Blood Substitutes and Oxygen Biotherapeutics

Foreword
Blood Substitutes and Oxygen Biotherapeutics
Is the Final Destination in the Long, Winding, Bumpy Road Finally in Sight?
Contents
Contributors
Part I: Transfusion: Science and Practice
1: Erythrocyte Transfusion: Brief History and Current Practice
Introduction
Milestones in Erythrocyte Transfusion
Karl Landsteiner and Discovery of Major Blood Groups
The Early Years of Transfusion: The First Milestone
Karl Landsteiner
Balancing the Risks and Benefits of Anemia and Transfusion: The Second Milestone
The Risks of Anemia
The Target Organs of Anemia-Induced Injury
Benefits and Risks of Erythrocyte Transfusion
The Benefits of Transfusion
The Risks of Transfusion
Transfusion Reactions
Transfusion Transmitted Infectious (TTI) Pathogens
Transfusion-Attributable Adverse Outcomes
Transfusion Avoidance and Blood Conservation
The Search for an Objective Transfusion “Trigger”
The Transfusion Requirements in Critical Care (TRICC) Study
Restrictive vs Liberal Transfusion in Cardiac Surgery
Patient Blood Management
Summary and Conclusions
References
2: Oxygen and ATP: the Energy Economy of the Cell
Introduction
Oxygen
Adenosine Triphosphate
ATP Production: An Overview
Oxygen Utilization: An Overview
The Cell’s Energy Economy
Aerobic Respiration
Glycolysis
In Summary
Exceptional Case: Glycolysis in the Erythrocyte
The Krebs Cycle
Overview
Some Details
The Electron Transport Chain, Oxidative Phosphorylation
Mitochondria; Friend or Foe?
The Energy Economy of Vital Organs
The Heart
The Brain
Neurovascular Coupling
Neurometabolic Coupling
The Kidney
The Liver
Oxygen Sensing
The Carotid Body Chemoreceptors
HIF Mediators
Cardiovascular System and Oxygen Supply Integration: The Role of NO
In Summary
“Bad” Oxygen Species
Summary and Conclusions
References
3: Physiological Functions of Blood
Introduction
Hematopoiesis
Basic Physiology of the Components of Blood
Transport of Oxygen and Carbon Dioxide
Transport of Hormones, Nutrients and Metabolic Waste
Hemostasis and Coagulation
Immune System
Acid–Base Regulation
Thermoregulation
Regulation of Body Fluids
Conclusion
References
4: Hemoglobin: Physiology and Hemoglobinopathy
Introduction
Hemoglobin and Oxygen Binding Regulation
Oxygen Binding
2,3-DPG
Hemoglobinopathies
Thalassemia Syndromes
Sickle Cell Disease
Summary
References
5: The Global Burden of Anemia
Introduction
Anemia Development and Classification
Health and Societal Implications of Anemia
Summary
References
6: Blood Component Therapy: The History, Efficacy, and Adverse Effects in Clinical Practice
Introduction
Red Cell Components
Red Blood Cell Concentrates
Collection and Processing
Principles of Preservation
RBC Storage Lesions
Metabolic Impairment
Oxidative Injury
Membrane Asymmetry
Vesiculation
Decreased Deformability
Physiological Considerations
Hemolysis
Oxygen Delivery
Hemostasis and Thrombosis
Immunomodulation
Clinical Outcomes
Component Therapy: All Things “Yellow”
Plasma Transfusions
The Origin of Plasmapheresis Leading to Fresh Frozen Plasma
Cryoprecipitate
Platelets
Platelet Activation and Adherence
References
7: Allogeneic Blood Transfusion: Complications and Side Effects
Introduction
Infectious Complications
Human Immunodeficiency Virus
Hepatitis C Virus
Hepatitis B Virus
Septic Transfusion Reactions
Immune-Mediated Complications
Hemolytic Transfusion Reaction
Allergic/Anaphylactic Complications
Allergic Transfusion Reactions
Anaphylactic Transfusion Reactions
Febrile Transfusion Reactions
Cardiac and Pulmonary Complications
Transfusion Associated Circulatory Overload
