Cell-Free Hemoglobin in the Pathophysiology of Trauma: A Scoping Review

Abstract

Objectives: Cell-free hemoglobin (CFH) is a potent mediator of endothelial dysfunction, organ injury, coagulopathy, and immunomodulation in hemolysis. These mechanisms have been demonstrated in patients with sepsis, hemoglobinopathies, and those receiving transfusions. However, less is known about the role of CFH in the pathophysiology of trauma, despite the release of equivalent levels of free hemoglobin.

Data sources: Ovid MEDLINE, Embase, Web of Science Core Collection, and BIOSIS Previews were searched up to January 21, 2023, using key terms related to free hemoglobin and trauma.

Data extraction: Two independent reviewers selected studies focused on hemolysis in trauma patients, hemoglobin breakdown products, hemoglobin-mediated injury in trauma, transfusion, sepsis, or therapeutics.

Data synthesis: Data from the selected studies and their references were synthesized into a narrative review.

Conclusions: Free hemoglobin likely plays a role in endothelial dysfunction, organ injury, coagulopathy, and immune dysfunction in polytrauma. This is a compelling area of investigation as multiple existing therapeutics effectively block these pathways.

Keywords: haptoglobin; hemolysis; hemopexin; multiple trauma; oxidative stress.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram.

Figure 2.

Endogenous mechanisms of cell-free hemoglobin and heme clearance. RBC lysis releases free hemoglobin. Cell-free hemoglobin is bound primarily by circulating haptoglobin, and the resulting hemoglobin–haptoglobin complexes are taken via CD163 (13, 14)^,. Smaller quantities of cell-free hemoglobin are also bound by megalin and cubilin receptors in the renal proximal tubule (15), and by apoA1 (16). Cell-free hemoglobin that is not cleared breaks down to hemoglobin dimers, and ultimately to free heme, free heme is bound by circulating hemopexin and taken up via the receptor CD91 (–19). Free heme also binds with low affinity to albumin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and α₁-microglobulin, all of which likely contribute to heme clearance (17, 20).

Figure 3.

Mechanisms of cell-free hemoglobin (Hb)- and heme-mediated injury. Cell-free Hb rapidly depletes local nitric oxide (26), leading to vasoconstriction, up-regulation of endothelial adhesion molecules, platelet activation, and thrombosis. Hb also catalyzes free radical production and the resulting reactive oxygen species (ROS) damage membrane lipids and proteins. Free heme also activates the endothelium, increasing local inflammation triggering complement activation, and targeting the endothelium (27). Heme also disrupts the endothelial barrier function through a disruption of tight and adherens junctions and via ROS-mediated necroptosis (–30). Free heme also acts as a damage-associated molecular pattern by binding to Toll-like receptor 4 (TLR4) on neutrophils and monocytes/macrophages (–33). These effects lead to broad activation of proinflammatory pathways including via the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, formation of neutrophil extracellular traps (NET) (–36) apoptosis of immune cells (37), and impaired phagocytosis (31, 38, 39).