Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-78c5997874-mlc7c Total loading time: 0 Render date: 2024-11-06T08:18:31.507Z Has data issue: false hasContentIssue false

4 - Disorders of hemoglobin synthesis

Thalassemias and structural hemoglobinopathies

from Section 1 - General and non-neoplastic hematopathology

Published online by Cambridge University Press:  03 May 2011

By
Alexander Kratz  and
Jeffrey Jhang
Edited by
Maria A. Proytcheva
Alexander Kratz
Affiliation:
Columbia University College of Physicians and Surgeons
Jeffrey Jhang
Affiliation:
Columbia University Medical Center
Maria A. Proytcheva
Affiliation:
Northwestern University Medical School, Illinois
Get access

Summary

Normal hemoglobins

Structure and function of hemoglobin

Hemoglobin consists of two alpha-like and two beta-like globin chains which combine to form a tetramer. The globin tetramer is hydrophilic on its surface, making the molecule water soluble. The center is hydrophobic, stabilizing the heme ring and the iron molecule in the ferrous state (Fe2+). Located in the interior of each globin chain is a heme ring with an iron molecule in the center. It is in the heme ring that oxygen binding and release take place. In addition to oxygen transport, hemoglobin also plays a minor role in the transport of carbon dioxide, and as a scavenger of nitric oxide (NO).

As the partial pressure of oxygen is increased, hemoglobin becomes saturated with oxygen. The partial pressure at which 50% of hemoglobin is saturated is called the p50. Normal subjects have a p50 between 23 and 27 mmHg. Binding of an oxygen molecule in one heme changes the tetrameric structure so that additional oxygen molecules are bound with greater ease; this property of hemoglobin is called cooperativity, and is dependent on interactions between the globin chains (“heme–heme interaction”). The oxygen dissociation curve for hemoglobin A is sigmoid shaped because of this cooperativity (Fig. 4.1) [1, 2]. The sigmoid shape reflects how oxygen binding is favored at high oxygen tensions (lungs) and is rapidly released at low oxygen tensions (tissues).

