A molecule best known for carrying oxygen may become a powerful driver of cardiovascular injury when it escapes the red blood cells that normally contain it. A new review in Nature Reviews Cardiology examines how haemolysis—the destruction or rupture of erythrocytes—releases haemoglobin into the bloodstream, where it can damage blood vessels, disrupt organ function and amplify inflammation. The authors describe plasma free haemoglobin as a complex biological threat whose effects extend far beyond the loss of red blood cells.
Haemoglobin is an intracellular protein built around ferrous iron, or Fe²⁺, which enables it to bind oxygen reversibly inside erythrocytes. Its functions are not limited to oxygen transport. Haemoglobin also contributes to carbon dioxide transport, acid–base buffering and cellular signalling involving nitric oxide oxidation and nitrite reduction. Under normal conditions, these activities take place within the protective environment of the red blood cell. When the erythrocyte membrane is damaged, however, haemoglobin is released directly into plasma, exposing tissues to a chemically reactive form of the protein.
The resulting plasma free haemoglobin can interfere with one of the body’s most important vascular signalling systems: nitric oxide. Nitric oxide normally relaxes vascular smooth muscle, helping blood vessels dilate and supporting efficient blood flow. Free haemoglobin rapidly binds and scavenges nitric oxide, reducing its availability. This reaction can promote vasoconstriction, increase vascular resistance and impair the regulation of blood pressure and tissue perfusion. In people whose cardiovascular systems are already under strain, the consequences may be particularly serious.
The review also highlights the role of haemoglobin’s iron-containing haem group in oxidative injury. Once outside the erythrocyte, haemoglobin is more exposed to oxidation and can participate in reactions that generate reactive oxygen species. These highly reactive molecules can damage lipids, proteins and cellular membranes, while also altering the function of endothelial cells lining the blood vessels. Oxidative stress may further reduce nitric oxide signalling, creating a damaging cycle in which vascular constriction and molecular injury reinforce one another.
Free haemoglobin can additionally act as a trigger for innate immune inflammation. The immune system detects molecular signals associated with tissue damage, and extracellular haemoglobin may contribute to the activation of inflammatory pathways. This response can disturb normal cellular communication and intensify injury in organs exposed to haemolytic plasma. The review describes haemolysis as a process capable of linking vascular dysfunction, oxidative stress and immune activation, rather than as an isolated blood abnormality.
The effects may also extend to the coagulation system. Haemolytic injury can promote activation of the coagulation cascade, a network of enzymatic reactions responsible for forming blood clots. When this system becomes excessively active, it may contribute to thrombosis and compromise blood flow through already vulnerable vessels. At the same time, direct exposure of tissues to free haemoglobin and its breakdown products can contribute to end-organ injury, including damage affecting the kidneys and cardiovascular system.
Clinical observations have associated haemolysis and elevated plasma free haemoglobin with increased cardiovascular mortality, haemodynamic disturbances, renal dysfunction and dysregulation of immune responses. The severity of injury is influenced by both concentration and exposure time: higher plasma free haemoglobin levels and longer periods of exposure generally intensify harmful effects. This relationship helps explain why persistent, low-grade haemolysis may still matter clinically, even when it does not produce an immediately dramatic change in laboratory measurements or symptoms.
The body is not entirely without protection. Endogenous scavenging systems normally bind and remove free haemoglobin from the circulation, limiting its access to blood vessels and organs. These pathways can become overwhelmed when haemolysis is extensive or prolonged. Their capacity, together with the rate at which haemoglobin is released and cleared, helps determine whether haemolysis remains a transient event or develops into sustained vascular and organ injury. Understanding these natural defence mechanisms could guide the development of treatments designed to neutralize free haemoglobin or accelerate its removal.
The cardiovascular field is encountering this problem more frequently as mechanical circulatory support technologies become more widely used. Devices that move blood mechanically can expose erythrocytes to abnormal forces, including shear stress, which may disrupt red-cell membranes and cause haemolysis. The authors also point to an ageing population in which chronic, low-level haemolysis may occur alongside cardiovascular disease and other conditions. The review calls attention to the need for strategies that prevent haemolysis, monitor plasma free haemoglobin and reduce downstream injury. Future approaches may focus on protecting erythrocytes, improving haemoglobin scavenging, controlling oxidative and inflammatory pathways, and limiting the vascular consequences of nitric oxide depletion. Together, these efforts could help transform haemolysis from an under-recognized complication into a more manageable cardiovascular risk.
Subject of Research: Haemolytic injury, plasma free haemoglobin and cardiovascular disease
Article Title: Haemolytic injury and cardiovascular disease
Article References: Hieromnimon, M.C., Basit, A., Hieromnimon, H.M. et al. Haemolytic injury and cardiovascular disease. Nature Reviews Cardiology (2026). https://doi.org/10.1038/s41569-026-01329-0
Image Credits: AI Generated
DOI: 10.1038/s41569-026-01329-0
Keywords: Haemolysis, plasma free haemoglobin, cardiovascular disease, nitric oxide scavenging, vasoconstriction, oxidative stress, inflammation, coagulation, renal dysfunction, mechanical circulatory support
