Haemolytic injury and cardiovascular disease

Haemoglobin is a ferrous iron (Fe²⁺)-containing intracellular protein that is crucial for multiple homeostatic functions, including transport of oxygen and carbon dioxide, acid-base buffering and cellular signalling through nitric oxide oxidation and nitrite reduction. When erythrocyte membranes are disrupted, a process known as haemolysis that is caused by either disease or an exogenous stressor, haemoglobin is liberated into the plasma. This plasma free haemoglobin is highly pathogenic, disrupting a range of physiological processes and causing downstream organ damage through multiple mechanisms, including nitric oxide scavenging, vasoconstriction, generation of reactive oxygen species, activation of innate immune inflammation, disruption of cellular signalling, activation of the coagulation cascade and direct end-organ injury. Haemolysis and an elevated level of plasma free haemoglobin are associated with increased cardiovascular mortality, haemodynamic derangements, renal dysfunction and immune system dysregulation. These injurious pathways are exacerbated as the plasma free haemoglobin concentration and duration of exposure increase and are mitigated by endogenous scavenging pathways. In cardiovascular disease, proliferation of the use of mechanical circulatory support technologies, as well as an ageing population with chronic low levels of haemolysis, has increased exposure to plasma free haemoglobin and its detrimental effects. In this Review, we summarize the relationship between chronic haemolysis and cardiovascular disease and discuss current and future approaches towards the prevention and treatment of haemolytic injury.