Chemistry and biochemistry of oxygen therapeutics : from transfusion to artificial blood

Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen – the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or “blood substitutes”) which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. __Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood__ links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development. The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery; hemoglobin and myoglobin; nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury. The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in ? thalassemia and sickle cell disease Finally “old”and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion; conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell storage; proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell; allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers; oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia – industry collaboration in blood substitute development. __Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood__ is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.Content: Chapter 1 Introduction (pages 1–7): Richard B. WeiskopfChapter 2 Hemoglobin Reactivity and Regulation (pages 9–22): Stefano Bettati and Andrea MozzarelliChapter 3 The Major Physiological Control Mechanisms of Blood Flow and Oxygen Delivery (pages 23–45): Raymond C. KoehlerChapter 4 The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen (pages 47–62): Tim J. McMahon and Joseph BonaventuraChapter 5 The Role of Reactive Oxygen and Nitrogen Species in Ischemia/Reperfusion Injury (pages 63–77): Ester Spagnolli and Warren M. ZapolChapter 6 Acute Traumatic Hemorrhage and Anemia (pages 79–106): Lena M. NapolitanoChapter 7 Diagnosis and Treatment of Haemorrhages in ‘Nonsurgical’ Patients (pages 107–119): Umberto Rossi and Rosa ChianeseChapter 8 Management of Perioperative Bleeding (pages 121–130): Sibylle A. Kozek?LangeneckerChapter 9 Oxygenation in the Preterm Neonate (pages 131–143): Vidheya Venkatesh, Priya Muthukumar, Anna Curley and Simon StanworthChapter 10 Ischemia (pages 145–158): Hooman Mirzakhani and Ala NozariChapter 11 Normobaric and Hyperbaric Oxygen Therapy for Ischemic Stroke and Other Neurological Conditions (pages 159–177): Ari Moskowitz, Yu?Feng Yvonne Chan and Aneesh B. SinghalChapter 12 Transfusion Therapy in ? Thalassemia and Sickle Cell Disease (pages 179–191): Carlo Brugnara and Lucia De FranceschiChapter 13 Transfusion: Political, Administrative and Logistic Issues (pages 193–204): John R. Hess and Giuliano GrazziniChapter 14 Conscientious Objection in Patient Blood Management (pages 205–211): Kenneth E. Nollet and Hitoshi OhtoChapter 15 Red?Cell Transfusion in Clinical Practice (pages 213–220): Harvey G. KleinChapter 16 Causes and Consequences of Red Cell Incompatibility (pages 221–230): Chisa Yamada and Robertson DavenportChapter 17 Biochemistry of Storage of Red Blood Cells (pages 231–241): Ryan Stapley, Dario A. Vitturi and Rakesh P. PatelChapter 18 Proteomic Investigations of Stored Red Blood Cells (pages 243–256): Lello Zolla and Angelo D'AlessandroChapter 19 Red Blood Cells from Stem Cells (pages 257–271): Anna Rita Migliaccio, Carolyn Whitsett and Giovanni MigliaccioChapter 20 The Universal Red Blood Cell (pages 273–284): Luca Ronda and Serena FaggianoChapter 21 Allosteric Effectors of Hemoglobin: Past, Present and Future (pages 285–300): Martin K. Safo and Stefano BrunoChapter 22 Hemoglobin?Based Oxygen Carriers: History, Limits, Brief Summary of the State of the Art, Including Clinical Trials (pages 301–316): Jonathan S. Jahr, Arezou Sadighi, Linzy Doherty, Alvin Li and Hae Won KimChapter 23 Oxygen Delivery by Natural and Artificial Oxygen Carriers (pages 317–325): Enrico BucciChapter 24 Crosslinked and Polymerized Hemoglobins as Potential Blood Substitutes (pages 327–344): Kenneth W. Olsen and Eugene TarasovChapter 25 Engineering the Molecular Shape of PEG?Hemoglobin Adducts for Supraperfusion (pages 345–369): Seetharama A. Acharya, Marcos Intaglietta, Amy G. Tsai, Kulal Ananda