked columnar rouleaux, which can reversibly form more complex clusters or branching networks. While these aggregates play an essential role in establishing hemorheological and pathological properties, the biophysics behind their self-assembly into dynamic mesoscopic structures remains under-explored. We employ coarse-grained molecular simulations to model low-hematocrit erythrocytes subject to short-range implicit depletion forces, and demonstrate not only that depletion interactions are sufficient to account for a sudden dispersion-aggregate transition, but also that the volume fraction of depletant macromolecules controls small aggregate morphology. We observe a sudden transition from a dispersion to a linear column rouleau, followed by a slow emergence of disorderly amorphous clusters of many short rouleaux at larger volume fractions. This work demonstrates how discocyte topology and short-range, non-specific, physical interactions are sufficient to self-assemble erythrocytes into various aggregate structures, with markedly different morphologies and biomedical consequences.