Type
Chapter
Information
Diagnostic Pediatric Hematopathology , pp. 57 - 74
Publisher: Cambridge University Press
Print publication year: 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Hsia, CC. Respiratory function of hemoglobin. New England Journal of Medicine. 1998;338:239–247.CrossRefGoogle ScholarPubMed
Adair, GS. The hemoglobin system. The Journal of Biological Chemistry. 1925;63:529–545.Google Scholar
Hardison, R. Hemoglobins from bacteria to man: evolution of different patterns of gene expression. The Journal of Experimental Biology. 1998;201:1099–1117.Google Scholar
Wood, WG. Haemoglobin synthesis during human fetal development. British Medical Bulletin. 1976;32:282–287.CrossRefGoogle ScholarPubMed
Goh, SH, Lee, YT, Bhanu, NV, et al. A newly discovered human alpha-globin gene. Blood. 2005;106:1466–1472.CrossRefGoogle ScholarPubMed
Colombo, B, Kim, B, Atencio, RP, Molina, C, Terrenato, L. The pattern of fetal haemoglobin disappearance after birth. British Journal of Haematology. 1976;32:79–87.CrossRefGoogle ScholarPubMed
Giardine, B, Baal, S, Kaimakis, P, et al. HbVar database of human hemoglobin variants and thalassemia mutations: 2007 update. Human Mutation. 2007;28:206.CrossRefGoogle ScholarPubMed
,WHO. Guidelines for the Control of Haemoglobin Disorders: Report of the Sixth Annual Meeting of the WHO Working Group on Haemoglobinopathies, Cagliari, Sardinia, 8–9 April 1989. Geneva: WHO; 1994.Google Scholar
,WHO. Community Approaches to the Control of Hereditary Diseases: Report of a WHO Advisory Group. Geneva: WHO; 1989.Google Scholar
Ashley-Koch, A, Yang, Q, Olney, RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. American Journal of Epidemiology. 2000;151:839–845.CrossRefGoogle ScholarPubMed
Bunn, HF. Pathogenesis and treatment of sickle cell disease. New England Journal of Medicine. 1997;337:762–769.CrossRefGoogle ScholarPubMed
Weatherall, DJ, Clegg, JB. Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization. 2001;79:704–712.Google Scholar
,ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy. Obstetrics and Gynecology. 2007;109:229–237.CrossRefGoogle Scholar
Angastiniotis, MA, Hadjiminas, MG. Prevention of thalassaemia in Cyprus. Lancet. 1981;1:369–371.CrossRefGoogle ScholarPubMed
Cao, A, Furbetta, M, Galanello, R, et al. Prevention of homozygous beta-thalassemia by carrier screening and prenatal diagnosis in Sardinia. American Journal of Human Genetics. 1981;33:592–605.Google ScholarPubMed
Vichinsky, E, Hurst, D, Earles, A, Kleman, K, Lubin, B. Newborn screening for sickle cell disease: effect on mortality. Pediatrics. 1988;81:749–755.Google ScholarPubMed
Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RR (eds.). Disorders of Hemoglobin. Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press; 2001, 1268 pp.
Weatherall, DJ, Clegg, JB. The Thalassemia Syndromes. Oxford: Blackwell Science; 2001, 846 pp.CrossRefGoogle Scholar
Piperno, A, Mariani, R, Arosio, C, et al. Haemochromatosis in patients with beta-thalassaemia trait. British Journal of Haematology. 2000;111:908–914.Google ScholarPubMed
Villard, L, Fontes, M. Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032). European Journal of Human Genetics: EJHG. 2002;10:223–225.CrossRefGoogle Scholar
Rund, D, Rachmilewitz, E. Beta-thalassemia. New England Journal of Medicine. 2005;353:1135–1146.CrossRefGoogle ScholarPubMed
Clarke, GM, Higgins, TN. Laboratory investigation of hemoglobinopathies and thalassemias: review and update. Clinical Chemistry. 2000;46:1284–1290.Google ScholarPubMed
Ohene-Frempong, K. Sickle cell diseases. In Rudolph, CD, Rudolph, AM, Hostetter, MK, Lister, G, Siegel, NJ, eds. Rudolph's Pediatrics. New York: McGraw-Hill; 2003, 1531–1539.Google Scholar
Brown, AK, Sleeper, , Miller, ST, et al. Reference values and hematologic changes from birth to 5 years in patients with sickle cell disease. Cooperative Study of Sickle Cell Disease. Archives of Pediatrics and Adolescent Medicine. 1994;148:796–804.CrossRefGoogle ScholarPubMed
Wethers, DL. Sickle cell disease in childhood: Part II. Diagnosis and treatment of major complications and recent advances in treatment. American Family Physician. 2000;62:1309–1314.Google ScholarPubMed
Wethers, DL. Sickle cell disease in childhood: Part I. Laboratory diagnosis, pathophysiology and health maintenance. American Family Physician. 2000;62:1013–1020, 1027–1028.Google ScholarPubMed
Joutovsky, A, Hadzi-Nesic, J, Nardi, MA. HPLC retention time as a diagnostic tool for hemoglobin variants and hemoglobinopathies: a study of 60000 samples in a clinical diagnostic laboratory. Clinical Chemistry. 2004;50:1736–1747.CrossRefGoogle Scholar
Masiello, D, Heeney, MM, Adewoye, AH, et al. Hemoglobin SE disease: a concise review. American Journal of Hematology. 2007;82:643–649.CrossRefGoogle ScholarPubMed
Schrier, SL, Bunyaratvej, A, Khuhapinant, A, et al. The unusual pathobiology of hemoglobin Constant Spring red blood cells. Blood. 1997;89:1762–1769.Google ScholarPubMed
Head, CE, Conroy, M, Jarvis, M, Phelan, L, Bain, BJ. Some observations on the measurement of haemoglobin A2 and S percentages by high performance liquid chromatography in the presence and absence of alpha thalassaemia. Journal of Clinical Pathology. 2004;57:276–280.CrossRefGoogle ScholarPubMed
Lafferty, JD, Crowther, MA, Ali, MA, Levine, M. The evaluation of various mathematical RBC indices and their efficacy in discriminating between thalassemic and non-thalassemic microcytosis. American Journal of Clinical Pathology. 1996;106: 201–205.CrossRefGoogle ScholarPubMed