Transfusion Associated Acute Lung Injury
Conclusion
References
8: The Effects of Hemoglobin-Based Oxygen Carriers (HBOC) on the Microcirculation
Background
Effects on the Microcirculation: A Hamster Skinfold Study
Effects on the Microcirculation: A Canine Bulbar Conjunctiva Study
Discussion
References
9: Nitric Oxide and Hemoglobin: Physiological Implications
Introduction
Nitric Oxide Cardiovascular Effects
Nitric Oxide Vascular Effects
Nitric Oxide and Hemodynamic Regulations
Hemoglobin (Hb)
Interactions Between NO and Hemoglobin
Nitrosyl Hemoglobin
NO Bioactivity and Hemoglobin
NO, Red Cell Biology and Blood Substitutes
NO Scavenging
Conclusion
References
10: A Brief History of the Development of Nanobiotechnology-Based Blood Substitutes
Introduction
Hemolysate and Stroma Free Hemoglobin
Early Basic Research on Nanobiotechnology Based RBC Substitute
Polyhemoglobin Based on Nanobiotechnology
First Generation Hemoglobin Based Oxygen Carriers (HBOCs)
Four General Types of HBOCs
Development During the HIV Contaminated Donor Blood Crisis
Intramolecularly Crosslinked Hemoglobin
Polyhemoglobin
Glutaraldehyde Crosslinked Human PolyHb
Glutaraldehyde Crosslinked Bovine PolyHb
Conjugated Hemoglobin
Nitric Oxide
Inhalation of Nitric Oxide to Prevent Vasoconstriction
Pyridoxalated Hemoglobin Polyoxyethylene as NO Scavenger in Distributive Shock
Other Sources of Hemoglobin
Bioengineering and Recombinant Methods
Nanobiotechnology Based Oxygen Carriers with Antioxidant Functions
Introduction
PolyHb-CAT-SOD
Convalently Binding of Nitroxides to PEG-Hb
Dual Carbon Monoxide and Oxygen Delivery Agent
Vitamin C as Antioxidant
Other Approaches
Preservation for Transplant Organ
Early Basic Research
Light’s Group
Zal’s Group
Nanobiotechnology Based Oxygen Carriers with Enhancement of All Three RBC Functions
Introduction
Polyhemoglobin with Enhanced Catalase-Superoxide Dismutase-Carbonic Anhydrase
Nanodimension Artificial Red Blood Cells
Early Artificial Red Blood Cells
Bilayer Lipid Membrane Nano Artificial RBC (Fig. 10.6)
Nano-Dimension Biodegradable Polymeric Artificial Cells
Variations in the Membrane and Configurations of Nano Artificial RBC
Nonfunctional or Functional Membrane (Fig. 10.8)
Other Areas
Nanobiotechnology Based Oxygen Carrier with Platelet Function
Nanobiotechnology Based Oxygen Carriers with Cancer Suppression Functions
Stem Cells
Future Development
Summary Discussions
What We Have Learned from Past History
What Needs to Be Done
References
Part II: Pharmacology and Physiology of Oxygen Therapeutics
11: Classifications of Blood Substitutes
Introduction
Blood Composition
Classification of Blood Substitutes
Classification Based on the Blood Components
Red Blood Cell Substitutes
White Blood Cell (Leukocyte) Substitutes
Platelet Substitutes
Plasma Substitutes
Classification of Erythrocyte Substitutes
Hemoglobin-Based Oxygen Carriers
Perfluorocarbon-Based Oxygen Carriers (PFBOC)
Genetic Engineered Recombinant Hemoglobin
Artificial and Cultured Red Blood Cells
Erythrocyte Substitutes Classification Based on Hemoglobin Sources
Erythrocyte Substitutes: Classification Based on RBC Membrane
Erythrocyte Substitutes: Classification Based on Organic Molecule
Erythrocyte Substitutes: Classification Based on Synthetic or Natural Molecule
Ideal Erythrocyte Substitutes
Potential Indications for Blood Substitutes
Summary
References
12: Hemoglobin-Based Oxygen Carriers: Brief History, Pharmacology and Design Strategies, Review of the Major Products in Clinical Trials, On-Going Studies, and Coagulation Concerns
Introduction
