Transfusion management and hemoglobin-based oxygen carrier treatment in a patient with anti-Rh17 antibody.

BACKGROUND: A 54-year-old Hispanic OPos female with known history of anti-Rh17 antibodies was diagnosed with Philadelphia-Chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Rh17, also known as Hr0, is a high-frequency antigen composed of several epitopes on the RhCE protein. Anti-Rh17 antibodies can be made by individuals with missing or varied C/c, E/e antigens. Anti-Rh17 antibodies are clinically significant given multiple case reports of hemolytic disease of the fetus and newborn (HDFN). Finding compatible units for patients with anti-Rh17 can be particularly difficult given that only 1 in 100,000 people are Rh17 negative. STUDY DESIGN AND METHODS: Search for compatible units was conducted by the American Rare Donor Program (ARDP) with no leads. After chemotherapy induction and despite erythropoiesis stimulating agent administration, the patient's hemoglobin continued to trend down to a nadir of 2.8 g/dL. Here we report transfusion of incompatible pRBC to this patient with critically symptomatic anemia. HBOC-201 (Hemopure) was obtained and administered under an emergency compassionate/expanded access designation from the Food and Drug Administration (FDA) under an emergency Investigational New Drug (IND) application. RESULTS AND DISCUSSION: Overall difficulties in this case included the challenge of finding compatible units, dilemma of transfusing incompatible units in a patient with severe anemia and obtaining alternatives to blood products. This case report demonstrates the successful use of HBOC-21 in treating life-threatening anemia.

[In searching for perfect blood substitute. Creation and application of perftorane]. / V poiskakh ideal'nogo krovezamenitelya. Sozdanie i primenenie perftorana.

The article is devoted to historiography of perfluorocarbons, as well as discoverers of perftorane and their discoveries. There would be no national priority in transfusiology without these discoveries. Perftorane is the only one of the world series of perfluorocarbon emulsion drugs that has passed all phases of clinical trials. Perftorane has been used in clinical medicine for 30 years.

Resuscitation of an exsanguinated obstetrics patient with HBOC-201: A case report.

BACKGROUND: Hemorrhagic shock is a clinically challenging disease process with high mortality. When conventional blood products are unable to be administered, oxygen-carrying blood alternatives are sometimes utilized. The international experience with this scenario is limited. We aim to add to this body of literature. STUDY DESIGN AND METHODS: This is a case report of the administration of bovine hemoglobin-based oxygen-carrying red blood cell (RBC) substitute HBOC-201 (HemoPure®) to a patient with post-partum bleeding and hemorrhagic shock because the patient declined RBC transfusion. HBOC-201 was administered with consent under a one-time Emergency Investigational New Drug (eIND) approval from the Food and Drug Administration with appropriate notification of the Institutional Review Board. RESULTS: The patient was successfully resuscitated with HBOC-201 from hemorrhagic shock. She was weaned off of vasopressor support and extubated with the recovery of her baseline mental status within 4 h. However, approximately 36 h after this, the patient developed multi-organ system dysfunction, volume overload, right heart failure and ultimately expired early on post-partum day 4. DISCUSSION: Resuscitation from hemorrhagic shock with HBOC-201 as an RBC alternative is feasible, but significant challenges remain with the management of sequelae resulting from prolonged low-flow, ischemic states as well as the significant colloid pressure and volume overload experienced after massive transfusion with an acellular colloid oxygen carrier.

Dose-dependent effects of perfluorocarbon-based blood substitute on cardiac function in myocardial ischemia-reperfusion injury.

