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Algorithm for the use of Hemopure to treat acute anemia when blood is not an option.
Source publication
Hemopure (hemoglobin glutamer-250 [bovine]; HBOC-201) is a hemoglobin (Hb)-based oxygen carrier registered with the Medicines Control Council of South Africa. It is indicated for the treatment of adult patients who are acutely anemic, for the purpose of maintaining tissue oxygen delivery thus eliminating, delaying, or reducing the need for allogene...
Context in source publication
Context 1
... standardized treatment algorithm (Fig. 1) was developed using the product when treating patients for whom blood is not an option. As the product is an HBOC with a rela- tively low Hb concentration (13 g/dL), and short half-life of 19 hours, this requires significant adjustments to the dose regimen compared to RBC transfusions. The achiev- able increases in Hb concentration for ...
Citations
... However, only a few HBOCs have received worldwide approved for clinical use. Glutaraldehyde-polymerized bovine hemoglobin (HBOC-201, BioPure company), was approved for the treatment of acute pernicious anemia in South Africa and Russia in 2001 and 2010, respectively [46,47]. PEGylated carboxyhemoglobin bovine (Sanguinate, Prolong Pharmaceuticals, USA), was registered in 2015 under the FDA classification as an "orphan drug" for the treatment of sickle cell anemia; it is currently in phase III clinical trials [48]. ...
Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases.
Graphical Abstract
... HBOCs, on the other hand, contain human-or animal-derived Hb or recombinant Hb, frequently chemically modified through polymerization, cross-linking, conjugation, or encapsulation to overcome free Hb-induced toxicity, reduce nitric oxide (NO) scavenging, and increase half-life (18). Second-generation products were limited by inadequate O 2 delivery and associated oxidative stress along with NO scavenging, resulting in tissue injury, increases in vascular resistance, and suboptimal microcirculatory blood flow (3,9,(19)(20)(21), However, one product, HemopureⓇ (HBOC-201), was approved over 20 years ago for the treatment of anemia in South Africa and remains in use (22), and eligible patients with severe life-threatening anemia have access to HBOC-201 under the FDA's expanded compassionate use access program (13). In addition, there are a number of third-generation HBOCs in development, which are modified to address issues seen with the earlier candidates and are reviewed extensively elsewhere (9,11,13,18). ...
Hemorrhagic shock is a major source of morbidity and mortality worldwide. While whole blood or blood product transfusion is a first line treatment, maintaining robust supplies presents significant logistical challenges, particularly in autere environments. OMX is a novel non-hemoglobin (Hb)-based oxygen carrier derived from the H-NOX (Heme-Nitric Oxide/Oxygen binding) protein family. Due to their engineered oxygen (O 2 ) affinities, OMX proteins only deliver O 2 to severely hypoxic tissues. Additionally, unlike Hb-based oxygen carriers, OMX proteins do not scavenge nitric oxide in the vasculature. To determine the safety and efficacy of OMX in supporting tissue oxygen delivery and cardiovascular function in a large-animal model of controlled hemorrhage, 2-3-week-old lambs were anesthetized, intubated, and mechanically ventilated. Hypovolemic shock was induced by acute hemorrhage to obtain a 50% reduction over 30 minutes. Vehicle (n = 16) or 400 mg/kg OMX (n = 13) treatment was administered over 15 minutes. Hemodynamics, arterial blood gases, and laboratory values were monitored throughout the 6 hour study. Comparisons between groups were made using T tests, Wilcoxon Rank Sum test, and Fisher’s Exact test. Survival was assessed using Kaplan Meier curves and the Log-Rank test. We found that OMX was well-tolerated and significantly improved lactate and base deficit trends, and hemodynamic indices (p < 0.05). Median survival time was greater in the OMX-treated group (4.7 vs. 6.0 hr., p < 0.003), and overall survival was significantly increased in the OMX-treated group (25% vs. 85%, p = 0.004). We conclude that OMX is well-tolerated and improves metabolic, hemodynamic and survival outcomes in an ovine model of controlled hemorrhagic shock.
