8.5 X12.5 Doublelines.P65

Cambridge University Press 978-0-521-87519-6 - Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, Second Edition Edited by Martin H. Steinberg, Bernard G. Forget, Douglas R. Higgs and David J. Weatherall Index More information

anti-inflammatory therapy, 762–763 thalassemia-related complications, 779 sulfasalazine, nuclear factor (NF)-kB, 762 transplant-related complications, 778–779 targeting ET-1, 762–763 ␤S-linked haplotypes, African/Indo-European, anti-oxidant therapy targeting erythrocyte, 638–640 765–766 burst forming unit-erythroid (BFU-E), 10, 29 deferiprone, 765 oral glutamine, 765 calcium-activated potassium channel (Gardos oral N-acetyl-cysteine, 765–766 pathway), 167–168 anti-oxidant therapy targeting vascular, 763–765 capillary electrophoresis, 660 Index Apo A-I mimetics, 764 capillary IEF, 660 NO, 763–764 carbon monoxide poisoning, 613–616 statins, 764 clinical features, 615 xanthine oxidase inhibitors, 764–765 diagnosis, treatment, 615–616 anti-thrombotic therapy epidemiology, 613–614 ␤-thalassemia, 761–762 cardiac, arterial abnormalities, 151 sickle cell disease, 761–762 cardiac abnormalities, ATRX syndrome, 305 aortagonad-mesonephros (AGM), 6 cardiovascular disease, 652 Apo A-I mimetics, 764 cation content, cellular hydration, 164–172 apoptosis, vasculature permeability, 193–194 calcium-activated potassium channel, 167–168 assays, assay systems, 7, 142 cation permeability alterations, 166–167 ATMDS. See ␣ thalassemia-myelodysplastic cell calcium, calcium pump activity, 167 syndromes cell sodium, 165–167 ATR-16 syndrome, 296–304 CHC, 164 abnormal transcranial Doppler ultrasonography chromosome imbalance, 301–303 deoxygenation-induced cation leak, 165–167 (TCD) genetic abnormalities definition, 299–301 deoxygenation-induced cation permeability, acetylation, 132–133, 600 summary, 303–304 165–166 acute chest syndrome, 695 ATRX syndrome, 304–311 Gardos channel activity modulation, 168–169 acute myeloid leukemia, HbA2, 127 associated phenotype, 308 KCC, 169–172 acute splenic sequestration, 694 ATMDS, 315–316 activation, 172 acute stroke, 694–695. See also stroke cardiac abnormalities, 305 cellular magnesium, 170–171 adhesive bridging proteins, sickle red cell clinical findings, 304–305 deoxygenation, 170 adhesion, 144 disease gene identification, 306–307 molecular basis, 171–172 adult blood system, HSCs, 3 gene, protein product, 307–308 sodium/hydrogen exchange, 165–167 AGM. See aortagonad-mesonephros head circumference, brain size, 304–305 sodium permeability, cell sodium, 167 alkaline Bohr effect, HbF, 120 hematologic findings, 305–306 sodium-potassium ATPase, 165–167 allantois, 5, 25–26 mutations, functional consequences, 311 stress, oxidation, 166–167 alloimmunization, 700–701 neonates, 304 cation permeability alterations, 166–167 sickle cell disease, 700–701 normal functional role, 310–311 cation transport thalassemia, 700 phenotype relationship, 308–309 other hemoglobinopathies, 174 amphibians, 13 skeletal abnormalities, 305 thalassemia, 174 animal models, transgenic mice subject behavior, 305 CBC. See complete blood count genetic background, 225 summary, 311 CBF transcription, 17 HbC impact, 233 urogenital abnormalities, 305 cell adhesion, erythropoiesis, 34 induced hemoglobinopathies, 232 X-linked condition, 306 cell calcium, calcium pump activity, 167 knock-out, knock-in, 225 avian, 12–13 cell hemoglobin concentration (CHC), 164 MCHC, 233 embryonic hematopoietic hierarchy, 12–13 cell sodium, 165–167 mouse age, 233 erythroid development, chicken, 12–13 cellular control, hemoglobin switching, 86–88 sickle cell disease models, 227–232 developmental clock, 87–88 erythrocytes, 229 bacteremia, 649 models, 86–87 organ pathology, 230–232 basal promoters, 52–53 cellular heterogeneity, HbF, 121–122 brain, 232 BFU-E. See burst forming unit-erythroid cellular hydration. See cation content, cellular kidney, 230 biochemical purification, transcription factors, hydration liver, 231 63–64 cellular magnesium, KCC, 170–171 lung, 232 blood product choice, 692–693 CFU-C, 9–10 microcirculation, 230–231 blood transfusion, HbH disease, 278–279 CFU-E. See colony forming units-erythroid pulmonary hypertension, 232 BMP-4, 16 CFU-S, 10 retina, 230 bone disease, 652 CHC. See cell hemoglobin concentration spleen, 232 bone marrow transplantation, thalassemia chelation therapy objectives, 710–721. See also sickle transgenic mice, 227–229 patient iron overload, chelation therapy strains, 225 effect, 778–780 harmful iron species detoxification, 711 technology, 225 endocrine dysfunction, 780 iron balance, 710 thalassemic mice, 225–227 hepatitis, 779–780 safe tissue iron concentrations maintenance, transgenic expression, 233 iron overload, 779 710–711 animal research, 3 mixed chimeric state, 778 chelator design constraints, 713–714 antenatal diagnosis, 681–682 patient selection, 777–778 ChIP analysis. See chromatin anti-adhesion therapy, sickle cell disease, risk classification, 777–778 immunoprecipitation analysis 759–761 thalassemia recurrence, 778 chloride binding, HbF, 120

815

© Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-87519-6 - Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management, Second Edition Edited by Martin H. Steinberg, Bernard G. Forget, Douglas R. Higgs and David J. Weatherall Index More information

816 Index

chorion, 5 effect on heart, 726 myelopoiesis, 8–9 chromatin conformation, EKLF, 38 heart, 726 neonatal repopulating hematopoietic stem chromatin immunoprecipitation (ChIP) analysis, pharmacology, 725 cells, 10 64–65 serum ferritin, liver iron, 725 T, B lymphoid lineage, mouse populations, 9 chromatin structure remodelling, EKLF, 72 treatment safety, 726 tyrosine c-kit receptor, 8 chromosomal organization, human globin genes, efﬁcacy, 722–724 epigenetic factors, 17–18 47–50 heart, 723–724 PcG proteins, 17 chromosome imbalance, ATR-16 syndrome, iron excretion, balance, 722 trxG, 17–18 301–303 liver iron, 722–723 extraembryonic ␣0 chromosome, 248–250 neutropenia, agranulocytosis, 724 allantois, 5 chronic transfusion therapy indications, 697–699 recommended dosing, 724 chorion, 5 other proposed indications, 699 serum ferritin, 722 placenta, 5 pregnancy, 698 unwanted effects, 724 yolk sac, 4–5 pulmonary hypertension, 698–699 deferoximine, 714–721 intraembryonic, PAS/AGM, 5–6 recurrent acute chest pain, 698–699 chemistry, pharmacology, 715 mesoderm induction, 3–4 recurrent painful episodes, 699 efﬁcacy, 715–717 molecular interactions, 14 recurrent splenic sequestration, 699 heart, 716–717 secondary territories silent cerebral infarcts, 698 historical perspective, 714–715 bone marrow, 6–7 stroke, 697 iron balance, liver iron, 715–716 liver, 6–7 TCD long-term effects on survival, 716 signalling pathways, 14–16 c-kit/SF signalling, 16 other long-term effects on morbidity, 717 BMP-4, 16 clinical applications, developmental serum ferritin, 716 c-kit/SF signalling, 16 hematopoiesis, 18 sickle cell disease, 720–721 hedgehog signalling, 15 coagulation, spleen, intravascular hemolysis, thalassemia intermedia, 721 TGF-␤ superfamily, 14–16 209–211 tolerability, 717–719 VEFG/Flk-1 axis, 16

