Polymerized Hemoglobin With Increased Molecular Size Reduces Toxicity in Healthy Guinea Pigs

Williams, Alexander T.; Muller, Cynthia R.; Eaker, Allyn M.; Belcher, Donald; Bolden-Rush, Crystal; Palmer, Andre F.; Cabrales, Pedro

doi:10.1021/acsabm.0c00039

Cited by 16 publications

(20 citation statements)

References 44 publications

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“…A more recently developed large molecular weight polymerized human Hb (PolyhHb), which preserves microvascular hemodynamics and effectively restores O 2 delivery during HS alone, could be a promising resuscitation alternative to current resuscitation strategies from HS after TBI 21 . Previously, our research group evaluated the efficacy of this next generation PolyhHb in different animal models 22 , but no studies of these therapies on resuscitation from HS after TBI have been completed until now. This study evaluated the efficacy of large molecular weight PolyhHb to restore blood pressure after resuscitation from hemorrhagic shock post-TBI compared to lactated Ringer’s solution (LR, electrolyte solution used to restore the loss of blood volume), and fresh whole blood (Blood, autologous blood drawn during hemorrhage).…”

Section: Introductionmentioning

confidence: 99%

Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin

Muller

Courelli

Lucas

et al. 2021

Sci Rep

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Traumatic brain injury (TBI) is often accompanied by hemorrhage, and treatment of hemorrhagic shock (HS) after TBI is particularly challenging because the two therapeutic treatment strategies for TBI and HS often conflict. Ischemia/reperfusion injury from HS resuscitation can be exaggerated by TBI-induced loss of autoregulation. In HS resuscitation, the goal is to restore lost blood volume, while in the treatment of TBI the priority is focused on maintenance of adequate cerebral perfusion pressure and avoidance of secondary bleeding. In this study, we investigate the responses to resuscitation from severe HS after TBI in rats, using fresh blood, polymerized human hemoglobin (PolyhHb), and lactated Ringer’s (LR). Rats were subjected to TBI by pneumatic controlled cortical impact. Shortly after TBI, HS was induced by blood withdrawal to reduce mean arterial pressure (MAP) to 35–40 mmHg for 90 min before resuscitation. Resuscitation fluids were delivered to restore MAP to ~ 65 mmHg and animals were monitored for 120 min. Increased systolic blood pressure variability (SBPV) confirmed TBI-induced loss of autoregulation. MAP after resuscitation was significantly higher in the blood and PolyhHb groups compared to the LR group. Furthermore, blood and PolyhHb restored diastolic pressure, while this remained depressed for the LR group, indicating a loss of vascular tone. Lactate increased in all groups during HS, and only returned to baseline level in the blood reperfused group. The PolyhHb group possessed lower SBPV compared to LR and blood groups. Finally, sympathetic nervous system (SNS) modulation was higher for the LR group and lower for the PolyhHb group compared to the blood group after reperfusion. In conclusion, our results suggest that PolyhHb could be an alternative to blood for resuscitation from HS after TBI when blood is not available, assuming additional testing demonstrate similar favorable results. PolyhHb restored hemodynamics and oxygen delivery, without the logistical constraints of refrigerated blood.

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Section: Introductionmentioning

confidence: 99%

Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin

Muller

Courelli

Lucas

et al. 2021

Sci Rep

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“…The PolyHb used in this study was shown to be vasoactive in other species (guinea pigs), and reduction of the LMW PolyHb species via diafiltration reduced the vasoactivity. 10 By targeting the LMW Hb species directly with apoHb-Hp and Hp, there is no need to balance a pressor response.…”

Section: Discussionmentioning

confidence: 99%

“…Future studies should examine the relative effectiveness of the apoHb-Hp complex after transfusion of larger volumes of PolyHb and explore the long-term consequences of the apoHb-Hp complex in other manifestations of acellular Hb toxicity beyond vasoactivity. Unfortunately, the results of this study cannot be directly extrapolated to humans, and additional preclinical studies in other species with different vasoactive mechanisms should be explored, including guinea pigs 10 and lambs, 48 to supplement the current investigation of the microcirculation in the window chamber model.…”

Section: Discussionmentioning

confidence: 99%

“…6 LMW PolyHb and unpolymerized Hb extravasate into the interstitial space where they scavenge nitric oxide (NO), resulting in vasoconstriction and systemic hypertension. [7][8][9][10] Moreover, free heme release from HBOCs can also lead to systemic toxicity. 11,12 Previously, we determined that increasing the molecular weight (MW) of PolyHb by increasing the molar ratio of glutaraldehyde to Hb attenuated hypertension and renal injury.…”

