Red Blood Cell Sublethal Damage: Hemocompatibility Is not the Absence of Hemolysis

Blood is a complex fluid owing to its two-phase suspension of formed cellular elements within a protein-rich plasma. Vital to its role in distributing nutrients throughout the circulatory system, the mechanical properties of blood - and particularly red blood cells (RBC)-primarily determine bulk flow characteristics and microcirculatory flux. Various factors impair the physical properties of RBC, including cellular senescence, many diseases, and exposure to mechanical forces. Indeed, the latter is increasingly relevant following the advent of modern life support, such as mechanical circulatory support (MCS), which induce unique interactions between blood and artificial environments that leave blood cells with the signature of aging, albeit accelerated, and crucially underlie various serious complications, including death. Accumulating evidence indicates that these complications appear to be associated with mechanical shear forces present within MCS that are not extreme enough to overtly rupture cells, yet may still induce "sublethal" injury and "fatigue" to vital blood constituents. Impaired RBC physical properties following elevated shear exposure-a hallmark of sublethal injury to blood-are notable and may explain, at least in part, systemic complications and premature mortality associated with MCS. Design of optimal next-generation MCS devices thus requires consideration of biocompatibility and blood-device interactions to minimize potential blood complications and promote clinical success. Presented herein is a contemporary understanding of "blood damage," with emphasis on shear exposures that alter microrheological function but do not overtly destroy cells (ie, sublethal damage). Identification of key cellular factors perturbed by supraphysiological shear exposure are examined, offering potential pathways to enhance design of MCS and blood-contacting medical devices.