CO2 binding, HbF, 120 auditory toxicity, 718 visceral endoderm contact, 15 colonization theory, developmental delivery methods, 719–720 transcription factors, 16–17 hematopoiesis, 3, 6 general, 717 CBF, 17 colony forming units-erythroid (CFU-E), 29 growth, bone, 718 GATA-2, 16–17 common vs. lineage-specific globin gene infections, 718 Runx1 haploinsufficiency, 17 regulation, 51–52 injection site reactions, 717–718 SCL, 16 complete blood count (CBC), 664–668 miscellaneous effects, 718–719 differential phylogenetic footprints, human globin automated methods, 665 rinal toxicity, 718 genes, 51 cell heterogeneity measures, 666–667 thalassemia major, 719–720 distal enhancers, human globin genes, 56–58 globin chain synthesis, 667–668 rescue therapy, 719 DLP. See dorsal lateral plate hemoglobin S polymerization, 668 standard therapy, 719 DNA diagnosis, 669–682 manual methods, 664 deoxygenation, KCC, 170 abnormal hemoglobins, 679–681 per cent HbS polymer, 668 deoxygenation-induced cation leak, 165–167 HbC, 679 rate of sickling, 668 deoxygenation-induced cation permeability, HbE, 679 reticulocyte count, 665–666 165–166 Hb O-Arab, 679 compound phenotypes, integrated measures, 651 developmental abnormalities, 296 HbS, 679 cooperative binding, 101 developmental hematopoiesis, 3–7 other variants, 679–681 CpG islands, human globin genes, 50 animal research, 3 Hb Lepore, 679 Cre-ERT. See Cre recombinase clinical application, 18 HPFH, 679 Cre-lox recombination system, 13 colonization theory, 3, 6 preimplantation diagnosis, 670–671 Cre recombinase (Cre-ERT), 14 current research, 3 ␣ thalassemia, 671–673 cutaneous leg ulceration, 212 developmental subsets, 14 deletion mutations by PCR diagnosis,671–672 ␤-93 cysteine, sickle cell hemoglobin (HbS), 110 embryonic hematopoietic hierarchy, 3, 7–14 diagnostic strategy, 671 cytochrome b5 deficiency, 608–610 amphibians, 13 point mutations by PCR diagnosis, 672–673 assays, 7 ␤ thalassemia, 673–679 deferasirox (ICL670, Exjade), 726–727 avian, 12–13 allele-specific oligonucleotide PCR, 673–674 chemistry, pharmacology, 726–727 Cre-ERT, 14 ␤-globin gene haplotype analysis, 678–679 effects on heart, 727 Cre-lox recombination system, 13 diagnostic strategy, 673 effects on iron balance, LIC, ferritin, 727 erythroid-myeloid-lymphoid multipotential gap-PCR, MLPA analysis, 677 historical perspective, 726 progenitors, 10 oligonucleotide microarrays, 674 unwanted effects/management, 727–729 erythroid-myeloid progenitors PCR methods, unknown mutations, 677–678 children, 728 BFU-E, 10 point mutations, other methods, 677 gastrointestinal disturbances, 728 CFU-C, 9–10 primer-specific amplification, 674–675 liver function, 728 CFU-S, 10 restriction enzyme PCR, 675–677 other effects, 728 erythropoiesis, 8 ␦␤-thalassemia, 679 recommended dosing regimen, 728–729 hematopoietic colonization, migration, 12 DNA sources, 669–671 renal effects, 728 hematopoietic lineages, direct precursors, 11 amniotic fluid, 669–670 skin rash, 728 HSCs, 10 blood, 669 deferiprone, 721–724, 765 ␤1 integrin, 13 chorionic villi, 670 chemistry, pharmacology, 721–722 lymphopoiesis, 9 fetal cells in maternal blood, 670 deferoximine, 725–726 mammals, 13–14 fetal DNA in maternal plasma, 670 clinical regimes assisted, 725 model, 11–12 dorsal lateral plate (DLP), 25

Index 817

double nucleation theory, HbS, 111 phosphoinositides, 163–164 hormonal influences, other, 33 dyshemoglobinemias. See carbon monoxide phospholipid asymmetry loss, 162–163 hypoxia sensing, 30 poisoning; methemoglobinemia; phospholipid asymmetry maintenance, 162 hypoxia stress, 34 sulfhemoglobinemia membrane loss, vesiculation, 161 ineffective erythropoiesis and, 34 membrane pathobiology, 158–159 macrophage-erythroblast attacher MAEA, 29 EKLF, 37–38, 72–73 membrane-associated iron, 159 mammalian, 26 chromatin structure remodelling, 72 oxidant stress, 158–159 hemoglobin tetramers, 26 post translational modifications, 72 membrane skeleton, 159–161 HPFH, 26 EKLF,CACCC box-binding proteins, 70–73 structure, function, 158 primitive cells, embryonic globins expression, ␤-globin gene expression, 70–71 erythrocyte proteins and lipids, 202–203 26 ␤-globin switching, 71 erythroid cell purification, 30 paladin, 34 electrophoresis, 658–659 erythroid cells, liquid culture, 29–30 primitive, 24–25 elevated HbF,medical conditions, 122–123 erythroid differentiation, 26–28 REDS signalling, 34 embryonic hematopoietic hierarchy, 3, 7–14 tissue culture models, 64 regulation, 30 amphibians, 13 erythroid maturation, gene expression, signal transduction molecules, knockout assays, 7 38–39 phenotypes, 32–33 avian, 12–13 erythroid-myeloid-lymphoid multipotential steady state, 33 ␤1 integrin, 13 progenitors, 10 stress erythropoiesis, 34–35 Cre-ERT, 14 erythroid progenitors, 29 transcription regulation, 35–36 Cre-lox recombination system, 13 BFU-E, 10, 29 turn over, production rates, 24 erythroid-myeloid-lymphoid multipotential CFU-C, 9–10 erythropoiesis, Xenopus laevis, 25 progenitors, 10 CFU-E, 29 DLP, 25 erythroid-myeloid progenitors CFU-S, 10 VBIs, 25 BFU-E, 10 erythroid transcription factors erythropoiesis, Zebrafish (Danio rerio), 24–25 CFU-C, 9–10 EKLF, 72–73 Epo production, 25 CFU-S, 10 chromatin structure remodelling, 72 morpholinos, morphants, 24 erythropoiesis, 8 post translational modifications, 72 sites, anatomical location, 25 hematopoietic colonization, migration, 12 EKLF,CACCC box-binding proteins, 70–73 erythropoietin (Epo), 25, 30–31 hematopoietic lineages, direct precursors, 11 ␤-globin gene expression, 70–71 ET-1. See targeting enothelin-1 hematopoietic stem cells, 10 ␤-globin switching, 71 ethical and counseling issues, 634–635

lymphopoiesis, 9 GATA-1, related proteins, 67–70 exceptionally high HbA2, 128 mammals, 13–14 GATA-1 interacting proteins, 68–69 excess iron distribution, 703–704 model, 11–12 GATA protein family, 67 exchange transfusion, 693 myelopoiesis, 8–9 human disease, 69–70, 75 expression regulation, polymorphisms, neonatal repopulating hematopoietic stem post translational modiﬁcations, 68 trans-acting regulatory elements, 642 cells, 10 structure-function analysis, 68 extracellular (EC) matrix adhesion molecules, T, B lymphoid lineage, mouse populations, 9 terminal erythroid maturation, platelet sickle red cell adhesion, sickle cell tyrosine c-kit receptor, 8 formation, 67 disease, 146 embryonic hemoglobins, thalassemias, transcription repression, 68 extraembryonic factors, developmental hemoglobinopathies, 130 general principles, 62–63 hematopoiesis EMP. See erythroblast-microphage protein NF-E2, related proteins, 73–74 allantois, 5 endothelial activation, sickle cell disease, 141–142 action mechanisms, 74 chorion, 5 endothelial adhesion molecules, sickle red cell Maf family, 73–74 placenta, 5 adhesion, 144–146 MARE elements, 73–74 yolk sac, 4–5 endothelial cell proliferation, angiogenesis, p45 family, 73 vasculature permeability, NO, 193 SCL, 70 facial appearance, ATRX syndrome, 305

endothelial response, sickle red cell adhesion, 146 erythroleukemia, HbA2, clinical aspects, 127 F cells, HbF, 121–122 epigenetic factors, developmental hematopoiesis, erythropoiesis, 8 fetal cells, HbF, 121 17–18 allantois, 25–26 fetal hemoglobin (HbF) induction PcG proteins, 17 cell adhesion, 34 background, 745 trxG, 17–18 chicken, 25–26 clinical efﬁcacy, 751 episodic transfusions, indications, 694–697 chromatin conformation, EKLF, 38 combination therapy, 751–752 epistatic interactions between protective during development, 24 DNA hypomethylating agents, 745–748 polymorphisms, 631 EKLF transcription factor, 37–38 histone deacetylases, inhibitors, 750 EpoR, cell-signalling, 31–32 EMP, 29 hydroxyurea, 748–750 erythroblastic islands, 33–34 Epo, 30–31 action mechanisms, 749–750 erythroblast-microphage protein (EMP), 29 EpoR, cell-signalling, 31–32 children, 748 erythrocyte dehydration inhibitors, 757–759 erythroblastic islands, 33–34 clinical use, 748–749 ␤-thalassemia, 759 erythroid cell puriﬁcation, 30 response to treatment prediction, 749 Gardos channel, 757–758 erythroid cells, liquid culture, 29–30 fetal hemoglobin synthesis, pharmacological K-C1 transport inhibition by magnesium, erythroid differentiation, 26–28 induction, 93–94 758–759 erythroid maturation, gene expression, 38–39 foamy virus vectors, 798 sickle cell disease, 757 erythroid progenitors, 29 F-reticulocytes, HbF, 122 erythrocyte membrane BFU-E, 29 ISCs, 161 CFU-E, 29 Gardos channel, 167–169, 757–758 membrane lipids, 161–164 GATA-1, 34, 36–37 gastro-intestinal abnormalities, ATRX syndrome, membrane lipid alterations, 162 hereditary anemias, 34 305