... 14 South African clinical experts have published usage guidelines. 15 South Africa is the only country in the world that has both an FDP and an oxygen carrier approved for medical use. Considering the burden of trauma in South Africa, there appears to be great potential for use of these products together in situations where transport of patients with severe hemorrhage for in-hospital transfusion may be delayed. ...
... The recommended rate of administration for Hemopure is 1 unit/25 min but can be adjusted. 15 This study used 1 unit/20 min. The recommended rate of infusion for Bioplasma FDP is <1 mL/kg/min (Bioplasma FDP package insert). ...
... 26 Nonetheless, this is the largest NHP study examining either Hemopure or Bioplasma FDP, and the first study in any species incorporating both products. The safety profiles of the individual products, Hemopure [13][14][15] and Bioplasma FDP, 7 8 have been reported. The specific question ...
Objectives
Prehospital transfusion can be life-saving when transport is delayed but conventional plasma, red cells, and whole blood are often unavailable out of hospital. Shelf-stable products are needed as a temporary bridge to in-hospital transfusion. Bioplasma FDP (freeze-dried plasma) and Hemopure (hemoglobin-based oxygen carrier; HBOC) are products with potential for prehospital use. In vivo use of these products together has not been reported. This study assessed the safety of intravenous administration of HBOC+FDP, relative to normal saline (NS), in rhesus macaques (RM).
Methods
After 30% blood volume removal and 30 minutes in shock, animals were resuscitated with either NS or two units (RM size adjusted) each of HBOC+FDP during 60 minutes. Sequential blood samples were collected. After neurological assessment, animals were killed at 24 hours and tissues collected for histopathology.
Results
Due to a shortage of RM during the COVID-19 pandemic, the study was stopped after nine animals (HBOC+FDP, seven; NS, two). All animals displayed physiologic and tissue changes consistent with hemorrhagic shock and recovered normally. There was no pattern of cardiovascular, blood gas, metabolic, coagulation, histologic, or neurological changes suggestive of risk associated with HBOC+FDP.
Conclusion
There was no evidence of harm associated with the combined use of Hemopure and Bioplasma FDP. No differences were noted between groups in safety-related cardiovascular, pulmonary, renal or other organ or metabolic parameters. Hemostasis and thrombosis-related parameters were consistent with expected responses to hemorrhagic shock and did not differ between groups. All animals survived normally with intact neurological function.
Level of evidence
Not applicable.
... This has been developed and tested in clinical trials. A glutaraldehyde crosslinked bovine polyhemoglobin has been approved for routine clinical use for surgical procedures in South Africa and Russia to avoid the use of HIV contaminated donor blood (9). Thus, the original aim has been reached as described in Jahr's article on Blood substitutes: Basic science, translational studies and clinical trials. ...
... Some academicians have harshly criticized the flawed methodological and conclusive validity of the study. [37][38][39] Consequently, numerous commercial enterprises shifted their target indication or relocated their operations outside the United States. This probably be the reason why a sharp decline on HBOC research during 2009-2014. ...
... Despite the fact that several HBOCs products have progressed to clinical phase, only Hemopure ® (HBOC-201, HbO 2 Therapeutics Corporation, USA) is commercially available for human use on a global scale. 38,53 Cross-linked bovine Hb was polymerized with glutaraldehyde to create this product, which after extensive purification contains 13.6 g/dL of Hb in a Ringer's solution with a pH of 7.6-7.9. 54 Instead of a single Hb molecule, these polymers consist of four or five Hb molecules with a total molecular weight of 250 kDa. ...
