Examining and Mitigating Acellular Hemoglobin Vasoactivity

Abstract

Significance: There has been a striking advancement in our understanding of red cell substitutes over the past decade. Although regulatory oversight has influenced many aspects of product development in this period, those who have approached the demonstration of efficacy of red cell substitutes have failed to understand their implication at the level of the microcirculation, where blood interacts closely with tissue. Recent Advances: The understanding of the adverse effects of acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) has fortunately expanded from Hb-induced renal toxicity to a more complete list of biochemical mechanism. In addition, various unexpected adverse reactions were seen in early clinical studies. The effects of the presence of acellular Hb in plasma are relatively unique because of the convergence of mechanical and biochemical natures. Critical Issues: Controlling the variables using genetic engineering and chemical modification to change specific characteristics of the Hb molecule may allow for solving the complex multivariate problems of acellular Hb vasoactivity. HBOCs may never be rendered free of negative effects; however, quantifying the nature and extent of microvascular complications establishes a platform for designing new ameliorative therapies. Future Directions: It is time to leave behind the study of vasoactivity and toxicity based on bench-top measurements of biochemical changes and those based solely on systemic parameters in vivo, and move to a more holistic analysis of the mechanisms creating the problems, complemented with meaningful studies of efficacy. Antioxid. Redox Signal. 18, 2329-2341.

Resuscitation from hemorrhagic shock using polymerized hemoglobin compared to blood

“…Second, acellular Hb enhances hyper-oxygenation of the tissues as O 2 is both dissolved and bound to Hb in the plasma, triggering autoregulatory metabolic mechanisms that induce vasoconstriction to limit blood flow (35). Third, acellular Hb extravasates through the endothelial lining, deposits in the interstitial space and undergoes uncontrolled autoxidation processes, forming methemoglobin (metHb), reactive O 2 species, and inflammation and vascular damage, hence affecting vascular function and diameter (36, 37). Independent of whatever underlying mechanism is ultimately responsible, it is clear that an increase in HBOC concentration results in increased vasoconstriction.…”

Investigational use of PEGylated carboxyhemoglobin bovine in a Jehovah's Witness with hemorrhagic shock

“…It is produced through the polyethylene glycol modification (PEGylation) of surface lysine residues on purified bovine Hb with 5000 Da PEG‐succinimidyl carbonate followed by carboxylation. Due to its hydrophilic nature, PEG increases the effective molecular size of Hb and inhibits its interaction with the vascular endothelium . PCHB was well tolerated by 18 healthy human volunteers in a Phase I clinical trial and was shown in preclinical trials to protect the myocardium against ischemia–reperfusion injury in diabetic and normal mice .…”

Recent and prominent examples of nano- and microarchitectures as hemoglobin-based oxygen carriers

“…[23,24] Further accumulation of oxy-Hb in the bloodstream will be filtered out by the kidney glomeruli and reabsorbed by the tubules (Scheme 8). [25] Overloading this system will result in oxidative damage and cell death within the kidneys. Additionally, upon dissociation of the oxy-Hb tetramer, the oxy-Hb dimers and monomers will be able to penetrate in between the endothelial cells lining the blood vessels due to their small size (Scheme 1C, 9).…”