and Fantao MengChapter 26 Hb Octamers by Introduction of Surface Cysteines (pages 371–380): Veronique Baudin?Creuza, Chien Ho and Michael C. MardenChapter 27 Hemoglobin Vesicles as a Cellular?Type Hemoglobin?Based Oxygen Carrier (pages 381–390): Hiromi Sakai, Hirohisa Horinouchi, Eishun Tsuchida and Koichi KobayashiChapter 28 Animal Models and Oxidative Biomarkers to Evaluate Preclinical Safety of Extracellular Hemoglobins (pages 391–411): Paul W. Buehler and Felice D'AgnilloChapter 29 Academia–Industry Collaboration in Blood Substitute Development: Issues, Case Histories and a Proposal (pages 413–428): Hae Won Kim, Andrea Mozzarelli, Hiromi Sakai and Jonathan S. Jahr Chemistry and Biochemistry of Oxygen Therapeutics......Page 3 Contents......Page 7 List of Contributors......Page 19 Preface......Page 25 1. Introduction......Page 27 References......Page 31 Part I. Oxygen: Chemistry, Biochemistry, Physiology and Toxicity......Page 35 2.2 Oxygen Loading and Transport......Page 37 2.3 NO Reactivity with Hb......Page 41 2.5 Nitrite Reactivity with Hb......Page 42 2.6.1 Modulation of Oxygen Affinity and Cooperativity......Page 43 2.7 Conclusion......Page 44 References......Page 45 3.2 Autoregulation of Blood Flow to Changes in Perfusion Pressure......Page 49 3.3 Metabolic Regulation of Blood Flow......Page 52 3.5 O2 Delivery......Page 53 3.6 Endothelial Control of Vasomotor Tone......Page 55 3.7 Effect of Cell-free Hb on Endothelial Function......Page 57 3.8 Hypoxic Hypoxia......Page 59 3.10 Anemia......Page 62 References......Page 65 4.2 Role of Mammalian Mb in O2 Homeostasis......Page 73 4.3 WhatŁfs Missing in the Mb Knockout Mouse......Page 74 4.6 Broad Reactivity and Influence of NO: Lessons from the Microcosm Hb......Page 75 4.7 Some Fish Demonstrate a Fundamental “Need” for Hb-dependent NO Cycling, as in Humans......Page 76 4.9 Mammalian RBC/Hb.NO Interactions......Page 78 4.11 Signaling by Hb-derived SNO: A Metabolically Responsive, Regulated Pathway......Page 80 4.12 Signaling by Hb-derived SNO: Pathway Complexity Revealed by Multiple Defects in Disease States......Page 81 4.14 HBOCs, NO, and SNO......Page 82 4.16 NO-related Enzymatic Activities of Hb: Reconciling Nitrite Reductase and SNO Synthase Functions......Page 83 Acknowledgments......Page 84 References......Page 85 5.1 Introduction......Page 89 5.2 Redox System and Free Radicals in Biological Systems......Page 90 5.3.1 Cell Death......Page 91 5.4.1 Ischemic Pre- and Post-conditioning......Page 93 5.4.2.1 The Protective Role of ROS and Antioxidants......Page 94 5.4.2.2 The Protective Role of NO......Page 95 5.4.2.3 NO-based Therapies for I/R Injury......Page 96 References......Page 98 Part II. Medical Needs for Oxygen Supply......Page 105 6.1 Introduction......Page 107 6.2.2 Massive Transfusion and Coagulopathy......Page 109 6.2.4 Hemostatic Resuscitation......Page 110 6.2.7 Efficacy of RBC Transfusion in Trauma and Associated Risks......Page 112 6.3 Oxygen Therapeutics in Trauma......Page 114 6.3.2 Hemopure......Page 116 6.3.3 PolyHeme......Page 117 6.3.4 MP4OX......Page 119 6.3.6 Adverse Effects of HBOCs......Page 121 6.3.7 HBOCs in Trauma: A Way Forward?......Page 122 References......Page 123 7.1.1 Aetiopathogenetic Classification......Page 133 7.1.3 Haemorrhagic Syndromes from Antithrombotic Treatment or Prophylaxis......Page 134 7.2.1 Medical History......Page 137 7.2.2 Physical Examination......Page 138 7.3.2 Second-level Laboratory Tests......Page 139 7.3.3 Other Tests......Page 140 7.4 Haemorrhagic Syndromes Clinically Indicative of Systemic Defects with Normal Screening Tests......Page 143 Further Reading......Page 144 8.2 Pathomechanisms of Coagulopathy in Massive Bleeding......Page 147 8.3 Perioperative Coagulation Monitoring......Page 148 8.4 Limitations of Routine Coagulation Tests in the Perioperative Setting......Page 149 8.6 Procoagulant Interventions......Page 150 8.7 Algorithm for Coagulation Management......Page 152 References......Page 153 9.1 Introduction......Page 157 9.2.1 Oxygenation of the Fetus......Page 158 9.3 Oxygen Therapy in the Postnatal Period......Page 159 