Physical alterations to erythrocytes following sublethal mechanical stresses

Abstract

Mechanical circulatory support (MCS) devices, extracorporeal membrane oxygenators, and dialysis machines are mechanical systems designed to replace and/or support the functionality of specific biological organs. These devices have been extensively developed over recent decades and are increasingly utilised in acute and chronic care, greatly improving patient outcomes and extending survival. Given these devices integrate into the human vasculature, the efficacy of mechanical circulation depends on: successful surgical implantation and infection prevention, long-term functional performance without mechanical failure, and biological compatibility minimising damaging interactions with blood (i.e., haemocompatibility). With improved device design, many current generation MCS devices have the capacity to adequately meet the required functional demands of associated biological organs, operating within parameters that avoid overt haemolysis and other extremes of inadequate haemocompatibility. Nevertheless, unfortunately the use of MCS remains plagued with severe secondary systemic complications which implicate impaired blood health and a functional decline of blood flow. While many precipitating determinants of these secondary complications remain unresolved, the accumulating clinical evidence indicates that the current haemocompatibility criteria is insufficient in predicting declines in blood function without the development of haemolysis (i.e., sublethal damage). Blood trauma may be induced by non-physiological flow environments, largely due to elevated shear forces, turbulence, and collision with other cellular and artificial surfaces within MCS. Consequently, fragmentation of red blood cells (RBCs), shortened cell life-spans, and decreased cell function may be observed at microvascular levels, leading to the development of acute tissue ischaemia, propagating chronic systemic complications (e.g., multi-system organ failure – where mortality is unavoidable). While there is need for improved, more sensitive, markers of haemocompatibility that can detect declining RBC function in non-haemolysed blood, only limited studies have investigated this sublethal trauma. The aim of the present dissertation was to mechanistically elucidate how non-physiological shear environments, typical of MCS, can adversely affect blood function and flow independent of haemolysis, leading to the development of multi-system organ failure and death. The dissertation provides a comprehensive discussion into the haemorheological alterations that occur following exposure of blood to shear stresses that are supraphysiological (i.e., >10 Pa) and subhaemolytic (i.e., less than that required to induce haemolysis), providing novel characterisation and avenues for future inspection. The findings of the current dissertation greatly enhance the understanding of the processes involved in the accumulation of functional blood damage observed in MCS, while progressing current understanding of red cell physiology. Further, the collective findings may in part explain current clinical complications associated with the use of MCS, possibly identifying rheological aetiologies for ischaemic complications, angiodysplasia, and the vascular related incidence of neurological complications. The collective studies conceivably provide the basis for the development of a more sensitive and holistic indicator of haemocompatibility, while facilitating the development of numerical models that will allow in silico optimisation that will rapidly accelerate the advancement of future MCS devices. Understanding the haemorheological interactions associated with blood trauma will also assist the clinical management of current patients exposed to various forms of mechanical circulation, providing potential avenues for targeted rheological pharmacotherapy and improved patient care.