Erythrocyte Heterogeneity as a Driver of Thrombus Architecture and Treatment Response

Thrombi are not uniform structures, and neither are the red blood cells (RBCs) that populate them. Most models of thrombosis, however, implicitly treat erythrocytes as mechanically and biologically uniform, obscuring a key determinant of clot architecture: RBC heterogeneity. Circulating RBCs vary widely in size, shape, deformability, membrane composition, and biochemical state, generating subpopulations that behave differently under flow and within forming thrombi. These differences actively govern how RBCs marginate, where they localize during thrombus growth, how they interact with fibrin and platelets, and how they resist or accommodate platelet-driven contraction. The outcome is not merely variable RBC content but spatially organized thrombi with region-specific mechanics, permeability, and fibrinolytic susceptibility. Experimental models and analyses of patient-derived thrombi demonstrate that RBCs are unevenly distributed within clots. This spatial variability shapes local fibrin architecture, platelet activity, and clot mechanics in ways that cannot be inferred from total RBC content or average erythrocyte properties, highlighting RBC heterogeneity as a critical, yet underrecognized, determinant of thrombus formation. In this review, we present a conceptual framework of thrombus heterogeneity along three coupled axes: mechanical, structural, and biochemical, illustrating how erythrocyte subpopulations influence clot formation and function. We synthesize emerging evidence, discuss approaches for identifying RBC subpopulations, and explore implications for thrombosis modeling, thrombolysis, thrombectomy, and clinical outcomes.