9.3.2.1 Retinopathy of Prematurity......Page 160 9.3.2.2 Oxygen and Chronic Lung Disease......Page 161 9.4 Oxygen and Resuscitation of the Newborn Infant......Page 162 9.7 Conclusion......Page 163 References......Page 164 10.2.1 Energy Failure......Page 171 10.2.3 Increased Cytosolic Calcium......Page 172 10.2.4 Inflammation......Page 174 10.2.6 Free Radicals and Reactive Oxygen Species......Page 175 10.3.1 Preconditioning......Page 176 10.3.4 Therapeutic Hypothermia......Page 177 10.3.7 Hemoglobin-based Oxygen Carriers......Page 178 References......Page 179 11.1 Introduction......Page 185 11.2 Rationale of Oxygen Therapy in AIS......Page 186 11.3 Hyperbaric Oxygen Therapy......Page 188 11.4 Normobaric Oxygen Therapy......Page 190 11.6 Comparison of HBO and NBO in AIS......Page 191 11.7 Safety Concerns......Page 194 11.9 Conclusion......Page 195 References......Page 196 12.2 β Thalassemia and Transfusion......Page 205 12.3 Sickle Cell Disease and Transfusion......Page 208 12.4 Iron Chelation Tools......Page 211 References......Page 212 Part III “Old” and New Strategies for Oxygen Supply......Page 219 13.1 Introduction......Page 221 13.2 Blood Safety......Page 222 13.3 Blood Availability......Page 224 13.4 Cost and Fairness......Page 226 13.5 Transfusion Medicine......Page 227 References......Page 228 14.2 Conscientious Objection......Page 231 14.3 Patient Blood Management......Page 232 14.4 JehovahŁfs Witnesses......Page 233 14.6 Conscientious Objection in Relation to Oxygen Therapeutics and Other Innovations......Page 234 Acknowledgements......Page 235 References......Page 236 15.1 Introduction......Page 239 15.2 Red-cell Use......Page 240 15.3 The Red-cell-transfusion Trigger......Page 241 15.4 Risks of Red-cell Transfusion......Page 242 References......Page 244 16.2.1 ABO and the H System......Page 247 16.2.4 Other Blood Group Systems......Page 248 16.3.1 Naturally Occurring Antibodies and Immune Antibodies......Page 249 16.4.2 Antibody Screening and Identification......Page 250 16.5 Hemolytic Transfusion Reactions......Page 251 16.5.1 Pathophysiology......Page 252 References......Page 254 17.1 Introduction......Page 257 17.3 Changes in Oxygen Affinity During RBC Storage......Page 258 17.4 Role of Oxidative Damage During RBC Storage......Page 259 17.6.1 ATP Release Hypothesis......Page 260 17.6.2 SNO-hemoglobin Hypothesis......Page 261 17.6.3 Nitrite Reductase/Anhydrase Hypothesis......Page 262 17.8 Conclusion......Page 263 References......Page 264 18.1 Introduction......Page 269 18.2 RBC Ageing and Metabolism in vivo......Page 270 18.3 RBC Storage Lesions Through Proteomics......Page 274 References......Page 278 19.1 Introduction......Page 283 19.2 Stem-cell Sources for ex vivo Generation of Erythroid Cells as a Transfusion Product......Page 284 19.3 Conditions that Favor ex vivo Erythroid Cell Expansion......Page 286 19.4.1 The Nature of the Production Process......Page 287 19.4.2 Cellular Composition of the Product......Page 289 19.4.3 Functional Status of Product......Page 290 19.4.4 Safety Considerations......Page 291 19.5.1 Drug Discovery......Page 292 19.5.2 Drug Delivery......Page 293 References......Page 294 20.1 Introduction......Page 299 20.1.2 The Rh System......Page 300 20.2.1 Conversion of B RBCs to Group O......Page 301 20.3 RBC Camouflage Through PEGylation......Page 303 20.3.1 Functionalized Methoxy PEG......Page 304 20.3.3 Extension Arm-facilitated RBC PEGylation......Page 305 References......Page 306 21.1 Introduction......Page 311 21.2.1 Organic Phosphates......Page 314 21.2.2 Synthetic Aromatic Propionate Right-shifters......Page 315 21.2.3 Aromatic Aldehyde Left-shifters......Page 316 21.3.1 Oxygen Binding Curve and Hb Structural Changes......Page 319 21.3.3 Decreasing Subunit Mobility and Changes in Allosteric Properties: Molecular Ratchets......Page 320 21.5 The Clinical Importance of Hemoglobin Allosteric Effectors......Page 321 References......Page 322 22.1 Introduction......Page 327 22.4 History......Page 328 22.5 Development......Page 329 22.6.1 Diaspirin Crosslinked Hemoglobin (DCLHb, HemeAssist, Baxter