818 Index

GATA-1, related proteins, 34, 36, 67, 70 compound phenotypes, integrated measures, ␤-globin switching, EKLF,CACCC box-binding GATA protein family, 67 651 proteins, 71

human disease, 69–70, 75 genetic polymorphisms, disease severity ␦-globin chain synthesis, HbA2, 124–125 interacting proteins, 68–69 predictors, 645–651 ␦-globin gene mutations, 36–37 G-6-PD deﬁciency, 650–651 ␦-globin, 124–126 post translational modiﬁcations, 68 hyperbilirubinemia, gallstones, 650 in vitro transcription, 125

structure-function analysis, 68 leg ulcers, 649 ␦-globin gene evolution, HbA2, 124

terminal erythroid maturation, platelet osteonecrosis, 649 ␦-globin gene mutations, HbA2, formation, 67 painful episodes, 646 ε-globin gene, regulatory elements, 88–89 transcription repression, 68 priapism, 649 globin gene locus regulatory elements, 801 GATA-2 transcription, 16–17 pulmonary disease, 649–650 globin gene splicing, 90–91 G+C content, human globin genes, 50–51 renal disease, 649 globin gene structure, introns, human globin gene competition, molecular control, 92 stroke, 646–649 genes, 46–47 gene mutation, ␥-globin genes, 123–124 ␣ thalassemia, ␥-globin genes gene therapy ␤ thalassemia, 644–645 ␥-globin structure, HbF, 119 foamy virus vectors, 798 sickle cell disease, lentiviral vectors, 803–804 future prospects, 807 ␤ thalassemia, 640–641, 651–652 regulatory elements, 89 gene transfer into hematopoietic stem cells alpha-hemoglobin stabilizing protein role, globin lentiviral vectors, 801 (HSCs), 798–799 644–645 globin retroviral vector, 801 ␤-globin lentiviral vectors, murine model bone disease, 652 globin synthesis ratios, ␣ thalassemia, 266–267 correction, 802–803 cardiovascular disease, 652 G-6-PD deﬁciency, 650–651 globin gene locus regulatory elements, genetic polymorphisms, disease severity growth, bone changes, HbH disease, 279 801 predictors, 651–652 ␥-globin lentiviral vectors, 803–804 hyperbilirubinemia, gallstones, 651 haptoglobin, hemolysis, sickle cell disease and globin lentiviral vectors, 801 iron loading, 651–652 thalassemia, 204

globin retroviral vector, 801 genetic polymorphisms, disease severity HbA2, 662

HFV, 798 predictors, 645–652 HbA2, Lepore hemoglobins, 125 human ␤-thalassemia erythroid cells genetic services in developing countries, HbA2 (HbB2), 125–126

correction, 804 635 HbA2 level, developmental changes, 126 human HSC transduction gene transfer into hematopoietic stem cells HbAS, 629 biological obstacles, 799 (HSCs), 798–799 Hb Bart’s hydrops fetalis syndrome, 282 enrichment, in vivo selection strategies, G␥ gene 5 regulatory region, 642 clinical, autopsy findings, 283 800–801 ␣- HbH hydrops fetalis, 284–285 multiplicity of infection (MOI), 800 ␤-globins, genomic context, 50–51 hemoglobin composition, developmental new approaches, 799–800 ␤-like globins, 46–47 changes, 282–283 vector titer, 800 ␣/␤ globin mRNA, ␣ thalassemia, 266–267 long term survival, 285–286 immunodeficiency disorders, 804–805 ␣ globin cluster maternal complications, 283–284 insertional mutagenesis, 805–807 ␣+ chromosomes expression, 248–250 mRNA, globin synthesis, 282 lentiviral vectors, 795–798 normal structure, 241 causes, 281 murine retroviral vectors, 792–795 ␣0 thalassemia, 248–250 ␣0 thalassemia defects, 281–282 positioning effects, globin vector expression, protein products, 241–243 severe fetal anemia, 282 804 transcription, 241 prevention, management, 285–286 progress, problems, 804–807 variants red cell indices, hematologic findings, 282 SCD, mouse models, 801–802 non-thalassemia causing, 243–246 HBB enhancer, 55 ␤ thalassemia, mouse models, 801–802 chromosomal rearrangements, 243–244 Hb Beth Bologna, 593 viral vectors, deletions and insertions, ␣−complex, 245 Hb Beth Israel, 593 genetic counselling gene conversion, 245 Hb Bruxelles, 593 HbH disease, 281 globin genes variation, 244–245 HbC, 629, 679 ␣ thalassemia, 273–274 16p telomere, 244 HbC impact, animal models, 233 genetic modulation restriction site polymorphisms, 245–246 Hb Constant Spring mutation, ␣ thalassemia, ␤S-linked haplotypes molecular characteristics, variable number tandem of repeats 275–276 African and Indo-European, 638–640 (VNTRs), 246 Hb Costa Rica, 601 ␤-globin gene cluster haplotype on HbF effects, ␣ thalassemia causing, 246–248 HbE, 629–630, 679 640–641 ␣ globin structural variants interaction, ␣ HbF, 638, 641, 644, 661–662 ␤-globin (HBB) gene-like cluster, 638–640 thalassemia, 286–287 ␤ cluster sequence differences, 348 HbF, 638, 641, 644 ␤-globin gene ␤-globin gene silencer, 641–642 ␤-globin gene silencer, 641–642 EKLF,CACCC box-binding proteins, 70–71 ␦␤ thalassemia and HPFH deletions, 344–345 expression regulation, polymorphisms in haplotype on HbF effects, 640–641 G␥A␥ and ␦␤ competition, 344 trans-acting regulatory elements, 642 regulatory elements, 89–90 newly apposed enhancer sequences, 344–345 G␥ gene 5 regulatory region, 642 silencer, 641–642 regulatory regions loss, 344 LCR and HbF, 641 ␤-globin gene-like cluster, 638–640 expression regulation, polymorphisms in sickle cell disease phenotype, ␤-globin gene ␤-globin gene silencer, 641–642 trans-acting regulatory elements, 642 cluster haplotype effects, 643–644 ␤-globin lentiviral vectors, murine model G␥ gene 5 regulatory region, 642 HbH disease, 652 correction, 802–803 hemoglobin switching, 121

hemoglobin A2, 645 ␤-globin locus control region (LCR), 90 LCR and HbF, 641 sickle cell anemia, 645 ␤ globin structural variants interaction, ␣ sickle cell disease phenotype, ␤-globin gene bacteremia, 649 thalassemia, 287–288 cluster haplotype effects, 643–644