The main goal of this study was to investigate the cardioprotective properties in terms of effects on cardiodynamics of perfluorocarbon emulsion (PFE) in ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. The first part of the study aimed to determine the dose of 10% perfluoroemulsion (PFE) that would show the best cardioprotective effect in rats on ex vivo-induced ischemia-reperfusion injury of an isolated rat heart. Depending on whether the animals received saline or PFE, the animals were divided into a control or experimental group. They were also grouped depending on the applied dose (8, 12, 16 ml/kg body weight) of saline or PFE. We observed the huge changes in almost all parameters in the PFE groups in comparison with IR group without any pre-treatment. Calculated in percent, dp/dt max was the most changed parameter in group treated with 8 mg/kg, while the dp/dt min, SLVP, DLVP, HR, and CF were the most changed in group treated with 16 mg/kg 10 h before ischemia. The effects of 10% PFE are more pronounced if there is a longer period of time from application to ischemia, i.e., immediate application of PFE before ischemia (1 h) gave the weakest effects on the change of cardiodynamics of isolated rat heart. Therefore, the future of PFE use is in new indications and application methods, and PFE can also be referred to as antihypoxic and antiischemic blood substitute with mild membranotropic effects.

Bloodless Management of the Anemic Patient in the Emergency Department.

Anemia is a commonly encountered condition in emergency medicine; transfusion of packed red blood cells is commonly performed for anemic patients in the emergency department (ED), but some patients are unable to accept transfusion of blood products due to medical or religious concerns. The unique, acute, and time-sensitive nature of emergency medicine practice requires that physicians maintain an enhanced awareness of bloodless medicine treatment modalities. Identification of bloodless medicine patient preferences in the ED can help guide physicians in the recommendation of acceptable methods of treating anemia in this patient population. A focus on early hemostasis and resuscitation, instead of attempts to convince the patient to accept blood transfusion, can be lifesaving in patients with acute bleeding. Treatment strategies including the use of methods to reduce unnecessary blood loss, enhance red blood cell production, and increase the oxygen-carrying capacity of blood should also be considered early in patient presentation. Timely involvement of the Hospital Liaison Committee can help facilitate successful interpersonal communication and shared decisionmaking between emergency physicians and bloodless medicine patients. By embracing an understanding of bloodless medicine patient needs as well as available treatment strategies, ED physicians can contribute to optimal overall outcomes for anemic bloodless medicine patients.

Perfluorocarbon-based oxygen carriers: from physics to physiology.

Developing biocompatible, synthetic oxygen carriers is a consistently challenging task that researchers have been pursuing for decades. Perfluorocarbons (PFC) are fascinating compounds with a huge capacity to dissolve gases, where the respiratory gases are of special interest for current investigations. Although largely chemically and biologically inert, pure PFCs are not suitable for injection into the vascular system. Extensive research created stable PFC nano-emulsions that avoid (i) fast clearance from the blood and (ii) long organ retention time, which leads to undesired transient side effects. PFC-based oxygen carriers (PFOCs) show a variety of application fields, which are worthwhile to investigate. To understand the difficulties that challenge researchers in creating formulations for clinical applications, this review provides the physical background of PFCs' properties and then illuminates the reasons for instabilities of PFC emulsions. By linking the unique properties of PFCs and PFOCs to physiology, it elaborates on the response, processing and dysregulation, which the body experiences through intravascular PFOCs. Thereby the reader will receive a scientific and easily comprehensible overview why PFOCs are precious tools for so many diverse application areas from cancer therapeutics to blood substitutes up to organ preservation and diving disease.

Industrially Compatible Transfusable iPSC-Derived RBCs: Progress, Challenges and Prospective Solutions.

Amidst the global shortfalls in blood supply, storage limitations of donor blood and the availability of potential blood substitutes for transfusion applications, society has pivoted towards in vitro generation of red blood cells (RBCs) as a means to solve these issues. Many conventional research studies over the past few decades have found success in differentiating hematopoietic stem and progenitor cells (HSPCs) from cord blood, adult bone marrow and peripheral blood sources. More recently, techniques that involve immortalization of erythroblast sources have also gained traction in tackling this problem. However, the RBCs generated from human induced pluripotent stem cells (hiPSCs) still remain as the most favorable solution due to many of its added advantages. In this review, we focus on the breakthroughs for high-density cultures of hiPSC-derived RBCs, and highlight the major challenges and prospective solutions throughout the whole process of erythropoiesis for hiPSC-derived RBCs. Furthermore, we elaborate on the recent advances and techniques used to achieve cost-effective, high-density cultures of GMP-compliant RBCs, and on their relevant novel applications after downstream processing and purification.