Laboratories, Deerfield, IL)......Page 330 22.6.2 Hemoglobin Raffimer (HR, Hemolink, Hemosol Inc., Ontario, Canada)......Page 332 22.6.3 Human Polymerized Hemoglobin (PolyHeme, Northfield Laboratories, Evanston, IL)......Page 333 22.6.4 Hemoglobin Glutamer-250 (Bovine) (HBOC-201, Hemopure, Biopure Corp., Cambridge, MA)......Page 334 22.6.5 Maleimide-polyethylene Glycol-modified Hemoglobin (MP4, Hemospan, Sangart Inc., San Diego, CA)......Page 335 22.7 Current Status and Future Directions of HBOCs......Page 337 References......Page 340 23.2 The Role of Oxygen Carriers......Page 343 23.3 The Role of Natural Cell-bound Oxygen Carriers......Page 344 23.4.2 The Rate of Oxygen Release from the Red Cells......Page 346 23.5.1 Facilitated Diffusion......Page 347 23.6 Other Parameters......Page 348 23.7 Clinical Use?......Page 349 References......Page 350 24.1 Introduction......Page 353 24.2 Crosslinking the Hb Tetramer......Page 354 24.3 Hb Polymers......Page 358 24.4 Conclusion......Page 363 References......Page 364 25.1 Introduction......Page 371 25.2 Enzon DecaPEGylated Bovine Hb is Nonhypertensive......Page 372 25.4 Molecular and Solution Properties of EAF HexaPEGylated Human Hb (EAF-P5K6-Hb)......Page 373 25.5 High O2 Affinity of EAF HexaPEGylated Hb and Tissue Oxygenation in Extreme Hemodilution......Page 375 25.6 Influence of Total PEG Mass Conjugated to Hb on O2 Affinity and Tissue Oxygenation by PEG-Hbs......Page 376 25.7 Influence of PEGylation Chemistry on Structural, Functional, and Solution Properties of HexaPEGylated Hb......Page 377 25.8 Reductive PEGylation-induced Weakening of Interdimeric Interactions of Tetrameric Hbs......Page 378 25.9 PEGylation-promoted Dissociation of Hb Tetramer is Attenuated by the Extension Arms of EAF PEGylated Hbs......Page 379 25.11 Hemospan: Prototype of EAF HexaPEGylated Hb Designed at Einstein......Page 380 25.13 Reversible Protection of Cys-93(β) during EAF PEGylation of Hb and Crosslinked Hbs: A Structural Requirement to Generate Medium- and Low-O2-af.nity PEG-Hbs......Page 381 25.14 Engineering Extension Arms between the Protein Core and PEG Shell Attenuates PEGylation-promoted Tetramer Dissociation......Page 382 25.16 Influence of the Extension Arm on the HexaPEGylation-enhanced Thermal Stability of Hb......Page 385 25.18 EAF HexaPEGylated Hb is a Superperfusion Agent......Page 386 25.20 In vivo Vasodilation by EAF PEG-Hb through its Enhanced Nitrite Reductase Activity......Page 387 25.21 EAF PEG-Hbs as Mechanotransducers of e-NOS Activity......Page 389 25.23 Conclusion......Page 390 Acknowledgments......Page 392 References......Page 393 26.1 Introduction......Page 397 26.2.1 Protein Expression......Page 399 26.2.2 Oligomer Size......Page 400 26.2.3 Disulfide Bond Formation......Page 401 26.2.4 Functional Properties of the Octamers......Page 402 References......Page 404 27.1 Introduction......Page 407 27.2 The Concept of Hb Encapsulation in Liposomes......Page 408 27.3 Hb Encapsulation Retards Gas Reactions......Page 409 27.4 HBOCs as a Carrier of not only O2 but also CO......Page 411 References......Page 413 28.1 Introduction......Page 417 28.2.1.2 Oxidative Stress......Page 418 28.2.2 Safety Pharmacology and Toxicology Studies......Page 419 28.2.3.1 Tissue Blood Flow and Oxygenation......Page 421 28.2.3.2 Traumatic Hemorrhage......Page 422 28.2.3.4 Sickle Cell Disease......Page 423 28.2.4.2 Chemically Induced Antioxidant Depletion......Page 424 28.2.4.3 Endothelial Dysfunction......Page 425 28.3.1 Heme Iron Oxidation......Page 426 28.3.3 Heme Catabolism and Iron Sequestration......Page 427 28.4.2 8-hydroxy-2 -deoxyguanosine (8-OHdG)......Page 429 28.5 Conclusion......Page 430 References......Page 431 29.1 Introduction......Page 439 29.2 Generic Issues in Academia.Industry Collaboration......Page 440 29.3 Academia.Industry Collaboration in HBOC Development......Page 441 29.4.3 Key Objectives......Page 443 29.4.4 Structure......Page 444 29.4.5 Operation......Page 445 29.5 Discussion......Page 446 29.6 Conclusions......Page 447 Case A: Waseda.Keio.Industry Research Collaboration......Page 448 Case B: EuroBloodSubstitutes