Index 819

HbF-containing erythrocytes, physiology, 120 ␤ thalassemia, 774–775 hemoglobin modifiers, 755–757 HbF control, adult, 92–93 first cases, 774 ␤-thalassemia, 756–757 HbF levels modulation, 120–121 Pesaro experience, 774–775 sickle cell disease, 755–756 HbF-Sardinia, HbF, 124 donor cells, alternate sources, 786–787 hemoglobinopathies, clinical evaluation, 668–669 HBG1 enhancer, human globin genes, 55 HLA-nonidentical related donor transplant, hemoglobin-oxygen affinity, tissue oxygen levels, HbG-Philadelphia, 601–602 777 NO, 189–190 HbH disease, 276, 652 matched unrelated donors, 777 hemoglobin Porto Alegre, 602 blood transfusion, 278–279 other transplant centers, 776 hemoglobins clinical features, 278–280 sickle cell disease, 780–787 abnormal, 679–681 blood transfusion, 278–279 current results, 780–784 HbC, 679 growth, bone changes, 279 donor hematopoiesis effect, sickle HbE, 679 hepatosplenomegaly, jaundice, 279 vasoocclusion, 784 Hb O-Arab, 679 iron status, 279–280 growth, development after, 785–786 HbS, 679 pregnancy, 279 non-myeloablative, 783–784 other variants, 679–681 presentation, 278 stable donor-host chimerism, 782–783 hyperunstable, 597 rare complications, 280 thalassemia patient, bone marrow unstable, 593–597 severe anemia episodes, 278 transplantation, 777–778 clinical aspects, 596–597 deletional, non-deletional, 277 effect, 778–780 Hb Koln,¨ 597 genetic counselling, 281 endocrine dysfunction, 780 Hb Zurich,¨ 597 genotype, 277 hepatitis, 779–780 miscellaneous, 597 phenotype relationship, 280 iron overload, 779 diagnosis, 596 geographic distribution, 276 mixed chimeric state, 778 blood smear, Heinz body preparation, 596 ␣/␤ globin mRNA, 277 patient selection, 777–778 hemoglobin stability tests, 596 globin synthesis ratios, 277 risk classification, 777–778 mutation analysis, 596 growth, bone changes, 279 thalassemia recurrence, 778 variant hemoglobin detection, 596 hematologic findings, 277 thalassemia-related complications, 779 hyperunstable, 597 hemoglobin analysis, 277–278 transplant-related complications, 778–779 pathophysiology, 594–596 hepatosplenomegaly, jaundice, 279 hemoglobin treatment, 597 iron status, 279–280 functional properties, 662–663 hemoglobin switching, 121 pathophysiology, 276–277 normal function, 101–105 cellular control, 86–88 patient treatment, 280–281 cooperative binding, 101 developmental clock, 87–88 blood transfusion, 280 methemoglobin, 105 models, 86–87 complications, 281 MWC/Perutz model, 102–104 developmental, 86 splenectomy, 280 oxygen transport, 101–104 fetal hemoglobin synthesis, pharmacological pregnancy, 279 transport, other gases, 104–105 induction, 93–94 presentation, 278 structural aspects, 101 HbF, 121

rare complications, 280 hemoglobin A2, 645 molecular control, 88–90, 93

red cell indices, 277 hemoglobin A2 (HbA2), 124–129 ␤-globin gene, regulatory elements, 89–90 severe anemia episodes, 278 African Americans, 125–126 ␤-globin locus control region (LCR), 90 HbH hydrops fetalis, 284–285 ␦-globin chain synthesis, 124–125 ε-globin gene, regulatory elements, 88–89 HbI, 602–603 ␦-globin gene gene competition, 92 Hb Kenya, 341–342 ␦-globin, 124–126 ␥-globin gene, regulatory elements, 89 Hb Lepore, 341–343, 679 in vitro transcription, 125 globin gene splicing, 90–91 Hb O-Arab, 679 ␦-globin gene evolution, 124 HbF control, adult, 92–93 Hb Raleigh, 600 ␦-globin gene mutations, 125–126 short chain fatty acids, 93–94 HbS, 629, 679 functional aspects, 125 hemoglobins with altered oxygen affinity, HbS co-polymerization, 110–111 Lepore hemoglobins, 125 590–593 Hb Setif pseudosickling, hemoglobin hemoglobin composition, developmental high oxygen affinity variants, 590–592 oligomerization, 602 changes, Hb Bart’s hydrops fetalis ␤-globin chain variants, 591–592 HbS higher order aggregation, 106–108 syndrome, 282–283 diagnosis, 590–591 HbS polymer, 105–106 hemoglobin disorders distribution, 625–626 ␣-globin chain variants, 591 HbS polymerization, red blood cells, 113 hemoglobin disorders frequency, 625–626 low oxygen affinity variants, 592–593 HbS polymer melting, 112–113 hemoglobin F (HbF), 119–124 clinical features, 593 HbS polymer rheology, 108 cellular heterogeneity, 121–122 diagnosis, 592–593 HbS thermodynamics, 108–109 elevated HbF,medical conditions, 122–123 Hb Beth Bologna, 593 hedgehog signalling, 15 F cells, 121–122 Hb Beth Israel, 593 hematologic phenotype, ␤ globin variants, ␣ fetal cells, 121 Hb Bruxelles, 593 thalassemia, 288 F-reticulocytes, 122 pathophysiology, 592 hematopoietic colonization, migration, 12 functional properties, 119–120 hemoglobin Vicksburg, 601 hematopoietic lineages, direct precursors, gene mutation, ␥-globin genes, 122–123 hemolysis, sickle cell disease and thalassemia, 11 ␥-globin genes, ␥-globin structure, 119 201–204 hematopoietic stem cells (HSCs), 10 HbF-containing erythrocytes physiology, adherent immunoglobulin G (IgG), 204 adult blood system, 3 120 complement-mediated, 204 hematopoietic stem cell transplantation hemoglobin switching, 120–121 extravascular, clinical consequences, 204 alternative donors, 776–777 laboratory detection, 122 extravascular vs. intravascular, 201 alternative sources, 776–780 protein conformation, 119 haptoglobin, 204 reduced intensity implants, 776 hemoglobin G Coushatta, 600–601 hemoglobin clearance, 204–206

820 Index

hemolysis, sickle cell disease (cont.) phylogenetic footprints, 51 iron loading, 651–652 hemolytic anemia-associated clinical proximal enhancers, 55–56 iron overload, chelation therapy, 702–729 subphenotypes, 211–215 RP score, 52 chelating therapy objectives, 710–721 cutaneous leg ulceration, 212 sequence alignments, quantitative analysis, harmful iron species detoxification, 711 priapism, 211–212 52 iron balance, 710 pulmonary hypertension, 211–213 tissue, developmental specificity safe tissue iron concentrations maintenance, children, 214–215 upstream regulatory sequences, 53–55 710–711 diagnosis, 215–216 G+C content, 50–51 chelator design constraints, 713–714 patient prognosis, 213 globin gene structure, introns, 46–47 consequences, 704–706 treatment, 215–216 ␣-, ␤- globins, genomic context, 50–51 deferoximine, 714–721 stroke, 212 ␣-, ␤-like globins, 46–47 chemistry, pharmacology, 715 hemopexin, 204–205 HPFH, 50 efficacy, 715–717 intravascular, clinical consequences, 206–211 introns, 46–47 heart, 716–717 coagulation, spleen, 209–211 number, chromosomal localization, 46–47 historical perspective, 714–715 NO resistance, 206–209 pseudogenes, 48 iron balance, liver iron, 715–716 NOS substrate bioavailability, arginasemia splicing, 47 long-term effects on survival, 716 limitations, 209 human HSC transduction other long-term effects on morbidity, 717 ISCs, 201 biological obstacles, 799 serum ferritin, 716 mechanical fragility, 203–204 enrichment, in vivo selection strategies, sickle cell disease, 720–721 shear stress, 203–204 800–801 thalassemia intermedia, 721 oxidation of erythrocyte proteins, lipids, MOI, 800 tolerability, 717–719 202–203 new approaches, 799–800 auditory toxicity, 718 hemopexin, 204–205 vector titer, 800 delivery methods, 719–720 hepatosplenomegaly, jaundice, 279 hydroxyurea general, 717 hereditary anemias, 34 HbF induction, 748–750 growth, bone, 718 hereditary methemoglobinemia action mechanisms, 749–750 infections, 718 Hereditary Persistence of Fetal Hemoglobin children, 748 injection site reactions, 717–718 (HPFH), 26, 679 clinical use, 748–749 miscellaneous effects, 718–719 deletional, 341 response to treatment prediction, 749 rinal toxicity, 718 human globin genes, 50 sickle red cell adhesion, 146 thalassemia major, 719–720 unliked to ␤ globin cluster, 341 hyperbilirubinemia, gallstones, 650–651 thalassemia major, rescue therapy, 719 chromosome 2 linked, 348 hypercoagulation thalassemia major, standard therapy, 719 chromosome 6 linked, 347–348 sickle cell disease, 150 excess iron distribution, 703–704 chromosome 8 linked, 348 thalassemia, 151 future perspectives, 729 X-linked, 347 hypersplenism, 701–702 iron loading rates, 702–703 heterogeneous nucleation, HbS hyperunstable hemoglobins, 597 iron overload monitoring, 707–710 HFV. See human foamy virus hypoxia sensing, erythropoiesis, 30 clinical effects iron overload, 709

