Marginated aberrant red blood cells induce pathologic vascular stress fluctuations in a computational model of hematologic disorders

Red blood cell (RBC) disorders affect billions worldwide. While alterations in the physical properties of aberrant RBCs and associated hemodynamic changes are readily observed, in conditions such as sickle cell disease and iron deficiency, RBC disorders can also be associated with vascular dysfunction. The mechanisms of vasculopathy in those diseases remain unclear and scant research has explored whether biophysical alterations of RBCs can directly affect vascular function. Here we hypothesize that the purely physical interactions between aberrant RBCs and endothelial cells, due to the margination of stiff aberrant RBCs, play a key role in this phenomenon for a range of disorders. This hypothesis is tested by direct simulations of a cellular scale computational model of blood flow in sickle cell disease, iron deficiency anemia, COVID-19, and spherocytosis. We characterize cell distributions for normal and aberrant RBC mixtures in straight and curved tubes, the latter to address issues of geometric complexity that arise in the microcirculation. In all cases aberrant RBCs strongly localize near the vessel walls (margination) due to contrasts in cell size, shape, and deformability from the normal cells. In the curved channel, the distribution of marginated cells is very heterogeneous, indicating a key role for vascular geometry. Finally, we characterize the shear stresses on the vessel walls; consistent with our hypothesis, the marginated aberrant cells generate large transient stress fluctuations due to the high velocity gradients induced by their near-wall motions. The anomalous stress fluctuations experienced by endothelial cells may be responsible for the observed vascular inflammation. Significance Statement A common and potentially life-threatening complication of blood cell disorders is inflammation and dysfunction of the vascular wall, for reasons that remain unclear. To address this issue, we explore a purely biophysical hypothesis involving red blood cells using detailed computational simulations. Our results show that red blood cells that are pathologically altered in cell shape, size, and stiffness, which occurs in various blood disorders, strongly marginate, residing primarily in the cell-free layer near blood vessel walls, generating large shear stress fluctuations at the vessel wall that may be responsible for endothelial damage and inflammation.