Transfusion Medicine
History of Hemoglobin-Based Oxygen Carriers
How HBOCs Are Made
Stroma Free Hemoglobin
α-α Cross Linked Hb
Glutaraldehyde Polymerized Hbs
Recombinant HBOC
Zero-Linked HBOCs
Pegylated HBOCs
Invertebrate Hb
Pharmacology and Physiology of HBOCs
Development of HBOCs
Development of αα-Hb and HemAssist
Development of Hemolink
Development of Polyheme
Development of Hemoximer
Development of Hemopure and Summary/Discussion of Pivotal HEM-0115 Trial
Adverse Events of Particular Interest
Recent Clinical Trials on Hemopure
Development of Third Generation HBOCs
Coagulation and HBOCs
Introduction
Single Site Clinical Study of Hemopure on Platelet Function
Summary of Hemopure
Summary and Moving Forward
References
13: Complications of HBOCs Including Clinical Safety Issues
Introduction
Criticism of the Natanson et al. Meta-Analysis
Safety Aspects of Specific HBOCs
HemAssist
Optro
Hemolink
Polyheme
MP40x-Hemospan (“3rd Generation”)
Hemopure (Biopure, OPK Pharma, HBO2 Therapeutics)
Sanguinate (Prolong Pharmaceuticals)
Adverse Events
Conclusion
References
14: On the Oxidative Toxicity of Hemoglobin
Red Blood Cell Oxidation Reactions in Health and Disease: What Have We Learned?
Oxidation of Hemoglobin and Cytosolic Antioxidative Proteins
The Role of Red Cell Band 3 in Hemoglobin Oxidation
Hemoglobin-Driven Oxidation Reactions Promote Microparticles Formation
Role of β Cysteine 93 in Oxidative Stability of Hemoglobin
Genetically and Chemically Modified HBOCs: The Impact of Molecular Modifications
Effects of Chemical and Genetic Modifications on the Oxidation of HBOCs
Effects of Altering Oxygen Affinity of HBOCs on Autoxidation and Oxidative Changes
Effects of Chemical Modifications on Heme Loss From HBOCs
Effects of Non-site-Specific modifications on Oxidative Stability of HBOCs
Countermeasures Against Hemoglobin Oxidation and the Design of Safer HBOCs
Intercepting Nitric Oxide and the Control of Hemodynamic Imbalance
Antioxidants and Reducing Agents for the Control HBOC Oxidative Toxicity
Engineering Oxidatively Stable HBOCs Based on Mutant Hemoglobins: The Case of the Providence Mutation
Haptoglobin and hemopexin Are First-Line-of Defense against Free Hemoglobin and Heme
Summary and Conclusion
References
15: Nanotechnology-Based Oxygen and Drug Carriers
Background/Introduction
Nanotechnology Based CCD Technique
Oxygen Carriers Fabricated by CCD Technique
Drug Carriers Fabricated by CCD Technique
Summary
References
16: Perfluorocarbon-Based Oxygen Carriers
Introduction
Chemical and Physical Properties
Perfluorocarbon Compounds
Perfluorocarbon-Based Oxygen Delivery
Clinical Applications
Future Directions
Liquid Ventilation
Albumin-Derived Perfluorocarbon Solutions
Summary
References
17: Platelet Substitutes
Introduction
Modified Erythrocytes
Non-Cellular Hemostatic Agents
Agents to Improve Platelet Function
Thrombopoietic Agents
Conclusion
References
18: Plasma Substitutes
Background
Crystalloids
Isotonic Solutions
Hypotonic and Hypertonic Solutions
Colloids
Natural Protein Colloid – Albumin
Synthetic Colloids
Dextrans (10% Dextran 40, 6% Dextran 70)
Gelatins
Summary
References
Part III: Products in Development
19: Soluble Nanobiotherapeutics with Enhancements of All Three Major Red Blood Cell Functions
Introduction
General
Hemoglobin Based Oxygen Carrier
Oxygen Carrier with Antioxidant Activity
Oxygen and Carbon Dioxide Carriers with Antioxidant Activity
Soluble Nanobiotherapeutics with Enhancement of All 3 RBC Functions: Poly-[Hb- SOD-CAT-CA]
Method
Result in a 2.3 Blood Loss 90 min Sustained Hemorrhagic Shock Rat Model
