Chemistry and Biochemistry of Oxygen Therapeutics -- Contents -- List of Contributors -- Preface -- 1. Introduction -- References -- Part I. Oxygen: Chemistry, Biochemistry, Physiology and Toxicity -- 2. Hemoglobin Reactivity and Regulation -- 2.1 Introduction -- 2.2 Oxygen Loading and Transport -- 2.3 NO Reactivity with Hb -- 2.4 Hb Oxidation -- 2.5 Nitrite Reactivity with Hb -- 2.6 Amino-acid Determinants of Hb Reactivity: Natural and Engineered Hbs -- 2.6.1 Modulation of Oxygen Affinity and Cooperativity -- 2.6.2 NO Reactivity and Oxidation -- 2.7 Conclusion -- Acknowledgments -- References -- 3. The Major Physiological Control Mechanisms of Blood Flow and Oxygen Delivery -- 3.1 Introduction -- 3.2 Autoregulation of Blood Flow to Changes in Perfusion Pressure -- 3.3 Metabolic Regulation of Blood Flow -- 3.4 O2 Transport -- 3.5 O2 Delivery -- 3.6 Endothelial Control of Vasomotor Tone -- 3.7 Effect of Cell-free Hb on Endothelial Function -- 3.8 Hypoxic Hypoxia -- 3.9 Carbon Monoxide Hypoxia -- 3.10 Anemia -- 3.11 Conclusion -- References -- 4. The Main Players: Hemoglobin and Myoglobin -- Nitric Oxide and Oxygen -- 4.1 Introduction -- 4.2 Role of Mammalian Mb in O2 Homeostasis -- 4.3 WhatŁfs Missing in the Mb Knockout Mouse -- 4.4 Evolutionary Origins of Mb and the Nitrogen Cycle -- 4.5 Human Hb: Evolved Sensor of pO2 and Redox -- 4.6 Broad Reactivity and Influence of NO: Lessons from the Microcosm Hb -- 4.7 Some Fish Demonstrate a Fundamental "Need" for Hb-dependent NO Cycling, as in Humans -- 4.8 Reactions of NO with Hb that Preserve NO Bioactivity -- 4.9 Mammalian RBC/Hb.NO Interactions -- 4.10 A Mutant Mouse Challenges the SNO-Hb Hypothesis, but does not Overthrow it -- 4.11 Signaling by Hb-derived SNO: A Metabolically Responsive, Regulated Pathway.

4.12 Signaling by Hb-derived SNO: Pathway Complexity Revealed by Multiple Defects in Disease States -- 4.13 Therapeutic Implications of the Hb.NO Signaling System -- 4.14 HBOCs, NO, and SNO -- 4.15 Other Gaseous Hb Ligands of Potential Therapeutic Significance -- 4.16 NO-related Enzymatic Activities of Hb: Reconciling Nitrite Reductase and SNO Synthase Functions -- 4.17 Measuring Biologically Relevant Hb.NO Adducts -- 4.18 Conclusion -- Acknowledgments -- References -- 5. The Role of Reactive Oxygen and Nitrogen Species in Ischemia/Reperfusion Injury -- 5.1 Introduction -- 5.2 Redox System and Free Radicals in Biological Systems -- 5.3 Pathophysiology of Ischemia/Reperfusion Injury -- 5.3.1 Cell Death -- 5.3.2 The Inflammatory Response -- 5.4 Protection Against I/R Injury -- 5.4.1 Ischemic Pre- and Post-conditioning -- 5.4.2 Pharmacological Conditioning -- 5.4.2.1 The Protective Role of ROS and Antioxidants -- 5.4.2.2 The Protective Role of NO -- 5.4.2.3 NO-based Therapies for I/R Injury -- 5.5 Conclusion -- Acknowledgments -- References -- Part II. Medical Needs for Oxygen Supply -- 6. Acute Traumatic Hemorrhage and Anemia -- 6.1 Introduction -- 6.2 Blood Transfusion in Trauma -- 6.2.1 Massive Transfusion -- 6.2.2 Massive Transfusion and Coagulopathy -- 6.2.3 Hypotensive or Delayed Resuscitation -- 6.2.4 Hemostatic Resuscitation -- 6.2.5 Massive Transfusion Protocols -- 6.2.6 Transfusion after Hemorrhage Control -- 6.2.7 Efficacy of RBC Transfusion in Trauma and Associated Risks -- 6.3 Oxygen Therapeutics in Trauma -- 6.3.1 Diaspirin Crosslinked Hb -- 6.3.2 Hemopure -- 6.3.3 PolyHeme -- 6.3.4 MP4OX -- 6.3.5 Recombinant Human Hb -- 6.3.6 Adverse Effects of HBOCs -- 6.3.7 HBOCs in Trauma: A Way Forward? -- 6.4 Conclusion -- References -- 7 Diagnosis and Treatment of Haemorrhages in 'Nonsurgical' Patients -- 7.1 Introduction.