high HbA2, 127–129 hypoxia stress, erythropoiesis, 34 heart, 708–709 homogeneous nucleation, HbS, 111–112 hypoxic vasodilation, NO, 190–191 liver iron concentration, 707–708 homozygotes, ␤ chain abnormalities, ␣ other markers, 710 thalassemia, 288–289 immunodeficiency disorders, 804–805 serum ferritin use, limitations, 708 hormonal influences, erythropoiesis, 33 induced hemoglobinopathies, animal models, 232 tissue iron monitoring, other organ, 709 HPFH. See Hereditary Persistence of Fetal ineffective erythropoiesis, 34 urine iron excretion, 709–710 Hemoglobin insertional mutagenesis, 805–807 iron overload pathophysiology, 702–703 HPFH and ␦␤ thalassemia, 338–341 ␤1 integrin, 13 iron overload toxicity mechanisms, 704–705 classification, 338–340 interesting ␣-globin gene variants, with point iron pools available for chelation, 711–713 deletion mechanisms, 344 mutations extracellular iron, 711–712 deletions, 340 HbG-Philadelphia, 601–602 intracellular iron, 712–713 intracellular HbF distribution, 343–344 HbI, 602–603 oral chelation therapy, 721–729 HPLC, 660 Hb Setif pseudosickling, hemoglobin deferasirox, unwanted effects/management, HSCs. See hematopoietic stem cells oligomerization, 602 727–729 human ␤-thalassemia erythroid cells correction, hemoglobin Porto Alegre, 602 children, 728 804 interesting ␤-globin gene variants, with point gastrointestinal disturbances, 728 human foamy virus (HFV), 798 mutations, 600–601 liver function, 728 human globin genes Hb Costa Rica, 601 other effects, 728 chromosomal organization, detailed, 47–50 hemoglobin G Coushatta, 600–601 recommended dosing regimen, 728–729 CpG islands, 50 hemoglobin Vicksburg, 601 renal effects, 728 evolutionary insights, 51–58 intraembryonic facotrs, developmental skin rash, 728 basal promoters, 52–53 hematopoiesis, PAS/AGM, 5–6 deferasirox (ICL670, Exjade), 726–727 common vs. lineage-specific regulation, intravascular hemolysis, clinical consequences, chemistry, pharmacology, 726–727 51–52 206–211 effects on heart, 727 differential phylogenetic footprints, 51 coagulation, spleen, 209–211 effects on iron balance, LIC, ferritin, 727 distal enhancers, 56–58 NO resistance, 206–209 historical perspective, 726 HBB enhancer, 55 NOS substrate bioavailability, arginasemia deferiprone, 721–724 HBG1 enhancer, 55 limitations, 209 chemistry, pharmacology, 721–722 motivation, 51 introns, 46–47 deferoximine, 725–726

phastCons score, 52 iron deﬁciency, HbA2, clinical aspects, 126–127 deferoximine, clinical regimes assisted, 725

Index 821

deferoximine, effect on heart, 726 HbS, 679 lentiviral vectors, 795–798 deferoximine, effect on serum ferritin and other variants, 679–681 leukocyte adhesion, vasculature permeability, liver iron, 725 ␤ thalassemia, 673–679 195–196 deferoximine, heart, 726 allele-speciﬁc oligonucleotide PCR, leukocytes, vasoocclusion, 147 deferoximine, pharmacology, 725 673–674 LIC. See liver iron concentration deferoximine, serum ferritin and liver iron, ␤-globin gene haplotype analysis, 678–679 liver iron concentration (LIC), 707–708

725 diagnostic strategy, 673 low HbA2, 126 deferoximine, treatment safety, 726 gap-PCR, MLPA analysis, 677 lymphopoiesis, 9 efﬁcacy, 722–724 oligonucleotide microarrays, 674 heart, 723–724 PCR methods, unknown mutations, macrophage-erythroblast attacher, 29 iron excretion, balance, 722 677–678 Maf family, NF-E2, related proteins, 73–74

liver iron, 722–723 point mutations, other methods, 677 malaria, HbA2, 129 neutropenia, agranulocytosis, 724 primer-speciﬁc ampliﬁcation, 674–675 malaria hypothesis, 626–629, 632 recommended dosing, 724 restriction enzyme PCR, 675–677 mammals, 13–14 serum ferritin, 722 ␦␤-thalassemia, 679 MARE elements, NF-E2, related proteins, 73–74 unwanted effects, 724 Hb Lepore, 679 maternal complications, Hb Bart’s hydrops fetalis other transfusion dependent anemias, HPFH, 679 syndrome, 283–284 706–707 preimplantation diagnosis, 670–671 MDS. See myelodysplastic syndromes

sickle cell disease, 706 ␣ thalassemia, 671–673 megaloblastic anemias, HbA2, 129 thalassemia, 704–706 deletion mutations by PCR diagnosis, membrane-associated iron, 159 thalassemia major, 705–706 671–672 membrane lipids, 161–164 iron overload monitoring, 707–710 diagnostic strategy, 671 alterations, 162 clinical effects iron overload, 709 point mutations by PCR diagnosis, membrane lipid alterations, 162 heart, 708–709 672–673 phosphoinositides, 163–164 other markers, 710 DNA sources, 669–671 phospholipid asymmetry loss, 162–163 serum ferritin use, limitations, 708 amniotic ﬂuid, 669–670 phospholipid asymmetry maintenance, 162 tissue iron monitoring, other organ, 709 blood, 669 membrane loss, vesiculation, 161 urine iron excretion, 709–710 chorionic villi, 670 membrane pathobiology, 158–159 iron overload toxicity mechanisms, 704–705 fetal cells in maternal blood, 670 membrane-associated iron, 159 iron pools available for chelation, 711–713 fetal DNA in maternal plasma, 670 oxidant stress, 158–159 extracellular iron, 711–712 protein and cellular based methods, membrane skeleton, 159–161 intracellular iron, 712–713 658–664 mental retardation, ATR-16 syndrome, 296 iron status, HbH disease, 279–280 capillary electrophoresis, 660 mesoderm induction, developmental irreversibly sickled cells (ISCs), 161 capillary IEF, 660 hematopoiesis, 3–4 hemolysis, sickle cell disease and thalassemia, electrophoresis, 658–659 methemoglobin, 105

201 HbA2, 662 methemoglobinemia, 607–613 mechanical fragility, hemolyis, sickle cell HbF, 661–662 acquired, 610–611 disease and thalassemia, 203–204 hemoglobin, functional properties, 662–663 clinical features, 611 shear stress, hemolysis, sickle cell disease and hemoglobinopathies, clinical evaluation, diagnosis, 611–612 thalassemia, 203–204 668–669 hereditary, 608–610 ISC. See irreversibly sickled cells HPLC, 660 cytochrome b5 deﬁciency, 610 isoelectric focusing (IEF), 659–660 isoelectric focusing (IEF), 659–660 cytochrome b5 reductase deﬁciency, IVSs. See intervening sequences mass spectrometry, 660–661 608–609

oxygen saturation measurements, P50, type I cytochrome b5 reductase deﬁciency, jaundice, HbH disease, 279 662–663 609

juvenile chronic granulocytic leukemia, HbA2, red cell polymer formation detection, type II cytochrome b5 reductase deﬁciency, cliinical aspects, 127 solutions containing HbS, 663–664 609–610

CSAT, 663–664 methemoglobin production, 607 KCC. See KC1 cotransport plasma hemoglobin, 664 methemoglobin reduction, 607–608 KC1 cotransport (KCC), 169–172 solubility, 663 pathophysiology, 607–608 activation, 172 sample preservation, preparation, laboratory treatment, 612–613 cellular magnesium, 170–171 safety, 658 acquired methemoglobinemia, 613 deoxygenation, 170 thalassemias, clinical evaluation, 668–669 hereditary methemoglobinemia molecular basis, 171–172 red blood cell characterization, 664–669 methemoglobin production, 607 KC-1 transport, inhibition by magnesium, complete blood count (CBC), 664–668 methemoglobin reduction, 607–608 758–759 automated methods, 665 microarray analysis, transcription factors, knock-out/knock-in animal models, 225 cell heterogeneity measures, 666–667 64–65 Kruppel-like¨ transcription factor. See EKLF globin chain synthesis, 667–668 mild hemolytic anaemia, ␣ thalassemia, 275–276 transcription factor hemoglobin S polymerization, 668 minor hemoglobins, post-translational manual methods, 664 modiﬁcation laboratory methods per cent HbS polymer, 668 glycated hemoglobins, 130–132 antenatal diagnosis, 681–682 rate of sickling, 668 hemoglobin acetylation, 132–133 DNA diagnosis, 669–682 reticulocyte count, 665–666 M (met) hemoglobins, 597–599 abnormal hemoglobins, 679–681 separation techniques, 658 clinical aspects, diagnosis, 599 HbC, 679 technique choice, 682 pathophysiology, 597–599 HbE, 679 LCR and HbF, 641 iron oxidation, 598–599 Hb O-Arab, 679 leg ulcers, 649 spectral characteristics, 598–599