Effects of 4 Weekly Toploading Followed by 30% Exchange: Safety and Immunological Effects [14]
General
Result
Test for Anaphylactic Reaction
Storage Stability and Pasteurization
Costs and Source of Enzymes
Comparison of Different Approaches
Potential Implications
Summary and Concluding Remarks
References
20: Paradigm Shift for Designing Oxygen Therapeutics: New Insights Emerging from Studies with Transgenic Mouse Models of Sickle Cell Disease
Introduction
Development of EAF P5K6 Hb and Its Prototype Hemospan as an Oxygen Carrying Colloidal Plasma Expanders
Interdimeric Interactions of Hb PEGylated Using Extension Arm Chemistry
Hemospan (MP4) Is Non-toxic in Phase III Clinical Trial, However Not Superior to Conventional Colloidal Plasma Expander
EAF P5K6 Hb Is a Semisynthetic, Colloidal Supra Plasma Expander
Tissue Oxygenation with Supra Plasma Expanders in Situations of Low Hematocrit
EAF Hexa-PEGylation Induced Supra Plasma Expansion Activity of Alb
Hypertensive Activity and Tissue Oxygenation by Hb Modified at Cys-93(β) with Maleimide PEG and with High Oxygen Affinity
Pattern of PEGylation on PEG Hb Dictates the Efficiency of Tissue Oxygenation During Extreme Hemodilution
PEG-Shell of High Oxygen Affinity of EAF P5K6 Hb Attenuates the Efficiency of Tissue Oxygenation
Design of EAF P3K6 Hb and Its Ability to Improve Tissue Oxygenation
Therapeutic Application of High Oxygen Affinity PEG Hb in Treating the Pathophysiology of Sickle Cell Disease
Novel Aspects of EAF PEGylated Albumin and EAF PEG-Hb as Oxygen Therapeutics
General Conclusions
Future Directions
References
21: Hemoglobin-Based Blood Substitute with Pharmacological Activities of ATP, Adenosine and Reduced Glutathione: A Review of Preclinical and Early Clinical Experience
Background/Introduction
Main Body of the Chapter
Realization Principle of HemoTech Pharmacologic Cross-linking
HemoTech Production Under the Concurent Good Manufacturing Practice (cGMP) Regulations
HemoTech Preclinical Studies
HemoTech Clinical Studies
Summary
References
22: Potential Clinical Application of Hemoglobin Vesicles as an Artificial Oxygen Carrier and Carbon Monoxide Carrier
Introduction
Preparation of Encapsulated Hb Using Liposomes
Potential Clinical Applications of HbV as a Transfusion Alternative
Potential Clinical Applications of HbV for Oxygen and Carbon Monoxide Therapeutics
Safety Evaluations of HbV
Summary
References
23: Potential Value of Polynitroxylated PEGylated Hemoglobin (SanFlow) in Pre-Hospital Medicine in Austere Environments including Military Deployments, Disasters and Remote Emergencies
Introduction
The Development of Artificial Oxygen Carriers and Hemoglobin Based Oxygen Carriers
Artificial Oxygen Carriers
Limitations of Cell-Free Hemoglobin
The Development of Polynitroxylated PEGylated Hemoglobin (SanFlow)
PNPH in Traumatic Brain Injury and Hemorrhagic Shock
Remote Pre-hospital Medicine Beyond the ‘Golden Hour’
Summary
References
24: Erythromer (EM), a Nanoscale Bio-Synthetic Artificial Red Cell
Introduction
Historical Context
Bioinspired Design and Preclinical Results
Design Strategy
Fabrication and Morphology
Inhibition of Hb Auto-oxidation
Control of NO Sequestration
Intelligent Control System (e.g., ‘Wetware’) for Modulation of EM O2 Affinity
Initial Biocompatibility (Complement)
Rheology
Exploratory Pharmacokinetic (PK) Profiling in Rats and Rabbits
O2 Delivery (in vivo)
Envisioned Use
Summary/Conclusion
References
25: OxyVita: History, Studies, and Future
Background
Preparation of OxyVita
The Properties of OxyVita