Consortium......Page 450 References......Page 452 Index......Page 455 Scientists are developing oxygen therapeutics, or "blood substitutes," with the same oxygen-carrying capability as blood, that can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. This book links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development, starting with the observation that an oxygen therapeutic agent can be developed only upon a deep understanding of oxygen and nitric oxide, homeostasis and regulation, and the well-documented correlations between adverse effects of a specific product and its biochemical-physiological properties. Read more... Content: Introduction / Richard B Weiskopf -- Oxygen: Chemistry, Biochemistry, Physiology and Toxicity. Hemoglobin Reactivity and Regulation / Stefano Bettati, Andrea Mozzarelli -- The Major Physiological Control Mechanisms of Blood Flow and Oxygen Delivery / Raymond C Koehler -- The Main Players: Hemoglobin and Myoglobin; Nitric Oxide and Oxygen / Tim J McMahon, Joseph Bonaventura -- The Role of Reactive Oxygen and Nitrogen Species in Ischemia/Reperfusion Injury / Ester Spagnolli, Warren M Zapol -- Medical Needs for Oxygen Supply. Acute Traumatic Hemorrhage and Anemia / Lena M Napolitano -- Diagnosis and Treatment of Haemorrhages in 1Nonsurgical2 Patients / Umberto Rossi, Rosa Chianese -- Management of Perioperative Bleeding / Sibylle A Kozek-Langenecker -- Oxygenation in the Preterm Neonate / Vidheya Venkatesh, Priya Muthukumar, Anna Curley, Simon Stanworth -- Ischemia / Hooman Mirzakhani, Ala Nozari -- Normobaric and Hyperbaric Oxygen Therapy for Ischemic Stroke and Other Neurological Conditions / Ari Moskowitz, Yu-Feng Yvonne Chan, Aneesh B Singhal -- Transfusion Therapy in Thalassemia and Sickle Cell Disease / Carlo Brugnara, Lucia De Franceschi -- 3Old4 and New Strategies for Oxygen Supply. Transfusion: Political, Administrative and Logistic Issues / John R Hess, Giuliano Grazzini -- Conscientious Objection in Patient Blood Management / Kenneth E Nollet, Hitoshi Ohto -- Red-Cell Transfusion in Clinical Practice / Harvey G Klein -- Causes and Consequences of Red Cell Incompatibility / Chisa Yamada, Robertson Davenport -- Biochemistry of Storage of Red Blood Cells / Ryan Stapley, Dario A Vitturi, Rakesh P Patel -- Proteomic Investigations of Stored Red Blood Cells / Lello Zolla, Angelo D'Alessandro -- Red Blood Cells from Stem Cells / Anna Rita Migliaccio, Carolyn Whitsett, Giovanni Migliaccio -- The Universal Red Blood Cell / Luca Ronda, Serena Faggiano -- Allosteric Effectors of Hemoglobin: Past, Present and Future / Martin K Safo, Stefano Bruno -- Hemoglobin-Based Oxygen Carriers: History, Limits, Brief Summary of the State of the Art, Including Clinical Trials / Jonathan S Jahr, Arezou Sadighi, Linzy Doherty, Alvin Li, Hae Won Kim -- Oxygen Delivery by Natural and Artificial Oxygen Carriers / Enrico Bucci -- Crosslinked and Polymerized Hemoglobins as Potential Blood Substitutes / Kenneth W Olsen, Eugene Tarasov -- Engineering the Molecular Shape of PEG-Hemoglobin Adducts for Supraperfusion / Seetharama A Acharya, Marcos Intaglietta, Amy G Tsai, Kulal Ananda, Fantao Meng -- Hb Octamers by Introduction of Surface Cysteines / V̌ronique Baudin-Creuza, Chien Ho, Michael C Marden -- Hemoglobin Vesicles as a Cellular-Type Hemoglobin-Based Oxygen Carrier / Hiromi Sakai, Hirohisa Horinouchi, Eishun Tsuchida, Koichi Kobayashi -- Animal Models and Oxidative Biomarkers to Evaluate Preclinical Safety of Extracellular Hemoglobins / Paul W Buehler, Felice D'Agnillo -- Academia-Industry Collaboration in Blood Substitute Development: Issues, Case Histories and a Proposal / Hae Won Kim, Andrea Mozzarelli, Hiromi Sakai, Jonathan S Jahr. Abstract: Scientists are developing oxygen therapeutics, or "blood substitutes," with the same oxygen-carrying capability as blood, that can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. This book links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development, starting with the observation that an oxygen therapeutic agent can be developed only upon a deep understanding of oxygen and