822 Index

MOI. See multiplicity of infection sickle red cell adhesion, sickle cell disease, 146 gastrointestinal disturbances, 728 molecular control, hemoglobin switching, 88–90, synthesis, 185–186 liver function, 728 93 tissue oxygen consumption, 190 other effects, 728 gene competition, 92 tissue oxygen levels, 189–190 recommended dosing regimen, 728–729 ␤-globin gene, regulatory elements, 89–90 vascular cell biology, 185–189 renal effects, 728 ␤-globin locus control region, 90 vascular tone, 191–192 skin rash, 728 ε-globin gene, regulatory elements, 88–89 vasculature homeostatic functions, 191–192 deferasirox (ICL670, Exjade), 726–727 globin gene splicing, 90–91 vasculature permeability chemistry, pharmacology, 726–727 ␥-globin gene, regulatory elements, 89 apoptosis, 193–194 effects on heart, 727 HbF control, adult, 92–93 endothelial cell proliferation, migration, effects on iron balance, LIC, ferritin, 727 molecular interactions, developmental angiogenesis, 193 historical perspective, 726 hematopoiesis, 14 leukocyte adhesion, 195–196 deferiprone, 721–724 morpholinos, morphants, 24 platelet adhesion, aggregation, 194–195 chemistry, pharmacology, 721–722 mRNA, globin synthesis, Hb Bart’s hydrops fetalis vascular smooth muscle cell proliferation, deferoximine, 725–726 syndrome, 282 194 clinical regimes assisted, 725 causes, 281 NO. See nitric oxide effect on heart, 726 severe fetal anemia, 282 NO bioavailability, vascular function, sickle cell effect on serum ferritin and liver iron, 725 ␣0 thalassemia defects, 281–282 disease, 148–149 heart, 726 multiplicity of infection (MOI) non-deletion ␦␤ thalassemia, 342 pharmacology, 725 human HSC transduction, 800 non-deletion HPHF serum ferritin and liver iron, 725 murine retroviral vectors, 792–795 ␥, ␤ genes competition, 347 treatment safety, 726 mutations, 589–590 ␥ genes promoters, mutations, 345 efficacy, 722–724 distribution, 589–590 non-NO vasodilators, vascular function, sickle cell heart, 723–724 rare, 599–604 disease, 148–149 iron excretion, balance, 722 interesting ␣-globin gene variants, point non-thalassemic fusion globins, 604 liver iron, 722–723 mutations NO resistance, intravascular hemolysis, 206–209 neutropenia, agranulocytosis, 724 HbG-Philadelphia, 601–602 NOS substrate bioavailability, arginasemia recommended dosing, 724 HbI, 602–603 limitations, intravascular hemolysis, 209 serum ferritin, 722 Hb Setif pseudosickling, hemoglobin novel compound heterozygous conditions, 604 unwanted effects, 724 oligomerization, 602 novel treatment approaches oral glutamine, 765 hemoglobin Porto Alegre, 602 anti-adhesion therapy, sickle cell disease, oral N-acetyl-cysteine, 765–766 interesting ␤-globin gene variants, point 759–761 organ pathology, sickle cell disease, animal mutations, 600–601 anti-inflammatory therapy, 762–763 models, 230–232 Hb Costa Rica, 601 ET-1, 762–763 brain, 232 hemoglobin G Coushatta, 600–601 sulfasalazine, nuclear factor (NF)-kB, 762 kidney, 230 hemoglobin Vicksburg, 601 anti-oxidant therapy targeting erythrocyte, liver, 231 non-thalassemic fusion globins, 604 765–766 lung, 232 N-terminal elongated globins, 600 deferiprone, 765 microcirculation, 230–231 post-translational modifications, 599–600 oral glutamine, 765 pulmonary hypertension, 232 acetylation, 600 oral N-acetyl-cysteine, 765–766 retina, 230 deamidation, 599 anti-oxidant therapy targeting vasculature, spleen, 232 Hb Raleigh, 600 763–765 osteonecrosis, 649 oxidation, 599–600 Apo A-I mimetics, 764 oxidation, 158–159, 166–167, 599–600 two mutation points in globin chain, 603 NO, 763–764 oxidative stress, sickle cell disease, 140–141

MWC/Perutz model, 102–104 statins, 764 oxygen saturation measurements, P50, 662–663 myelodysplastic syndromes (MDS), ATMDS, xanthine oxidase inhibitors, 764–765 oxygen tension, red cell rheology, sickle cell 312–317 anti-thrombotic therapy disease, 139–140 myelopoiesis, 8–9 sickle cell disease, 761–762 oxygen transport, 101–104 ␤-thalassemia, 761–762 natural selection, 626–629 erythrocyte dehydration inhibitors, 757–759 paladin, 34 neonatal repopulating HSCS, 10 Gardos channel, 757–758 para-aortic splanchnopleura (PAS), 6 neonates, ATRX syndrome, 304 K-C1 transport inhibition by magnesium, PAS. See para-aortic splanchnopleura NF-E2, related proteins, 73–74 758–759 PcG. See polycomb group proteins action mechanisms, 74 sickle cell disease, 757 p45 family, NF-E2, related proteins, 73 Maf family, 73–74 ␤-thalassemia, 759 phastCons score, 52 MARE elements, 73–74 hemoglobin modiﬁers, 755–757 phosphoinositides, 163–164 p45 family, 73 sickle cell disease, 755–756 phospholipid asymmetry loss, 162–163 nitric oxide (NO), 763–764 ␤-thalassemia, 756–757 phospholipid asymmetry maintenance, 162 biolochemistry, 185–189 N-terminal elongated globins, 600 phylogenetic footprints, 51 bioreactivity, 186 number, chromosomal localization, 46–47 physical interactions deﬁnition, distant DNA export from erythrocytes, 189 elements, 65–66

genetics, 185–189 O2 pressure, HbS, 109–110 placenta, 5 hemoglobin, nitrite reductase activity, 187–189 oral chelation therapy, 721–729 platelet adhesion, aggregation, vasculature hemoglobin bioreactivity, 187–189 deferasirox, unwanted effects/management, permeability, NO, 194–195 hemoglobin-oxygen afﬁnity, 189–190 727–729 polycomb group (PcG) proteins, 17 hypoxic vasodilation, 190–191 children, 728 polymerization effectors, HbS, 109–110

Index 823

polymerization kinetics, HbS, 111–112 thalassemia, 151 leg ulcers, 649 population dynamics, 633–635 treatment, 215–216 osteonecrosis, 649 population genetics, global health burden painful episodes, 646 control and management issues, 634–635 rare complications, HbH disease, 280 priapism, 649 epidemiological transition, 633–635 recombinant hemoglobins, 604 pulmonary disease, 649–650 epistatic interactions between protective recurrent acute chest pain, 698–699 renal disease, 649 polymorphisms, 631 recurrent painful episodes, 699 stroke, 646–649 ethical and counseling issues, 634–635 recurrent splenic sequestration, 699 sickle cell dehydration, pharmacology, 173 genetic services in developing countries, 635 red blood cell characterization, 664–669 sickle cell disease, 139–150, 692, 706, 757 HbAS, 629 CBC, 664–668 acute chest syndrome, 695 HbC, 629 automated methods, 665 acute splenic sequestration, 694 HbE, 629–630 cell heterogeneity measures, 666–667 acute stroke, 694–695 HbS, 629 globin chain synthesis, 667–668 blood product choice, 692–693 hemoglobin disorders distribution, 625–626 hemoglobin S polymerization, 668 clinical application, 694 hemoglobin disorders frequency, 625–626 manual methods, 664 episodic transfusions, indications, 694–697 malaria hypothesis, 626–629, 632 per cent HbS polymer, 668 exchange transfusion, 693 natural selection, 626–629 rate of sickling, 668 hematopoietic stem cell transplantation, population dynamics, 633–635 reticulocyte count, 665–666 780–787 severe forms of hemoglobinopathy red cell indices current results, 780–784 ␣ thalassemia, 630 hematologic ﬁndings donor hematopoiesis effect, sickle ␤ thalassemia, 630–631 Hb Bart’s hydrops fetalis syndrome, 282 vasoocclusion, 784 positioning effects, globin vector expression, HbH disease, 277 growth, development after, 785–786 804 ␣ thalassemia, 267–270 non-myeloablative, 783–784 post translational modiﬁcations, 599–600 red cell polymer formation detection, solutions stable donor-host chimerism, 782–783 acetylation, 600 containing HbS, 663–664 hypercoagulability, 150