Selected Studies
Traumatic Brain Injury (TBI)
Whole Blood Approach
Future Direction
Assessment of Effectiveness of OxyVita in the Treatment of Myocardial Infarction and Cardiac Arrest
Effectiveness of OxyVita in Treatment of Carbon Monoxide (CO) Poisoning
Organ Storage Solution
The Effect of OxyVita Hb on Erythrocytes Sickling in Patients with Sickle Cell Disease (SCD)
ROS Induced Oxidative Stress: Blood Transfusion Versus Blood Substitutes
Summary
References
26: Lumbricus terrestris Erythrocruorin: A Novel Blood Substitute from a Terrestrial Earthworm
Introduction
Macromolecular Structure of LtEc
Assembly of the Hexagonal Bilayer
Structural Stability of LtEc
Glycosylation
Oxygen Transport and Interactions with NO
Oxygen Affinity and Cooperativity
Heme Oxidation
Nitric Oxide
Synthetically Modified LtEc
Summary
References
Part IV: Products, Not Approved, in Progress, and Approved for Human/Veterinary Use
27: HemAssist: Development, Clinical Trials, Lessons Learned
Introduction
Preclinical Testing
Clinical Testing
Subsequent Analyses – Myocardial Infarction
Summary and Lessons Learned
References
28: Development of Recombinant Hemoglobin-Based Oxygen Carriers-Somatogen: Studies and Lessons Learned
Background
Second Generation Recombinant Hemoglobin Development
Summary
References
29: O-Raffinose Cross-Linked Human Hemoglobin (Hemolink): History, Clinical Trials and Lessons Learned
Introduction
History of Hemoglobin-Based Oxygen Carriers
Properties of Hemoglobin-Based Oxygen Carriers
Deficiency of Red Blood Cell Membrane
Deficiency of Red Blood Cell
Source of Hemoglobin Molecule
Structure of Hemoglobin Molecule
Iron Moiety
Properties of Hemolink
Clinical Trials of Hemolink
Phase I: Safety Trial
Phase II: CABG Trial
Phase III: CABG Trial
Discontinuation of Clinical Trials
Lessons Learned
References
30: PolyHeme: History, Clinical Trials, and Lessons Learned
Product Development of PolyHeme
Phase I Clinical Trials
Phase II Clinical Trials
PolyHeme’s Immunoinflammatory Effect Compared to Stored RBCs
Phase III Clinical Trials
Ethical Issues and Lessons Learned
Summary
References
31: Clinical Evaluation of MP4CO: A Phase 1b Escalating-Dose, Safety and Tolerability Study in Stable Adult Patients with Sickle Cell Disease
Introduction
Methods
Results
Discussion and Conclusions
References
32: Oxygent™, a Perfluorochemical-Based Oxygen Therapeutic for Surgical Patients
Introduction
Emulsion Characteristics
Non-Clinical Safety
Clinical Safety
Preclinical Efficacy
Potential Clinical Applications
Tissue Oxygenation and Hemodilution
Cardiopulmonary Bypass
Shock and Trauma
Decompression Sickness
Organ Preservation
Tumor Oxygenation
Sickle Cell Disease
Phase II Clinical Studies
General Surgery
Cardiac Surgery
Phase III Clinical Studies
General Surgery
Cardiac Surgery
Future Clinical Development
References
33: Sanguinate: History and Clinical Evaluation of a Multimodal HBOCs
Introduction
Sanguinate Characteristics
PEGylation
Carbon Monoxide Delivery
Hemoglobin-Oxygen Binding
Clinical Trials Using Sanguinate
Case Reports and Other Trials
Conclusion
References
34: M101, the Hemoglobin from the Sea: History and Therapeutic Perspectives
Introduction
Preclinical Investigations
Clinical Applications and Investigations
Additional Applications and Indications
Moving Forward
References
35: HBOC-201: History, Clinical Trials, and Path Forward
History
Clinical Trials
Future Work
Expanded Access
Current Use
Future Directions
Summary
References
36: Perftoran: History, Clinical Trials, and Pathway Forward
Introduction
History
Composition and Pharmacology