7.1.1 Aetiopathogenetic Classification -- 7.1.2 Multifactorial Pathogenesis -- 7.1.3 Haemorrhagic Syndromes from Antithrombotic Treatment or Prophylaxis -- 7.2 Clinical Assessment -- 7.2.1 Medical History -- 7.2.2 Physical Examination -- 7.3 Laboratory Tests -- 7.3.1 Screening Tests -- 7.3.2 Second-level Laboratory Tests -- 7.3.3 Other Tests -- 7.4 Haemorrhagic Syndromes Clinically Indicative of Systemic Defects with Normal Screening Tests -- 7.5 Blood and Blood Components in the Treatment of Haemorrhagic Syndromes -- Further Reading -- 8. Management of Perioperative Bleeding -- 8.1 Introduction -- 8.2 Pathomechanisms of Coagulopathy in Massive Bleeding -- 8.3 Perioperative Coagulation Monitoring -- 8.4 Limitations of Routine Coagulation Tests in the Perioperative Setting -- 8.5 Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM) -- 8.6 Procoagulant Interventions -- 8.7 Algorithm for Coagulation Management -- References -- 9. Oxygenation in the Preterm Neonate -- 9.1 Introduction -- 9.2 Physiology of Oxygen Transport in Fetal and Postnatal Life -- 9.2.1 Oxygenation of the Fetus -- 9.2.2 Measuring Oxygenation in the Neonate -- 9.3 Oxygen Therapy in the Postnatal Period -- 9.3.1 Oxidative Stresses in the Newborn Period -- 9.3.2 Clinical Sequelae of Hyperoxia -- 9.3.2.1 Retinopathy of Prematurity -- 9.3.2.2 Oxygen and Chronic Lung Disease -- 9.3.2.3 Oxygen and Periventricular Leukomalacia -- 9.4 Oxygen and Resuscitation of the Newborn Infant -- 9.5 Transfusion in the Newborn -- 9.6 ROP and Transfusions -- 9.7 Conclusion -- References -- 10. Ischemia -- 10.1 Introduction -- 10.2 Pathophysiology -- 10.2.1 Energy Failure -- 10.2.2 Cell Membrane Damage -- 10.2.3 Increased Cytosolic Calcium -- 10.2.4 Inflammation -- 10.2.5 The No-reflow Phenomenon -- 10.2.6 Free Radicals and Reactive Oxygen Species -- 10.2.7 Excitotoxicity.