deamidation, 599 CSAT, 663–664 leukocytes, vasoocclusion, 147 EKLF, 72 plasma hemoglobin, 664 perioperative management, 695–696 GATA-1, related proteins, 68 solubility, 663 priapism, 696–697 Hb Raleigh, 600 red cell receptors, sickle red cell adhesion, red cell rheology, 139–140 oxidation, 599–600 143–144 oxygen tension, 139–140 pregnancy, 698 red cell rheology sickle red cell heterogeneity, 140 HbF, 122 sickle cell disease, 139–140 sickle erythrocyte adhesive interactions, HbH disease, 279 oxygen tension, 139–140 pathophysiology, 146 ␣ thalassemia, 274–275 sickle red cell heterogeneity, 140 sickle red cell adhesion, 142 priapism, 211–212, 649, 696–697 thalassemia, 150–151 endothelial response, 146 primitive cells, embryonic globins expression, 26 vascular tone response, 147–148 mechanics, 142–146 primitive erythropoiesis, 24–25 REDS signalling, 34 adhesive bridging proteins, 144

protein and cellular based methods, 658–664 reduced HbA2, post-translational causes, HbA2, assay systems, 142 capillary electrophoresis, 660 clinical aspects, 126 endothelial adhesion molecules, 144–146 capillary IEF, 660 Regulatory Potential (RP) score, 52 extracellular matrix adhesion molecules, electrophoresis, 658–659 renal disease, 649 146

HbA2, 662 RP score. See Regulatory Potential score hydroxyurea, 146 HbF, 661–662 Runx1 haploinsufﬁciency, 17 NO, 146 hemoglobin, functional properties, 662–663 red cell receptors, 143–144 hemoglobinopathies, clinical evaluation, sample preservation, preparation, laboratory simple transfusion, 693 668–669 safety, 658 transfusion methods, 693 HPLC, 660 SCL. See stem cell leukemia transient aplastic episode, 694 isoelectric focusing, 659–660 SCL transcription, 16 vascular biology factors, 140–142 mass spectrometry, 660–661 secondary territories, developmental endothelial activation, 141–142

oxygen saturation measurements, P50, 662–663 hematopoiesis oxidative stress, 140–141 red cell polymer formation detection, solutions bone marrow, 6–7 vascular function, 147–150 containing HbS, 663–664 liver, 6–7 NO bioavailability, 148–149

CSAT, 663–664 separation techniques, 658 non-NO vasodilators, 148–149 plasma hemoglobin, 664 severe anemia episodes, HbH disease, 278 red cell rheology, vascular tone response, solubility, 663 severe forms of hemoglobinopathy 147–148 sample preservation, preparation, laboratory SF. See steel factor vascular reactivity, 148–149 safety, 658 short chain fatty acids, hemoglobin switching, vasoconstrictors, altered vascular responses, thalassemias, clinical evaluation, 668–669 93–94 149–150 protein conformation, HbF, 119 sickle cell anemia, 645 vasoocclusive pain episode, 696 proximal enhancers, human globin genes, 55–56 bacteremia, 649 sickle cell disease models pseudogenes, human globin genes, 48 compound phenotypes, integrated measures, animal models, transgenic mice, 227–232, pulmonary disease, 649–650 651 801–802 pulmonary hypertension, 211–213, 698–699 genetic polymorphisms, disease severity erythrocytes, 229 children, 214–215 predictors, 645–651 sickle transgenic mice, 227–229 diagnosis, 215–216 G-6-PD deﬁciency, 650–651 organ pathology, animal models, transgenic patient prognosis, 213 hyperbilirubinemia, gallstones, 650 mice, 230–232

824 Index

sickle cell disease models (cont.) simple transfusion, 693 in-frame deletions, 252–255 brain, 232 skeletal abnormalities, ATRX syndrome, 305 mRNA translation initiation, 254–255 kidney, 230 sodium/hydrogen exchange, 165–167 nonsense mutations, 252–255 liver, 231 sodium permeability, cell sodium, 167 poly(A) addition signal, 252–254 lung, 232 sodium-potassium ATPase, 165–167 sickle cell disease microcirculation, 230–231 spleen, intravascular hemolysis, 209–211 ␤ thalassemia, 644–645 pulmonary hypertension, 232 splicing, human globin genes, 47 unstable ␤ chain variants, 255–256 retina, 230 statins, 764 unusual types spleen, 232 steel factor (SF), 16 ATMDS, 312–317 transgenic mice, 230–232 stem cell leukemia (SCL), 70 ATRX mutations in, 315–316 brain, 232 stress, oxidation, 158–159, 166–167 clinical features, 313 kidney, 230 stress erythropoiesis, 34–35 drug therapies, 316 liver, 231 stroke, 212, 646–649, 694–695, 697 ␣-to␤-globin chain synthesis ratio, 313 lung, 232 structural globin variants interaction, ␣ ␣-to␤-globin mRNA ratio, 313 microcirculation, 230–231 thalassemia, 286 hemoglobin analysis, 314–315 pulmonary hypertension, 232 structure-function analysis, GATA-1, related MDS pathobiology, 316 retina, 230 proteins, 68 molecular, cellular basis, 315 spleen, 232 sulfasalazine, nuclear factor (NF)-kB, 762 red cell indices, hematologic findings, sickle cell disease phenotype, ␤-globin gene sulfhemoglobinemia, 616–617 313–314 cluster haplotype effects, 643–644 clinical presentation, diagnosis, treatment, sex imbalance, 316 sickle cell hemoglobin (HbS), 105–113 616–617 summary, 316–317 ␤−93 cysteine, 110 definition, pathogenesis, 616 ATR-16 syndrome, 296–304 double nucleation theory, 111 chromosomal imbalance, 301–303 HbS co-polymerization, 110–111 T, B lymphoid lineage, mouse populations, 9 genetic abnormalities definition, 299–301 HbS higher order aggregation, 106–108 targeted mutagenesis, transcription factors, mental retardation, 296 HbS polymer, 105–106 66–67 summary, 303–304 HbS polymerization, red blood cells, 113 targeting enothelin-1 (ET-1), 762–763 ATRX syndrome, 304–311 HbS polymer melting, 112–113 TCD. See abnormal transcranial Doppler associated phenotype, 308 HbS polymer rheology, 108 ultrasonography ATMDS, 315–316 HbS thermodynamics, 108–109 terminal erythroid maturation, platelet formation ATRX, normal functional role, 310–311 heterogeneous nucleation, 112 GATA-1, related proteins, 67 ATRX gene, protein product, 307–308 homogeneous nucleation, 111–112 TGF-␤ superfamily, 14–16 cardiac abnormalities, 305 o O2 pressure, 109–110 ␣ thalassemia, 248–250 clinical findings, 304–305 polymerization effectors, 109–110 ␣1globin gene deletion, ␣2 globin gene disease gene identification, 306–307 polymerization kinetics, 111–112 inactivation, 250–251 facial appearance, 305 sickle cell volume regulation pathology, ␣2globin gene deletion, ␣1 globin promoter, 250 gastro-intestinal abnormalities, 305 multi-track model, 172–174 ␣ thalassemia, 630, 671–673 head circumference, brain size, 304–305 cation transport deletion mutations by PCR diagnosis, 671–672 hematologic findings, 305–306 other hemoglobinopathies, 174 diagnostic strategy, 671 mutations, functional consequences, 311 thalassemia, 174 ζ -globin regulatory element deletions, 251–252 neonates, 304