Physiologic Properties
Pre-clinical Trials
Other Animal Studies
Human Trials: Russia, Mexico
Discussion
Conclusion
References
37: Oxycyte™
Introduction
Anemia
Central Nervous System
Stroke
Traumatic Brain Injury
Spinal Cord Injury
Bubble Related Diseases
Air Gas Embolism (AGE)
Decompression Sickness (DCS)
Oxycyte Safety in DCS
Central Nervous System Oxygen Toxicity
Pulmonary Artery Pressure (PAP)
Hematologic
Summary
References
38: Hemoximer: History, Pharmacology, Pre-Clinical Studies, Clinical Trials, and Lessons Learned
Introduction
Chemistry and Physical Properties
Non-clinical Studies
Clinical Studies
Phase 1
Phase 2a
Phase 2b
Phase 3a
Phase 3b
Conclusions
References
Part V: Specific Indications, Regulatory Issues and Future Directions
39: Hemoglobin-Based Oxygen Carrier Solutions for Organ and Tissue Preservation and Transplantation
Introduction
Machine Perfusion for Organ and Tissues Preservation
Rationale for the Use of Machine Perfusion Devices
Developing HBOCs for Specific Ex-Vivo Utilization in Organ and Tissue Preservation
Pharmacodynamics (PD) and Pharmacokinetic (PK) Experiments with OxyBridge
Perfusate (OxyBridge) Gas Analysis
Hemoximetry
Results: Perfusion Parameters Ex-Vivo
Mitochondrial Function
Nitrite and Nitrate Measurements
Mitochondrial Respiration Measurements
Reactive Oxygen Species (ROS) Measurements
Results
Mitochondrial H2O2
Nitrite and Nitrate Measurements
Histopathology
Conclusions from the Liver Experiments
Preliminary Pre-clinical Studies with Vascularized Composed Allotransplants (VCA) Utilizing the MP/HBOC Preservation System at 21 °C
Rationale and Unmet Clinical Needs for VCA
Methods
Histological Analysis
Inflammatory Markers
Metabolomics
Statistical Analysis
Results
Clinical and Histopathologic Analysis
Post-reperfusion Findings
Inflammatory Markers
Metabolomics
Discussion
Final Conclusions
References
40: Resuscitation of Traumatic Hemorrhagic Shock
Introduction
Pathophysiology of Coagulopathy in Trauma
Resuscitation Practices in Trauma
Damage Control Resuscitation (DCR)
Permissive Hypotension
Appropriate Hemostatic Resuscitation
Whole Blood
Blood Product Ratio
Plasma
Massive Transfusion Protocol
Adjuncts
Tranexamic Acid
Kcentra
Cryoprecipitate
Fibrinogen Concentrate
ROTEM and TEG Guided Resuscitation
Summary
References
41: Hemoglobin-Based Oxygen Carrier (HBOC) Development in Trauma: Previous Regulatory Challenges, Lessons Learned, and a Path Forward
Introduction
Medical Need in Trauma and Rationale for HBOCs
Clinical Experience: Lessons Learned with HBOCs in Trauma
Regulatory Challenges, Safety, and a Pathway Forward
Future Directions and Indications for HBOC Development
References
42: Use of Oxygen Therapeutics in Patients for Whom Blood Is Not an Option
Background
Expanded Access and Right to Try
Reports of Use of HBOCs Under Expanded Access Programs
Summary and Lessons Learned from the Use of HBOCs Under Expanded Access Programs
References
43: Regulatory Perspectives on Clinical Trials for Oxygen Therapeutics When Transfusion of Red Blood Cells is Not an Option
Status of Red Blood Cell Transfusion in the United States
General Regulatory Background in the United States
Requirements for Approval/Licensure of Drugs and Biologics
Expedited Programs
Real World Evidence
Rare Diseases
Animal Rule
Regulatory Programs to Permit Product Use Not Part of Drug Development Pathways Leading to Approval
Expanded Access
Right to Try
Emergency Use Authorization
Considerations for Use When Red Blood Cells Are Indicated but Are Not Available or Cannot Be Transfused
References
Index