Cell-free hemoglobin (cfHb)

Cell-free hemoglobin (cfHb) is the form of hemoglobin released into the plasma following the rupture of red blood cells, a process known as hemolysis (Gueye et al., 2016, PMID: 27101144). Under physiological conditions, hemoglobin is sequestered within erythrocytes to transport oxygen; however, when released into the extracellular environment, it becomes a potent toxin (Schar et al., 2013, PMID: 23515925). cfHb exhibits a high affinity for nitric oxide (NO), and its scavenging of NO leads to impaired vasodilation, smooth muscle dystonia, and hypertension (Gladwin et al., 2012, PMID: 22586068). Additionally, the breakdown of cfHb releases redox-active iron and heme, which catalyze the formation of reactive oxygen species and activate innate immune pathways like TLR4, contributing to organ damage (Belcher et al., 2014, PMID: 24403440). Therapeutic interventions aim to mitigate these effects by using haptoglobin to facilitate cfHb clearance or by employing small molecules like Voxelotor to stabilize hemoglobin within cells to prevent its release (Vichinsky et al., 2019, PMID: 31199090).

Other names

Extracellular hemoglobinAcellular hemoglobinPlasma hemoglobinFree hemoglobin

The primary therapeutic mechanism involves the high-affinity binding and sequestration of extracellular hemoglobin by scavenger proteins like haptoglobin, which facilitates its clearance via the CD163 receptor on macrophages (Schar et al., 2013, PMID: 23515925). Alternatively, small molecule stabilizers like Voxelotor increase the oxygen affinity of hemoglobin, thereby inhibiting the polymerization of sickle hemoglobin and reducing the subsequent hemolysis that releases cfHb into the plasma (Vichinsky et al., 2019, PMID: 31199090).