Section: Introductionmentioning

confidence: 99%

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Apohemoglobin-haptoglobin complexes attenuate the hypertensive response to low-molecular-weight polymerized hemoglobin

et al. 2020

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Polymerized hemoglobin (PolyHb) is a promising hemoglobin (Hb)-based oxygen carrier currently undergoing development as a red blood cell substitute. Unfortunately, commercially developed products are composed of low-molecular-weight (LMW) PolyHb molecules, which extravasate, scavenge nitric oxide, and result in vasoconstriction and hypertension. The naturally occurring Hb-scavenging species haptoglobin (Hp), combined with the purified heme-scavenging species apohemoglobin (apoHb), is a potential candidate to alleviate the pressor effect of PolyHb. This study evaluated the protective activity of administering the apoHb-Hp complex to mitigate the vasoactive response induced by the transfusion of LMW PolyHb. Hp binding to PolyHb was characterized in vitro. The effectiveness of apoHb–Hp administration on reducing the vasoconstriction and pressor effects of PolyHb was assessed by measuring systemic and microcirculatory hemodynamics. Transfusion of LMW PolyHb to vehicle control pretreated animals increased mean arterial pressure while decreasing arteriole diameter and functional capillary density. However, transfusion of LMW PolyHb to apoHb–Hp pretreated animals prevented changes in mean arterial pressure, heart rate, arteriole diameter, blood flow, and functional capillary density relative to before transfusion. These results indicate that the increased size of PolyHb after binding to the apoHb-Hp complex may help compartmentalize PolyHb in the vascular space and thus reduce extravasation, nitric oxide scavenging, and toxicity responsible for vasoconstriction and systemic hypertension.

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“…PolybHb preserves microvascular hemodynamics, does not induce vasoconstriction, and effectively restores O 2 delivery and utilization by tissues 11 . However, even after filtration, the solution still possesses a small amount of highly vasoactive low molecular weight material, and as such, before clinical trials can proceed with high MW PolybHb formulations, new studies are necessary to characterize the safety and efficacy of PolybHb 12 . The clinical trial failures with previous HBOCs suggest that preclinical animal testing may not have been sufficiently predictive of safety in humans.…”

Section: Introductionmentioning

confidence: 99%

Safety profile of high molecular weight polymerized hemoglobins

et al. 2020

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Background Hemoglobin (Hb)‐based oxygen (O2) carriers (HBOCs) are being developed as alternatives to red blood cells and blood when these products are unavailable. Clinical trials of previous HBOC generations revealed side effects, including hypertension and vasoconstriction, that were not observed in preclinical studies. Large molecular weight (MW) polymerized bovine Hb (PolybHb) represents a new class of HBOC with promising results. We evaluated the safety profile of PolybHb after an exchange transfusion (ET) in guinea pigs (GPs). This study compares changes in indices of cardiac, inflammatory, and organ function after ET with high (R‐state) and low (T‐state) O2 affinity PolybHb with high MW. Study Design and Methods Guinea pigs underwent a 20% ET with PolybHb. To assess the implication of PolybHb ET on the microcirculation, hamsters instrumented with a dorsal window chamber were subjected to a similar volume ET. Results T and R‐state PolybHb did not induce significant alterations in cardiac function. T‐state PolybHb induced mild vasoconstriction shortly after transfusion, while R‐state did not have acute effects on microvascular tone. Conclusion Large MW PolybHbs were found to be safe and efficacious in increasing O2 carrying capacity and the O2 affinity of the PolybHb did not affect O2 delivery or extraction by tissues in relevant preclinical models. In conclusion, these results suggest that both T‐state and R‐state PolybHb are safe and do not impair O2 delivery. The results are encouraging and support further evaluation of high MW PolybHbs and their future feasibility compared to allogenic blood in a trauma model.

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Polymerized Hemoglobin With Increased Molecular Size Reduces Toxicity in Healthy Guinea Pigs

Cited by 16 publications

References 44 publications

Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin

Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin

Apohemoglobin-haptoglobin complexes attenuate the hypertensive response to low-molecular-weight polymerized hemoglobin

Safety profile of high molecular weight polymerized hemoglobins

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