Proceedings From the Society for Advancement of Blood Management Annual Meeting 2017: Management Dilemmas of the Surgical Patient-When Blood Is Not an Option.

Vigilance is essential in the perioperative period. When blood is not an option for the patient, especially in a procedure/surgery that normally holds a risk for blood transfusion, complexity is added to the management. Current technology and knowledge has made avoidance of blood transfusion a realistic option but it does require a concerted patient-centered effort from the perioperative team. In this article, we provide suggestions for a successful, safe, and bloodless journey for patients. The approaches include preoperative optimization as well as intraoperative and postoperative techniques to reduce blood loss, and also introduces current innovative substitutes for transfusions. This article also assists in considering and maneuvering through the legal and ethical systems to respect patients' beliefs and ensuring their safety.

Use of the blood substitute HBOC-201 in critically ill patients during sickle crisis: a three-case series.

BACKGROUND: Red blood cell (RBC) transfusion is an important treatment modality during severe sickle cell crisis (SCC). SCC patients who refuse, or cannot accept, RBCs present a unique challenge. Acellular hemoglobin (Hb)-based oxygen carriers (HBOCs) might be an alternative for critically ill patients in SCC with multiorgan failure due to life-threatening anemia. HBOC-201 (HbO2 Therapeutics) has been administered to more than 800 anemic patients in 22 clinical trials, but use of any HBOCs in critically ill sickle cell patients with organ failure is exceedingly rare. In the United States, HBOC-201 is currently only available for expanded access. CASE REPORT: We report three cases of HBOC-201 administered to critically ill sickle cell disease patients in SCC with multiorgan failure, either who refused RBCs (Jehovah's Witnesses) or for whom compatible RBCs were not available. RESULTS: Two patients received more than 20 units of HBOC-201, while the other received 6. The 27 units used in the third case equals the largest volume a patient has successfully received to date. All three patients survived to hospital discharge. CONCLUSION: These reports suggest that blood substitutes such as HBOC-201 can provide an oxygen bridge in SCC with multiorgan failure, until corpuscular Hb levels recover to meet metabolic demand, and highlight the compelling biochemical properties that warrant further investigation.

Vox Sanguinis International Forum on the use of prehospital blood products and pharmaceuticals in the treatment of patients with traumatic haemorrhage.

While specific practices and transported blood products vary around the world, most of the respondents in this International Forum transported at least one blood product for the transfusion to bleeding patients en route to the hospital. The most commonly carried product was RBCs, while the use of whole blood will likely increase given the recent reports of its successful use in the civilian setting, and because of the change in the AABB's Standards regulating its use. It will be interesting to see if plasma use in the prehospital setting becomes more widely used given today's enhanced appreciated of the coagulopathy of trauma and plasma's beneficial effect in reversing it, and if blood products are transported to the scene of injury by more vehicles, that is, not just predominantly in helicopters. It was not surprising that TXA is being widely administered as close to the time of injury as possible given its potential benefit in these patients. This International Forum highlights the importance of focusing attention on prehospital transfusion management with a need to further high­quality research in this area to guide optimal resuscitation strategies.

A phase Ib, open-label, single arm study to assess the safety, pharmacokinetics, and impact on humoral sensitization of SANGUINATE infusion in patients with end-stage renal disease.