sickle cell dehydration, pharmacology, 173 HbA2 clinical aspects, 127 phenotype relationship, 308–309 sickle erythrocyte adhesive interactions, molecular diagnosis, 256–257 skeletal abnormalities, 305 pathophysiology, 146 new transcription promoter, mutation, 256 subject behavior, 305 sickle red cell adhesion, sickle cell disease, non-deletion types, 252 summary, 311 142 physiology/clinical features, 266 urogenital abnormalities, 305 endothelial response, 146 ␣/␤ globin mRNA, 266–267 X-linked condition, 306 mechanics, 142–146 ␣ globin structural variants interaction, developmental abnormalities, 296 adhesive bridging proteins, 144 286–287 ␤ thalassemia, 630–631, 640–641, 651–652, assay systems, 142 ␤ globin structural variants interaction, 673–679, 759 endothelial adhesion molecules, 144–146 287–288 allele-speciﬁc oligonucleotide PCR, 673–674 extracellular matrix adhesion molecules, globin synthesis ratios, 266–267 alpha-hemoglobin stabilizing protein role, 146 Hb Constant Spring mutation, 275–276 644–645 hydroxyurea, 146 hematologic ﬁndings, 267–270 bone disease, 652 NO, 146 hematologic phenotype, ␤ globin variants, cardiovascular disease, 652 red cell receptors, 143–144 288 diagnostic strategy, 673 sickle red cell heterogeneity, 140 hemoglobin analysis, 270–273 gap-PCR, MLPA analysis, 677 signalling pathways, developmental homozygotes, ␤ chain abnormalities, 288–289 genetic polymorphisms, disease severity hematopoiesis, 14–16 management, genetic counselling, 273–274 predictors, 651–652 BMP-4, 16 mild hemolytic anaemia, 275–276 ␤-globin gene haplotype analysis, 678–679 c-kit/SF signalling, 16 pregnancy, 274–275 hyperbilirubinemia, gallstones, 651 hedgehog signalling, 15 red cell indices, 267–270 iron loading, 651–652 TGF-␤ superfamily, 14–16 secondary effects, 266 molecular basis VEFG/Flk-1 axis, 16 structural globin variants interaction, 286 deletions restricted to ␤ globin gene, 331 visceral endoderm contact, 15 point mutations by PCR diagnosis, 672–673 dominantly inherited, 323, 332 signal transduction molecules, knockout RNA splicing, mutations, 252–255 ␤-globin chain reduction, 323 phenotypes, 32–33 chain termination mutants, 255–256 missense mutations, 332–335 silent cerebral infarcts, 698 frameshifts, 252–255 dominant pathophysiology, 336

Index 825

elongated/truncated variants, abnormal hypercoagulation, 151 transcription repression, GATA-1, related proteins, carboxy terminal ends, 335–336 red cell rheology, 150–151 68 intact codons, deletion or insertion, 335 vascular pathobiology, 151 transfusion methods, 693 nonsense mediated decay, 336 cardiac, arterial abnormalities, 151 transfusion therapy nonsense mutation, 335 pulmonary hypertension, 151 chronic transfusion therapy indications, premature termination, 335 thalassemic mice, 225–227. See also animal 697–699 mutations models, transgenic mice abnormal transcranial Doppler abnormal posttranscriptional ␣ thalassemia-myelodysplastic syndromes ultrasonography (TCD) modification, 330 (ATMDS), 312–317 other proposed indications, 699 premature translation termination, 330 ATRX mutations in, 315–316 pregnancy, 698 mutations, RNA processing, 328–330 clinical features, 313 pulmonary hypertension, 698–699 alternative splice sites, exons, 330 drug therapies, 316 recurrent acute chest pain, 698–699 initiation codon, 330–331 ␣-to␤-globin chain synthesis ratio, 313 recurrent painful episodes, 699 splice site consensus sequence, 328 ␣-to␤-globin mRNA ratio, 313 recurrent splenic sequestration, 699 splice site junction, 328 hemoglobin analysis, 314–315 silent cerebral infarcts, 698 non deletion forms, 323 MDS pathobiology, 316 stroke, 697 nonsense mutation, 335 molecular, cellular basis, 315 complications, 699–702 phenotype severity, 323 red cell indices, hematologic findings, alloimmunization, 700–701 transcriptional mutants, 328 313–314 sickle cell disease, 700–701 unusual causes, 337–338 sex imbalance, 316 thalassemia, 700 ␤ globin gene, somatic deletion, 337–338 summary, 316–317 encephalopathy, 702 trans-acting mutations, 337 tissue, developmental specificity hypersplenism, 701–702 transposable element insertion, 337 tissue oxygen consumption, NO, 190 hypertension, 702 variants, 336–337 tissue oxygen levels, NO, hemoglobin-oxygen transfusion-transmitted infections, 701

normal HbA2, 336–337 afﬁnity, 189–190 other approaches, 699 silent ␤, 337 transcription factors other hemoglobinopathies, 699

unusually high HbA2, 337 developmental hematopoiesis, 16–17 sickle cell disease, 692 mouse models, 801–802 CBF, 17 acute chest syndrome, 695 oligonucleotide microarrays, 674 GATA-2, 16–17 acute splenic sequestration, 694 PCR methods, unknown mutations, 677–678 Runx1 haploinsufficiency, 17 acute stroke, 694–695 point mutations, other methods, 677 SCL, 16 blood product choice, 692–693 primer-specific amplification, 674–675 erythroid clinical application, 694 restriction enzyme PCR, 675–677 EKLF, 72–73 episodic transfusions, indications, 694–697 ␦␤ thalassemia, 679 chromatin structure remodelling, 72 exchange transfusion, 693 HPFH deletions, 344–345 post translational modifications, 72 perioperative management, 695–696 G␥A␥ and ␦␤ competition, 344 EKLF,CACCC box-binding proteins, priapism, 696–697 newly apposed enhancer sequences, 344–345 70–73 simple transfusion, 693 regulatory regions loss, 344 ␤-globin gene expression, 70–71 transfusion methods, 693

␦ thalassemia, HbA2 clinical aspects, 127 ␤-globin switching, 71 transient aplastic episode, 694 ε␥␦␤ thalassemia, 338 GATA-1, related proteins, 67–70 vasoocclusive pain episode, 696 G␥(A␥␦␤)␥ thalassemia, 342–343 GATA-1 interacting proteins, 68–69 thalassemia major (Cooley’s anemia) ␥ thalassemia, HbF, 124 GATA protein family, 67 beginning, 690–691 thalassemia major (Cooley’s anemia), 705–706 human disease, 69–70, 75 blood product choice, 690 beginning, 690–691 post translational modifications, 68 frequency, amount, 691 blood product choice, 690 structure-function analysis, 68 hemoglobin level frequency, amount, 691 terminal erythroid maturation, platelet blood requirements, 689–690 hemoglobin level formation, 67 physiological parameters, 689 blood requirements, 689–690 transcription repression, 68 partial exchange transfusion, 691–692 physiological parameters, 689 general principles, 62–63 thalassemia major, 689 partial exchange transfusion, 691–692 NF-E2, related proteins, 73–74 transfusion programs, 689 thalassemia major, 689 action mechanisms, 74 young blood cells, 691 transfusion programs, 689 Maf family, 73–74 transfusion-transmitted infections, 701 young blood cells, 691 MARE elements, 73–74 transient aplastic episode, 694 thalassemia patient, bone marrow transplantation p45 family, 73 transport, other gases, hemoglobin, normal effect, 778–780 SCL, 70 function, 104–105 endocrine dysfunction, 780 experimental approaches, 63–67 trithorax group (trxG), 17–18 hepatitis, 779–780 biochemical purification, 63–64 trxG. See trithorax group iron overload, 779 ChIP analysis, 64–65 two mutation points in globin chain, 603 mixed chimeric state, 778 chromatin immunoprecipitation, 64 type I cytochrome b5 reductase deficiency, 609 patient selection, 777–778 erythroid differentiation, tissue culture type II cytochrome b5 reductase deficiency, risk classification, 777–778 models, 64 609–610 thalassemia recurrence, 778 microarray analysis, 64–65 tyrosine c-kit receptor, 8 thalassemia-related complications, 779 physical interactions definition, distant DNA transplant-related complications, 778–779 elements, 65–66 unstable hemoglobins. See hemoglobins, unstable thalassemias, 150–151 targeted mutagenesis, 66–67 upstream regulatory sequences, human globin clinical evaluation, 668–669 general principles, 62–63 genes, 53–55 embryonic hemoglobins, 130 transcription regulation, erythropoiesis, 35–36 urogenital abnormalities, ATRX syndrome, 305

826 Index

vascular biology factors, sickle cell disease, vascular reactivity, sickle cell disease, 148–149 VBIs. See ventral blood islands 140–142 vascular smooth muscle cell proliferation, 194 VEFG/Flk-1 axis, 16 endothelial activation, 141–142 vasculature permeability, NO ventral blood islands (VBIs), 25 oxidative stress, 140–141 apoptosis, 193–194 viral vectors vascular function, sickle cell disease, 147–150 endothelial cell proliferation, migration, visceral endoderm contact, 15 NO bioavailability, 148–149 angiogenesis, 193 non-NO vasodilators, 148–149 leukocyte adhesion, 195–196 xanthine oxidase inhibitors, 764–765 red cell rheology, vascular tone response, platelet adhesion, aggregation, 194–195 x-linked condition, ATRX syndrome, 306 147–148 vascular smooth muscle cell proliferation, vascular reactivity, 148–149 194 yolk sac, 4–5 vasoconstrictors, altered vascular responses, vasoconstrictors, altered vascular responses,

149–150 149–150 zidovudine-treated patients, HbA2, clinical vascular pathobiology, thalassemia, 151 vasoocclusive pain episode, 696 aspects, 129