nitric oxide, homeostasis and regulation, and the well-documented correlations between adverse effects of a specific product and its biochemical-physiological properties Human blood performs many important functions including defence against disease and transport of biomolecules, but perhaps the most important is to carry oxygen – the fundamental biochemical fuel - and other blood gases around the cardiovascular system. Traditional therapies for the impairment of this function, or the rapid replacement of lost blood, have centred around blood transfusions. However scientists are developing chemicals (oxygen therapeutics, or “blood substitutes”) which have the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired.

Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development.

The first part of the book deals with the chemistry, biochemistry, physiology and toxicity of oxygen, including chapters on hemoglobin reactivity and regulation; the major cellular and physiological control mechanisms of blood flow and oxygen delivery;  hemoglobin and myoglobin;  nitric oxide and oxygen; and the role of reactive oxygen and nitrogen species in ischemia/reperfusion Injury.

The book then discusses medical needs for oxygen supply, including acute traumatic hemorrhage and anemia; diagnosis and treatment of haemorrhages in "non-surgical" patients; management of perioperative bleeding; oxygenation in the preterm neonate; ischemia

normobaric and hyperbaric oxygen therapy for ischemic stroke and other neurological conditions; and transfusion therapy in β thalassemia and sickle cell disease

Finally “old”and new strategies for oxygen supply are described. These include the political, administrative and logistic issues surrounding transfusion;  conscientious objection in patient blood management; causes and consequences of red cell incompatibility; biochemistry of red blood cell storage;  proteomic investigations on stored red blood cells; red blood cells from stem cells; the universal red blood cell;  allosteric effectors of hemoglobin; hemoglobin-based oxygen carriers;  oxygen delivery by natural and artificial oxygen carriers; cross-linked and polymerized hemoglobins as potential blood substitutes; design of novel pegylated hemoglobins as oxygen carrying plasma expanders; hb octamers by introduction of surface cysteines; hemoglobin-vesicles as a cellular type hemoglobin-based oxygen carrier; animal models and oxidative biomarkers to evaluate pre-clinical safety of extracellular hemoglobins; and academia – industry collaboration in blood substitute development.

Chemistry and Biochemistry of Oxygen Therapeutics: From Transfusion to Artificial Blood is an essential reference for clinicians, haematologists, medicinal chemists, biochemists, molecular biologists, biotechnologists and blood substitute researchers.

"Scientists are developing oxygen therapeutics, or "blood substitutes," with the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. This book links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development, starting with the observation that an oxygen therapeutic agent can be developed only upon a deep understanding of oxygen and nitric oxide, homeostasis and regulation, and the well-documented correlations between adverse effects of a specific product and its biochemical-physiological properties"-- "First book to cover the full range of new oxygen therapeutics"-- "Scientists are developing oxygen therapeutics, or "blood substitutes," with the same oxygen-carrying capability as blood and can be used as replacements for blood transfusion or to treat diseases where oxygen transport is impaired. This book links the underlying biochemical principles of the field with chemical and biotechnological innovations and pre-clinical development, starting with the observation that an oxygen therapeutic agent can be developed only upon a deep understanding of oxygen and nitric oxide, homeostasis and regulation, and the well-documented correlations between adverse effects of a specific product and its biochemical-physiological properties"-- Provided by publisher