Numerous studies on the formulation and clinical applications of novel hemoglobin-based oxygen carriers (HBOCs) are reported in the scientific literature. However, there are fewer scientometric analysis related to HBOCs. Here, we illustrate recent studies on HBOCs using both a scientometric analysis approach and a scope review method. We used the former to investigate research on HBOCs from 1991 to 2022, exploring the current hotspots and research trends, and then we comprehensively analyzed the relationship between concepts based on the keyword analysis. The evolution of research fields, knowledge structures, and research topics in which HBOCs located are revealed by scientometric analysis. The elucidation of type, acting mechanism, potential clinical practice, and adverse effects of HBOCs helps to clarify the prospects of this biological agent. Scientometrics analyzed 1034 publications in this research field, and these findings provide a promising roadmap for further study.
... Since then, others have prepared a number of polyHbs using this basic glutaraldehyde method using bovine, human, pork, and cord blood Hb (Chang et al., 2022). Some of these have been developed and improved into products for clinical trials (Moore et al., 2009), and one has been approved for routine clinical use in South Africa and Russia (Mer et al., 2016;Chang, 2019). Laboratory research also includes the use of glutaraldehyde to prepare PolyHb-CAT-SOD-CA, which is an oxygen carrier with enhanced antioxidant function and CO2 transport function 5 . ...
... The enzyme activities were measured following the procedures mentioned in a previous report (Mer et al., 2016). Briefly, carbonic anhydrase activity was determined by observing the time taken for the pH of 0.02 M Tris CO 2 buffer to decrease from pH 8.3 to 6.3. ...
This is a study on a simple solution of chemically prepared small chemical molecules of synthetic enzymes: catalase, superoxide dismutase, and carbonic anhydrase (CAT, SOD, and CA). We carried out a study to see if these synthetic enzymes can replace the natural enzymes (CAT, SOD, and CA) and avoid the need for the complicated cross-linking of natural enzymes to PolyHb to form PolyHb-CAT-SOD-CA. We compared the effect a solution of these three synthetic enzymes has on the viability of warm-ischemic hepatocytes that were exposed to nitrogen for 1 h at 37°C. PolyHb significantly increased the viability. The three synthetic enzymes themselves also significantly increased the viability. The use of both PolyHb and the three synthetic enzymes resulted in an additive effect in the recovery of viability. Increasing the concentration of the synthetic enzymes resulted in further increase in the effect due to the synthetic enzymes.
Implications: In addition to PolyHb, there are a number of other HBOC oxygen carriers. However, only Biopure’s HBOC product has received regulatory approval, but only in Russia and South Africa. None of the HBOCs has received regulatory approval by other countries. If regulatory agencies require HBOCs to have antioxidant or CO2 transport properties, all that is needed is to add or inject the solution of synthetic enzymes as a separate component.
... Some studies have proposed that the clinical benefits of these products may still outweigh their safety risks, especially in severe anemia settings when RBCs are not an option (10-12). While there are no HBOCs licensed for human use in the United States, a glutaraldehyde-polymerized bovine Hb (Hemopure R , HbO 2 Therapeutics, Souderton, PA, USA) was approved in South Africa for acute anemia settings (13). ...
... As evidence of this point, we previously showed that a glutaraldehyde-polymerized bovine Hb oxidized more readily in the circulation of guinea pigs (a non-ascorbate-producing species), compared to rats (an ascorbate-producing species with plasma and tissue antioxidant capacities different than that of humans) (17). The reductive capacity of ascorbate has also been used to mitigate methemoglobin formation in clinical settings with HBOCs such as Hemopure R (HbO 2 Therapeutics, Souderton, PA, USA) (13). Studying animal species that can accurately recapitulate the redox activity of HBOCs in vivo may also be important for the proper assessment of Hb-mediated nitric oxide (NO) scavenging reactions thought to underlie the reported hypertensive effects of HBOCs (14,24,25). ...
Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and volume replacement therapeutics, however, their molecular and cellular effects on the vasculature and different organ systems are not fully defined. Using a guinea pig transfusion model, we examined the renal glomerular and tubular responses to PolyHeme, a highly characterized glutaraldehyde-polymerized human hemoglobin with low tetrameric hemoglobin content. PolyHeme-infused animals showed no major changes in glomerular histology or loss of specific markers of glomerular podocytes (Wilms tumor 1 protein, podocin, and podocalyxin) or endothelial cells (ETS-related gene and claudin-5) after 4, 24, and 72 h. Relative to sham controls, PolyHeme-infused animals also showed similar expression and subcellular distribution of N-cadherin and E-cadherin, two key epithelial junctional proteins of proximal and distal tubules, respectively. In terms of heme catabolism and iron-handling responses, PolyHeme induced a moderate but transient expression of heme oxygenase-1 in proximal tubular epithelium and tubulointerstitial macrophages that was accompanied by increased iron deposition in tubular epithelium. Contrary to previous findings with other modified or acellular hemoglobins, the present data show that PolyHeme does not disrupt the junctional integrity of the renal glomerulus and tubular epithelium, and triggers moderate activation of heme catabolic and iron sequestration systems likely as part of a renal adaptive response.
... Since Bcl-2 can inhibit cell death caused by a variety of cytotoxic factors, its overexpression gives cells resistance to most cytotoxins. The increased amount of Bcl-2 in HBOC is beneficial in this respect to further defend the brain tissue against stroke (9). Interestingly, this study found that BAX mRNA expression increased after hypoxia, and cell apoptosis reduced. ...
... Previous studies have used blood products to treat cerebral infarction, but the researchs of interventional technology infusion of HBOC for acute cerebral infarction are very rare (14,15). HBOC can not only increase the oxygen-carrying function of blood, but also its ability to release oxygen to tissues is stronger than that of hemoglobin in red blood cells (9). It is speculated that the time window of application of HBOC may be longer than that of tissue plasminogen activator (tPA) and there were no obvious complications through this experiment. ...
Aim:
To save brain cells in acute cerebral infarction by injecting hemoglobin oxygen carrier (HBOC) into the blood vessel blockage of the cerebral infarction site through a microcatheter.
Methods:
120 male rats were divided into four groups: control (CTRL), ischemia (I), ischemia + low perfusion (I + LP), and ischemia + high perfusion (I + HP). Perfusion groups (ischemia, I + LP, and I + HP) underwent MCAO surgery with intraluminal monofilament. These groups were subdivided into 6 h, 12 h, and 24 h (n = 10/group). RT-PCR, Western-Blot, immunohistochemistry, and apoptosis assays were used to detect apoptosis, hypoxia range and extent, and ischemia.
Results:
Compared with the I group, the neurological deficit sign scores of the I + HP group were statistically significant at 12 h. Compared with the I group, the neurological deficit sign scores of the I + LP group and the I + HP group were statistically significant at 24 h. At all time points, compared with the I group and the I + LP group, Caspase-3, HIF-1α, and Cytochrome C protein levels were significantly decreased in the I + HP group. Bcl-2 and BAX mRNA levels were also significantly decreased in the same group. TNF-α, IL-6, and IL-1β cytokines were significantly decreased in the I + HP group as well. The infarct size of rats in the I + HP group was smaller than that of the I + LP group, which was smaller than ischemia alone. Time of perfusion had an obvious effect as infarct size was smaller with longer perfusion. The number of Nissl stained cells in the I + HP group was increased compared with the ischemia and the I + LP group, and was proportional to the time of perfusion.
Conclusion:
Time- and rate-controlled perfusion of HBOC to acutely occluded cerebral vascular regions through microcatheters can effectively protect ischemic brain tissue in rats.
... This agent has been found to be a suitable means of maintaining adequate oxygen delivery in hypovolaemic shock states (in trauma, post-partum haemorrhage or in the prehospital setting). 32 The South African consensus guideline on haemopure usage finds it to be well tolerated in normal adults and indicated in patients who are unwilling to receive blood transfusions. 32 Whilst haemopure contains no human blood products, it is bovine derived and therefore may not be acceptable to certain JW patients. ...
