The Novel Hemoglobin-based Oxygen Carrier HRC 101 Improves Survival in Murine Sickle Cell Disease

Crawford, Mark W.; Shichor, Tal; Engelhardt, Thomas; Adamson, Gord; Bell, David S.H.; Carmichael, F. J.; Kim, Peter C.W.

doi:10.1097/01.anes.0000271872.14311.b4

Cited by 13 publications

(6 citation statements)

References 35 publications

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“…12,13 Interruption of the cardiovascular responses to increase CBF has been associated with cerebral hypoxia 14,15 and stroke. 16 Exposure to hypoxia increased the mortality rate in a mouse model of sickle cell disease, 17 suggesting that these mice are susceptible to hypoxia-induced organ failure and death. In humans, adult sickle cell patients demonstrate impairment in cerebrovascular reserve (CVR) capacity 9 and autoregulation of CBF, 18 suggesting a deficiency in cerebrovascular reactivity in the brain of these patients.…”

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confidence: 99%

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

Cahill

Gazdzinski

Tsui

et al. 2016

J Cereb Blood Flow Metab

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Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

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confidence: 99%

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

Cahill

Gazdzinski

Tsui

et al. 2016

J Cereb Blood Flow Metab

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“…Studies using cell-free hemoglobin (CFH) solutions have been performed on SCD patients, but their scope has been very limited (Gonzalez et al 1997, Feola et al 1992) and their effi cacy as a treatment has not been proved yet. A CFH with low-oxygen-affi nity (HRC 101, Hemosol; Mississauga, Ontario, Canada) prevented sicklerelated mortality in transgenic SCD mice during exposure to acute, sev er e hypoxic stress (Crawford et al 2007). Th e mechanism proposed for the improved outcome with CFH was its early release of oxygen prior to deoxygenation of the sickle RBC.…”

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confidence: 99%

Effect of oxygenated polyethylene glycol decorated hemoglobin on microvascular diameter and functional capillary density in the transgenic mouse model of sickle cell anemia

Tsai

Cabrales

Young³

et al. 2014

Artificial Cells, Nanomedicine, and Biotechnology

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Malemide polyethylene glycol-conjugated Hb (MP4OX, Sangart Inc.), a high-affinity low-concentration acellular hemoglobin (P50 = 5 mmHg, 4.3 g/dl) solution, has been shown to optimize microvascular perfusion and target oxygen delivery to anoxic tissue. Microvascular perfusion during an acute hypoxic challenge in a transgenic anemic sickle cell disease mouse model was studied with MP4OX and saline. Arterioles were dilated in both groups. Functional capillary density (FCD) was maintained at a higher level with MP4OX. In conclusion, MP4OX treatment reduced the hypoxia-mediated decline in FCD, an effect in part due to higher arterial pressure resulting in increased microvascular perfusion pressures.

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“…HRC-101 contains less than 10% Hb-hydroxyethyl starch that are less than 192 kDa, the remainder comprising high-molecular-weight Hb-hydroxyethyl starch conjugates. HRC 101 was found to decrease sickle cell related mortality during exposure to acute hypoxic stress in transgenic mice expressing Hb SAD (α 2 human β 2 S, Antiles, D-Punjab ) [61]. …”

Section: Second-generation Hbocs and The Treatment Of Sickle Cell mentioning

confidence: 99%

Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?

Alayash

2017

Biomolecules

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Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as “blood substitutes”. Human trials conducted so far by several manufactures in a variety of clinical indications, including trauma, and elective surgeries have failed and no product has gained the Food and Drug Administration approval for human use. Safety concerns due to frequent incidences of hemodynamic, cardiac events, and even death led to the termination of some of these trials. Several second generation HBOC products that have been chemically and/or genetically modified (or in some cases ligated with carbon monoxide (CO)) found a new clinical application in conditions as complex as sickle cell disease (SCD). By virtue of higher oxygen affinity (P50) (R-state), and smaller size, HBOCs may be able to reach the microvasculature unload of oxygen to reverse the cycles of sickling/unsickling of the deoxy-sickle cell Hb (HbS) (T-state), thus preventing vaso-occlusion, a central event in SCD pathophysiology. However, biochemically, it is thought that outside the red blood cell (due to frequent hemolysis), free HbS or infused HBOCs are capable of interfering with a number of oxidative and signaling pathways and may, thus, negate any benefit that HBOCs may provide. This review discusses the advantages and disadvantages of using HBOCs in SCD.

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The Novel Hemoglobin-based Oxygen Carrier HRC 101 Improves Survival in Murine Sickle Cell Disease

Abstract: HRC 101 significantly decreased sickle-related mortality during exposure to acute hypoxic stress in transgenic mice expressing hemoglobin SAD. HRC 101 warrants further evaluation as a therapeutic modality in sickle cell disease.

Cited by 13 publications

References 35 publications

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

Effect of oxygenated polyethylene glycol decorated hemoglobin on microvascular diameter and functional capillary density in the transgenic mouse model of sickle cell anemia

Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?

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