The endeavor to study desensitization in kidney transplantation has not been matched by an effort to investigate strategies to prevent sensitization. In this study (NCT02437422), we investigated the safety, impact on sensitization, and pharmacokinetics of SANGUINATE (SG), a hemoglobin-based oxygen carrier, as a potential alternative to packed red blood cells (PRBC) in transplant candidates with end-stage renal disease (ESRD). Ten ESRD subjects meeting inclusion/exclusion (I/E) criteria were planned to receive three weekly infusions of SG (320 mg/kg). The study was stopped after five subjects were enrolled, and their data were analyzed after completing a follow-up period of 90 days. Two subjects had elevated troponin I levels in setting of SG infusion, one of which was interpreted as a non-ST elevation myocardial infarction. All other adverse events were transient. SG pharmacokinetic analysis showed mean (SD) Cmax , Tmax , AUC, and half-life of 4.39 (0.69) mg/mL, 2.42 (0.91) hours, 171.86 (52.35) mg h/mL, and 40.60 (11.96) hours, respectively. None of the subjects developed new anti-HLA antibodies following SG infusion and throughout the study period. In conclusion, SG is a potential alternative to PRBCs in ESRD patients considered for kidney transplantation as it was not associated with humoral sensitization. Larger studies in highly sensitized patients are required to further evaluate for potential safety signals.

Artificial Organs 2017: A Year in Review.

In this Editor's Review, articles published in 2017 are organized by category and summarized. We provide a brief reflection of the research and progress in artificial organs intended to advance and better human life while providing insight for continued application of these technologies and methods. Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery, and Regeneration from all over the world. Peer-reviewed Special Issues this year included contributions from the 12th International Conference on Pediatric Mechanical Circulatory Support Systems and Pediatric Cardiopulmonary Perfusion edited by Dr. Akif Undar, Artificial Oxygen Carriers edited by Drs. Akira Kawaguchi and Jan Simoni, the 24th Congress of the International Society for Mechanical Circulatory Support edited by Dr. Toru Masuzawa, Challenges in the Field of Biomedical Devices: A Multidisciplinary Perspective edited by Dr. Vincenzo Piemonte and colleagues and Functional Electrical Stimulation edited by Dr. Winfried Mayr and colleagues. We take this time also to express our gratitude to our authors for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons for their expert attention and support in the production and marketing of Artificial Organs. We look forward to reporting further advances in the coming years.

PEGylated carboxyhemoglobin bovine (SANGUINATE) ameliorates myocardial infarction in a rat model.

Artificial oxygen (O2 ) carriers were reported to be protective in ischemia/reperfusion (I/R) in various organs including the heart. In the current study, 20 rats underwent ligation (MI) of the left anterior descending artery, were treated with 10 mL/kg of PEGylated carboxyhemoglobin bovine (SANGUINATE, S+, n = 10) or saline (S-, n = 10) 10 minutes after MI and daily thereafter for 3 days, and were followed by weekly echocardiography for 4 weeks, when they had left ventricular pressure volume relationship (PVR) analyses followed by necropsy. Echocardiography showed an increase in end-systolic dimension rather than end-diastolic dimension, preserved fractional shortening (36 vs. 26%, P < .01), and milder mitral regurgitation in S+ compared with S- rats. PVR revealed a milder increase in end-systolic volume, larger stroke volume (101 vs. 74 µL, P < .005) and cardiac output (33.4 vs. 23.8 mL/min, P = .004) in S+ rats in actual determination and under a wide range of standardized loading conditions 4 weeks after MI. Excised heart showed significantly limited area of MI (8.9 vs. 13.3%, P = .028). The results suggest that SANGUINATE in short-term repeated doses may accelerate weight recovery, preserving the myocardium, mitral competence, and cardiac function after MI. The mechanism of action and optimal treatment for MI remain to be studied.

Hemoglobin-Based Oxygen Carrier Rescues Double-Transplant Patient From Life-Threatening Anemia.

