Safety profile of high molecular weight polymerized hemoglobins

Muller, Cynthia R.; Williams, Alexander T.; Muñoz, Carlos; Eaker, Allyn M.; Breton, Amanda; Palmer, Andre F.; Cabrales, Pedro

doi:10.1111/trf.16157

Cited by 9 publications

(9 citation statements)

References 37 publications

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“… 3 First-generation acellular chemically modified HBOCs were shown to entail statistically higher risks of myocardial infarction and death in the clinical trials, 4 , 5 which are presumably related to their small molecular sizes, high intrinsic affinities to nitric oxide, and their acellular structure, which collectively cause extravasation, vasoconstriction, hypertension, and oxidative lesion. 5 , 6 , 7 , 8 To mitigate such risks, we have developed hemoglobin vesicles (HbVs), which are cellular-structured HBOCs encapsulating a purified and concentrated Hb solution in PEGylated phospholipid vesicles (liposomes; mean particle diameter, 225-285 nm), shielding all the toxic effects of molecular hemoglobin by means of a lipid bilayer membrane and by mimicking erythrocytes ( Figure 1 A). 9 , 10 , 11 , 12 The efficacy of HbVs, when used as a resuscitative fluid, has been studied extensively using animal models.…”

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confidence: 99%

First-in-human phase 1 trial of hemoglobin vesicles as artificial red blood cells developed for use as a transfusion alternative

et al. 2022

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First-in-human phase 1 trial of hemoglobin vesicles as artificial red blood cells developed for use as a transfusion alternative

et al. 2022

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“…Animals were euthanized for 2 h post‐transfusion to collect the blood, liver, heart, spleen, and kidneys for analysis. Organ tissue was processed for inflammatory and organ damage markers as previously described 28 using the kits and assays outlined in Table S1.…”

Section: Methodsmentioning

confidence: 99%

Purification and analysis of a protein cocktail capable of scavenging cell‐free hemoglobin, heme, and iron

et al. 2021

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Background Hemolysis releases toxic cell‐free hemoglobin (Hb), heme, and iron, which overwhelm their natural scavenging mechanisms during acute or chronic hemolytic conditions. This study describes a novel strategy to purify a protein cocktail containing a comprehensive set of scavenger proteins for potential treatment of hemolysis byproducts. Study Design and Methods Tangential flow filtration was used to purify a protein cocktail from Human Cohn Fraction IV (FIV). A series of in vitro assays were performed to characterize composition and biocompatibility. The in vivo potential for hemolysis byproduct mitigation was assessed in a hamster exchange transfusion model using mechanically hemolyzed blood plasma mixed with the protein cocktail or a control colloid (dextran 70 kDa). Results A basis of 500 g of FIV yielded 62 ± 9 g of a protein mixture at 170 g/L, which bound to approximately 0.6 mM Hb, 1.2 mM heme, and 1.2 mM iron. This protein cocktail was shown to be biocompatible in vitro with red blood cells and platelets and exhibits nonlinear concentration dependence with respect to viscosity and colloidal osmotic pressure. In vivo assessment of the protein cocktail demonstrated higher iron transport to the liver and spleen and less to the kidney and heart with significantly reduced renal and cardiac inflammation markers and lower kidney and hepatic damage compared to a control colloid. Discussion Taken together, this study provides an effective method for large‐scale production of a protein cocktail suitable for comprehensive reduction of hemolysis‐induced toxicity.

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“…Recently, we have developed and evaluated a high molecular weight (MW) polymerized human Hb (PolyhHb) as an alternative to blood. Increasing the MW of the PolyhHb appears to resolve the issues associated with vasoactivity, thus mitigating vasoconstriction and hypertension previously observed in earlier generations of HBOCs 13 , 14 . High MW PolyhHb has also been shown to be safer and well-tolerated at higher doses, and capable of preserving microvascular blood flow and increasing O 2 delivery with limited toxicity 13 , 14 .…”

Section: Introductionmentioning

confidence: 90%

“…Increasing the MW of the PolyhHb appears to resolve the issues associated with vasoactivity, thus mitigating vasoconstriction and hypertension previously observed in earlier generations of HBOCs 13 , 14 . High MW PolyhHb has also been shown to be safer and well-tolerated at higher doses, and capable of preserving microvascular blood flow and increasing O 2 delivery with limited toxicity 13 , 14 . Moreover, our most recent publication demonstrated that a high MW PolyhHb can restore hemodynamics to a similar degree as blood in a severe model of traumatic brain injury followed by HS in rats 15 .…”

Section: Introductionmentioning

confidence: 90%

Safety and efficacy of human polymerized hemoglobin on guinea pig resuscitation from hemorrhagic shock

Muller

Williams

Walser

et al. 2022

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For the past thirty years, hemoglobin-based oxygen carriers (HBOCs) have been under development as a red blood cell substitute. Side-effects such as vasoconstriction, oxidative injury, and cardiac toxicity have prevented clinical approval of HBOCs. Recently, high molecular weight (MW) polymerized human hemoglobin (PolyhHb) has shown positive results in rats. Studies have demonstrated that high MW PolyhHb increased O2 delivery, with minimal effects on blood pressure, without vasoconstriction, and devoid of toxicity. In this study, we used guinea pigs to evaluate the efficacy and safety of high MW PolyhHb, since like humans guinea pigs cannot produce endogenous ascorbic acid, which limits the capacity of both species to deal with oxidative stress. Hence, this study evaluated the efficacy and safety of resuscitation from severe hemorrhagic shock with high MW PolyhHb, fresh blood, and blood stored for 2 weeks. Animals were randomly assigned to each experimental group, and hemorrhage was induced by the withdrawal of 40% of the blood volume (BV, estimated as 7.5% of body weight) from the carotid artery catheter. Hypovolemic shock was maintained for 50 min. Resuscitation was implemented by infusing 25% of the animal’s BV with the different treatments. Hemodynamics, blood gases, total hemoglobin, and lactate were not different before hemorrhage and during shock between groups. The hematocrit was lower for the PolyhHb group compared to the fresh and stored blood groups after resuscitation. Resuscitation with stored blood had lower blood pressure compared to fresh blood at 2 h. There was no difference in mean arterial pressure between groups at 24 h. Resuscitation with PolyhHb was not different from fresh blood for most parameters. Resuscitation with PolyhHb did not show any remarkable change in liver injury, inflammation, or cardiac damage. Resuscitation with stored blood showed changes in liver function and inflammation, but no kidney injury or systemic inflammation. Resuscitation with stored blood after 24 h displayed sympathetic hyper-activation and signs of cardiac injury. These results suggest that PolyhHb is an effective resuscitation alternative to blood. The decreased toxicities in terms of cardiac injury markers, vital organ function, and inflammation following PolyhHb resuscitation in guinea pigs indicate a favorable safety profile. These results are promising and support future studies with this new generation of PolyhHb as alternative to blood when blood is unavailable.

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Safety profile of high molecular weight polymerized hemoglobins

Cited by 9 publications

References 37 publications

First-in-human phase 1 trial of hemoglobin vesicles as artificial red blood cells developed for use as a transfusion alternative

First-in-human phase 1 trial of hemoglobin vesicles as artificial red blood cells developed for use as a transfusion alternative

Purification and analysis of a protein cocktail capable of scavenging cell‐free hemoglobin, heme, and iron

Safety and efficacy of human polymerized hemoglobin on guinea pig resuscitation from hemorrhagic shock

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