... 32 The South African consensus guideline on haemopure usage finds it to be well tolerated in normal adults and indicated in patients who are unwilling to receive blood transfusions. 32 Whilst haemopure contains no human blood products, it is bovine derived and therefore may not be acceptable to certain JW patients. 16,22 Unlike HBOCs, PFCs are not animal or human derived and are completely synthetic. ...
South Africa has a high burden of trauma related injuries with haemorrhage remaining a leading treatable complication of trauma. Expedient management of haemorrhage serves to reduce patient morbidity and mortality. Damage control surgery aims to minimise haemorrhage, contain contamination, and allow restoration of physiology in an intensive care unit (ICU) before proceeding to definitive surgery. Over time, damage control surgery has found favour in non-traumarelated surgeries in unstable patients. The Jehovah's Witness (JW) religion believes that blood is sacred and strictly do not consent to blood or blood product transfusions, including in emergency settings. Thus, the management of a bleeding or bled-out JW patient proves to be a unique challenge in modern medicine. For the JW patient who is undergoing damage control surgery, the primary goal is to win time for recovery of the haemoglobin level by maintaining adequate oxygen delivery to tissues. We review the multiple methods available to optimise haemodynamic stability in a bleeding JW patient. These include techniques aimed at (i) minimising blood loss, (ii) optimising oxygen delivery (DO2), (iii) optimising oxygen consumption (VO2), and (iv) correction of coagulopathy. The management of haemorrhage in the JW patient remains challenging. It is imperative for healthcare professionals to be aware of all options available when treating these patients in order to provide optimal treatment whilst maintaining respect for their beliefs.
... [4][5][6][7][18][19][20][21] Polymerized bovine Hb (Hemopure ® ) was licensed in South Africa in 2001, but it has very limited availability. 22 We earlier reported a coreshell protein cluster containing bovine hemoglobin (HbBv) in the center and human serum albumins (HSA) at the periphery, hemoglobin-albumin cluster (HbBv-HSA 3 ) (Figure 1), as a unique HBOC. [23][24][25] The average HSA/Hb ratio of HbBv-HSA 3 was 3.0 (Table 1). ...
A bovine hemoglobin (HbBv) or human adult hemoglobin (HbA) wrapped covalently by human serum albumins (HSAs), hemoglobin–albumin clusters (HbBv–HSA3 and HbA–HSA3), are artificial O2 carriers used as a red blood cell substitute. This article describes the physicochemical properties of the HbBv–HSA3 and HbA–HSA3 solutions, and their abilities to restore the systemic condition after resuscitation from hemorrhagic shock in anesthetized rats. The HbBv–HSA3 and HbA–HSA3, which have high colloid osmotic activity, showed equivalent solution characteristics and O2 binding parameters. Shock was induced by 50% blood withdrawal. Rats exhibited hypotension and significant metabolic acidosis. After 15 min, the rats were administered shed autologous blood (SAB), HbBv–HSA3, HbA–HSA3, or Ringer's lactate (RL) solution. Survival rates, circulation parameters, hematological parameters, and blood gas parameters were monitored during the hemorrhagic shock and for 6 h after administration. All rats in the SAB, HbBv–HSA3, and HbA–HSA3 groups survived for 6 h. The HbBv–HSA3 and HbA–HSA3 groups restored mean arterial pressure after the resuscitation. No remarkable difference was observed in the time courses of blood gas parameters in any resuscitated group except for the RL group. Serum biochemical tests showed increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the HbBv–HSA3 and HbA–HSA3 groups compared to the SAB group. Therefore, we observed other rats awakened after resuscitation with HbA–HSA3 for 7 days. The blood cell count, AST, and ALT recovered to the baseline values by 7 days. All the results implied that HbBv–HSA3 and HbA–HSA3 clusters provide restoration from hemorrhagic shock as an alternative material for SAB transfusion.