This case describes a 46-year-old male recipient of a kidney-pancreas transplant who is Jehovah's Witness. Early in the postoperative period, he was found to have splenic vein thrombosis requiring heparin infusion. Two days later, he developed severe symptomatic anemia (hemoglobin <6 g/dL). Standard medical therapy for bloodless surgical patients with severe anemia was instituted. Nevertheless, the patient's hemoglobin concentration continued to decline to critical levels (2 g/dL). Because he was Jehovah's Witness, transfusion of allogeneic blood products was not an option, prompting use of a hemoglobin-based oxygen carrier (HBOC). After approval by the U.S. Food and Drug Administration and the local institutional review board, 12 U of HBOC-201 were transfused over a period of 8 days. Two weeks later, the patient's hemoglobin levels had increased to 6.8 g/dL. The patient's overall clinical condition improved, and he was discharged home. This case describes the first use of HBOC transfusion in a double solid organ transplant patient. HBOC may represent a viable option in patients with severe symptomatic anemia when allogeneic blood transfusion is not an option.

Beneficial effects of novel cross-linked hemoglobin YQ23 on hemorrhagic shock in rats and pigs.

BACKGROUND: To overcome the problems of previously reported hemoglobin-based oxygen carriers, we developed a stabilized nonpolymeric cross-linked tetrameric hemoglobin solution (YQ23). The aims of this study were to investigate the oxygen carrying and releasing properties of this novel hemoglobin-based oxygen carrier and to determine whether it has beneficial effects for hemorrhagic shock. METHODS: Using a hemorrhagic shock model in Sprague-Dawley rats and mini-pigs, we tested the effects of infusing 0.1, 0.3, and 0.5 g/kg YQ23 on animal survival, tissue oxygen delivery (DO2) and consumption (VO2), hemodynamics parameters, and liver, renal, and cardiac function. RESULTS: YQ23 infusion increased the survival rate of rats and pigs with severe hemorrhagic shock in a dose-dependent manner. Moreover, it improved the hemodynamic parameters, cardiac output, DO2 and VO2, and the mitochondrial respiratory function of vital organs. Among the three doses of YQ23, 0.5 gHb/kg YQ23 achieved a similar beneficial effect as whole blood. CONCLUSIONS: This study indicated that the novel cross-linked tetrameric hemoglobin YQ23 has good oxygen carrying and releasing properties and exhibits beneficial effects on hemorrhagic shock in rats and pigs by improving the oxygen carrying and delivery function of blood, which maintains organ function.

SANGUINATE (PEGylated Carboxyhemoglobin Bovine): Mechanism of Action and Clinical Update.

Historically, blood substitutes were under development that would provide oxygen carrying capacity as well as fluid replacement for both trauma and surgical indications. Their development was halted by the inability of the products to deliver therapeutic amounts of oxygen targeted to hypoxic tissue as well as from the inherent toxicity of the molecules. This led to the concept of an oxygen therapeutic that would be targeted for indications caused by anemia/ischemia/hypoxia but would not exhibit the toxicity that plagued earlier products. The complex pathophysiology of diseases such as sickle cell and hemorrhagic stroke not only has hypoxia as a pivotal event but also includes inflammation and vasoconstriction that perpetuate the oxygen deprivation. There is a need for an effective therapeutic that addresses the multiple events of inflammation and oxygen deprivation. SANGUINATE acts as a dual mode carbon monoxide (CO) and oxygen delivery therapeutic. SANGUINATE is designed not only to treat hypoxia but also to act on concurrent pathologies such as inflammation and reperfusion injury. This expands the potential therapeutic utility of SANGUINATE beyond anemia into indications such as early brain injury and delayed kidney graft function, where inflammation plays a pivotal pathological role as well as in indications such as sickle cell disease where the inflammation and hypoxia contribute to the development of comorbidities such as vaso-occlusive crisis. Clinical trials in multiple indications are underway.

Effect of Oxygen Affinity of Liposome-Encapsulated Hemoglobin on Cerebral Ischemia and Reperfusion as Detected by Positron Emission Tomography in Nonhuman Primates.

