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

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