10.3 Therapeutic Potentials -- 10.3.1 Preconditioning -- 10.3.2 Antioxidants -- 10.3.3 Anti-inflammation Therapy -- 10.3.4 Therapeutic Hypothermia -- 10.3.5 Hydrogen Sulfide -- 10.3.6 Hyperoxia and Hyperbaric Oxygen -- 10.3.7 Hemoglobin-based Oxygen Carriers -- 10.4 Conclusion -- References -- 11. Normobaric and Hyperbaric Oxygen Therapy for Ischemic Stroke and Other Neurological Conditions -- 11.1 Introduction -- 11.2 Rationale of Oxygen Therapy in AIS -- 11.3 Hyperbaric Oxygen Therapy -- 11.4 Normobaric Oxygen Therapy -- 11.5 The Status of Supplemental Oxygen Delivery -- 11.6 Comparison of HBO and NBO in AIS -- 11.7 Safety Concerns -- 11.8 HBO and NBO in Other Conditions -- 11.9 Conclusion -- References -- 12 Transfusion Therapy in β Thalassemia and Sickle Cell Disease -- 12.1 Introduction -- 12.2 β Thalassemia and Transfusion -- 12.3 Sickle Cell Disease and Transfusion -- 12.4 Iron Chelation Tools -- 12.5 Conclusion -- References -- Part III "Old" and New Strategies for Oxygen Supply -- 13. Transfusion: Political, Administrative and Logistic Issues -- 13.1 Introduction -- 13.2 Blood Safety -- 13.3 Blood Availability -- 13.4 Cost and Fairness -- 13.5 Transfusion Medicine -- References -- 14. Conscientious Objection in Patient Blood Management -- 14.1 Introduction -- 14.2 Conscientious Objection -- 14.3 Patient Blood Management -- 14.4 JehovahŁfs Witnesses -- 14.5 Will the Real Objection Please Stand Up? -- 14.6 Conscientious Objection in Relation to Oxygen Therapeutics and Other Innovations -- Acknowledgements -- References -- 15. Red-cell Transfusion in Clinical Practice -- 15.1 Introduction -- 15.2 Red-cell Use -- 15.3 The Red-cell-transfusion Trigger -- 15.4 Risks of Red-cell Transfusion -- 15.5 Conclusion -- Disclaimer -- References -- 16. Causes and Consequences of Red Cell Incompatibility -- 16.1 Introduction -- 16.2 Red Cell Antigens.

16.2.1 ABO and the H System -- 16.2.2 The Lewis System and Structurally Related Antigens -- 16.2.3 The Rh System -- 16.2.4 Other Blood Group Systems -- 16.3 Red Cell Antibodies -- 16.3.1 Naturally Occurring Antibodies and Immune Antibodies -- 16.3.2 Autoantibodies -- 16.3.3 Drug Induced Antibodies -- 16.4 Compatibility Testing -- 16.4.1 ABO and Rh D Typing -- 16.4.2 Antibody Screening and Identification -- 16.4.3 Selection of Appropriate Blood -- 16.4.4 Crossmatch Testing -- 16.5 Hemolytic Transfusion Reactions -- 16.5.1 Pathophysiology -- 16.5.2 Prevention -- References -- 17. Biochemistry of Storage of Red Blood Cells -- 17.1 Introduction -- 17.2 Pathologic Consequences of Transfusion with Aged RBCs -- 17.3 Changes in Oxygen Affinity During RBC Storage -- 17.4 Role of Oxidative Damage During RBC Storage -- 17.5 Changes in the Physical Properties of RBCs During Storage -- 17.6 RBCs as Modulators of Vascular Flow -- 17.6.1 ATP Release Hypothesis -- 17.6.2 SNO-hemoglobin Hypothesis -- 17.6.3 Nitrite Reductase/Anhydrase Hypothesis -- 17.7 RBC-dependent Modulation of Inflammation -- 17.8 Conclusion -- Acknowledgements -- References -- 18. Proteomic Investigations of Stored Red Blood Cells -- 18.1 Introduction -- 18.2 RBC Ageing and Metabolism in vivo -- 18.3 RBC Storage Lesions Through Proteomics -- 18.4 Conclusion -- References -- 19. Red Blood Cells from Stem Cells -- 19.1 Introduction -- 19.2 Stem-cell Sources for ex vivo Generation of Erythroid Cells as a Transfusion Product -- 19.3 Conditions that Favor ex vivo Erythroid Cell Expansion -- 19.4 A Clinical-grade Production Process for ex vivo Generation of Red-cell Transfusion Products -- 19.4.1 The Nature of the Production Process -- 19.4.2 Cellular Composition of the Product -- 19.4.3 Functional Status of Product -- 19.4.4 Safety Considerations.

19.5 Time Line of the Clinical Application of ex vivo-generated Erythroid Cells.