We tested a hypothesis that liposome-encapsulated hemoglobin (LEH) with high oxygen (O2 ) affinity (h-LEH, P50 O2 = 10 mm Hg) may work better than LEH with low O2 affinity (l-LEH, P50 O2 = 40 mm Hg) in cerebral ischemia and reperfusion injury using positron emission tomography (PET) in primates undergoing middle cerebral artery (MCA) occlusion and reperfusion. Cerebral blood flow (CBF), O2 extract fraction (OEF), and cerebral metabolic rate of O2 (CMRO2 ) were successively determined by PET before ischemia, at 2 h of ischemia, immediately after reperfusion, and 3 h after reperfusion. Five minutes after MCA occlusion, 10 mL/kg of h-LEH (n = 6) was intravenously infused and compared with the results from previous data of monkeys treated with l-LEH (n = 6), empty liposome (n = 4), or saline (n = 8) as control. After the series of PET studies, the integrated area of cerebral infarction was determined histologically in 12 coronal brain slices. There was no significant difference in CBF, OEF, or CMRO2 up to 2 h of ischemia. A high CBF with a low OEF tended to be suppressed after reperfusion in LEH-treated monkeys. Three hours after reperfusion, the area of mild CMRO2 reduction (down to -30%) decreased (P < 0.05) and the area of mild CMRO2 increase (up to 30%) expanded in LEH-treated monkeys (P < 0.05) regardless of O2 affinity with no difference in the area of moderate-to-severe reduction (<-30%) or increase (<+30%) in CMRO2 compared to animals treated with empty liposome or saline. Distribution of CMRO2 reduction and histological damages showed that LEH mainly protected the cerebral cortex rather than basal ganglia where neuronal dendritic processes were severely lost. There was little difference between the animals treated with l-LEH or h-LEH both at 10 mL/kg or between treatment with empty liposome or saline. In conclusion, LEH was effective regardless of O2 affinity in preserving CMRO2 and in reducing the area of histological damage in the cerebral cortex, but not in basal ganglia, shortly after occlusion/reperfusion of MCA in monkey.

Hemoglobin-Based Oxygen Carrier (HBOC) Development in Trauma: Previous Regulatory Challenges, Lessons Learned, and a Path Forward.

Historically, hemoglobin-based oxygen carriers (HBOCs) were being developed as "blood substitutes," despite their transient circulatory half-life (~ 24 h) vs. transfused red blood cells (RBCs). More recently, HBOC commercial development focused on "oxygen therapeutic" indications to provide a temporary oxygenation bridge until medical or surgical interventions (including RBC transfusion, if required) can be initiated. This included the early trauma trials with HemAssist ® (BAXTER), Hemopure ® (BIOPURE) and PolyHeme ® (NORTHFIELD) for resuscitating hypotensive shock. These trials all failed due to safety concerns (e.g., cardiac events, mortality) and certain protocol design limitations. In 2008 the Food and Drug Administration (FDA) put all HBOC trials in the US on clinical hold due to the unfavorable benefit:risk profile demonstrated by various HBOCs in different clinical studies in a meta-analysis published by Natanson et al. (2008). During standard resuscitation in trauma, organ dysfunction and failure can occur due to ischemia in critical tissues, which can be detected by the degree of lactic acidosis. SANGART'S Phase 2 trauma program with MP4OX therefore added lactate >5 mmol/L as an inclusion criterion to enroll patients who had lost sufficient blood to cause a tissue oxygen debt. This was key to the successful conduct of their Phase 2 program (ex-US, from 2009 to 2012) to evaluate MP4OX as an adjunct to standard fluid resuscitation and transfusion of RBCs. In 2013, SANGART shared their Phase 2b results with the FDA, and succeeded in getting the FDA to agree that a planned Phase 2c higher dose comparison study of MP4OX in trauma could include clinical sites in the US. Unfortunately, SANGART failed to secure new funding and was forced to terminate development and operations in Dec 2013, even though a regulatory path forward with FDA approval to proceed in trauma had been achieved.