d'Onofrio, G, Zini, G, Ricerca, BM, Mancini, S, Mango, G. Automated measurement of red blood cell microcytosis and hypochromia in iron deficiency and beta-thalassemia trait. Archives of Pathology and Laboratory Medicine. 1992;116:84–89.Google ScholarPubMed
Harris, N, Kunicka, J, Kratz, A. The ADVIA 2120 Hematology System: flow cytometry-based analysis of blood and body fluids in the routine hematology laboratory. Laboratory Hematology. 2005;11:47–61.CrossRefGoogle ScholarPubMed
Kotisaari, S, Romppanen, J, Penttila, I, Punnonen, K. The Advia 120 red blood cells and reticulocyte indices are useful in diagnosis of iron-deficiency anemia. European Journal of Haematology. 2002;68:150–156.CrossRefGoogle ScholarPubMed
Bain, BJ. Disorders of Red Cells and Platelets. Oxford: Blackwell Science; 2002, 241–337.Google Scholar
Bain, BJ. Sickle Cell Haemoglobin and its Interactions with other Variant Haemoglobins and with Thalassemias. Malden: Blackwell Publishing; 2006, 139–189.Google Scholar
General Haematology Task Force of the British Committee for Standards in Haematology. The laboratory diagnosis of haemoglobinopathies. British Journal of Haematology. 1998;101:783–792.
Louahabi, A, Philippe, M, Lali, S, Wallemacq, P, Maisin, D. Evaluation of a new Sebia kit for analysis of hemoglobin fractions and variants on the Capillarys system. Clinical Chemistry and Laboratory Medicine: CCLM/FESCC. 2006;44:340–345.CrossRefGoogle ScholarPubMed
Cotton, F, Lin, C, Fontaine, B, et al. Evaluation of a capillary electrophoresis method for routine determination of hemoglobins A2 and F. Clinical Chemistry. 1999;45:237–243.Google ScholarPubMed
Wild, BJ, Stephens, AD. The use of automated HPLC to detect and quantitate haemoglobins. Clinical and Laboratory Haematology. 1997;19:171–176.CrossRefGoogle ScholarPubMed
Campbell, M, Henthorn, JS, Davies, SC. Evaluation of cation-exchange HPLC compared with isoelectric focusing for neonatal hemoglobinopathy screening. Clinical Chemistry. 1999;45:969–975.Google ScholarPubMed
Fucharoen, S, Winichagoon, P, Wisedpanichkij, R, et al. Prenatal and postnatal diagnoses of thalassemias and hemoglobinopathies by HPLC. Clinical Chemistry. 1998;44:740–748.Google ScholarPubMed
Howanitz, PJ, Kozarski, TB, Howanitz, JH, Chauhan, YS. Spurious hemoglobin Barts caused by bilirubin: a common interference mimicking an uncommon hemoglobinopathy. American Journal of Clinical Pathology. 2006;125:608–614.CrossRefGoogle ScholarPubMed
Grey, V, Wilkinson, M, Phelan, L, Hughes, C, Bain, BJ. Inaccuracy of high-performance liquid chromatography estimation of haemoglobin F in the presence of increased haemoglobin A1c. International Journal of Laboratory Hematology. 2007;29:42–44.Google ScholarPubMed
Baine, RM, Brown, HG. Evaluation of a commercial kit for microchromatographic quantitation of hemoglobin A2 in the presence of hemoglobin S. Clinical Chemistry. 1981;27:1244–1247.Google ScholarPubMed
Chen, JC, Bigelow, N, Davis, BH. Proposed flow cytometric reference method for the determination of erythroid F-cell counts. Cytometry. 2000;42:239–246.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Davis, BH, Olsen, S, Bigelow, NC, Chen, JC. Detection of fetal red cells in fetomaternal hemorrhage using a fetal hemoglobin monoclonal antibody by flow cytometry. Transfusion. 1998;38:749–756.CrossRefGoogle ScholarPubMed
Scioscia, AL. Prenatal genetic diagnosis. In Creasy, RK, Resnik, R, eds. Maternal-Fetal Medicine. Philadelphia: WB Saunders; 1999, 40–62.Google Scholar
Nagel, RL. Hemoglobin Disorders: Molecular Methods and Protocols. New York: Springer-Verlag; 2003, 322 pp.CrossRefGoogle Scholar
Clark, BE, Thein, SL. Molecular diagnosis of haemoglobin disorders. Clinical and Laboratory Haematology. 2004;26:159–176.CrossRefGoogle ScholarPubMed
Patrinos, GP, Kollia, P, Papadakis, MN. Molecular diagnosis of inherited disorders: lessons from hemoglobinopathies. Human Mutation. 2005;26:399–412.CrossRefGoogle ScholarPubMed
Ristaldi, MS, Pirastu, M, Rosatelli, C, et al. Prenatal diagnosis of beta-thalassaemia in Mediterranean populations by dot blot analysis with DNA amplification and allele specific oligonucleotide probes. Prenatal Diagnosis. 1989;9:629–638.CrossRefGoogle ScholarPubMed
Newton, CR, Graham, A, Heptinstall, , et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Research. 1989;17:2503–2516.CrossRefGoogle ScholarPubMed
Fischel-Ghodsian, N, Hirsch, PC, Bohlman, MC. Rapid detection of the hemoglobin C mutation by allele-specific polymerase chain reaction. American Journal of Human Genetics. 1990;47:1023–1024.Google ScholarPubMed
Wu, DY, Ugozzoli, L, Pal, BK, Wallace, RB. Allele-specific enzymatic amplification of beta-globin genomic DNA for diagnosis of sickle cell anemia. Proceedings of the National Academy of Sciences of the United States of America. 1989;86:2757–2760.CrossRefGoogle ScholarPubMed
Eastman, JW, Wong, R, Liao, CL, Morales, DR. Automated HPLC screening of newborns for sickle cell anemia and other hemoglobinopathies. Clinical Chemistry. 1996;42:704–710.Google ScholarPubMed
,The Thalassaemia Working Party of the BCSH General Haematology Task Force. Guidelines for investigation of the alpha and beta thalassaemia traits. Journal of Clinical Pathology. 1994;47:289–295.CrossRefGoogle Scholar
Coleman, E, Inusa, B. Sickle cell anemia: targeting the role of fetal hemoglobin in therapy. Clinical Pediatrics. 2007;46:386–391.CrossRefGoogle ScholarPubMed
Honig, GR, Suarez, CR, Vida, LN, Lu, SJ, Liu, ET. Juvenile myelomonocytic leukemia (JMML) with the hematologic phenotype of severe beta thalassemia. American Journal of Hematology. 1998;58:67–71.3.0.CO;2-2>CrossRefGoogle ScholarPubMed
Passmore, SJ, Hann, IM, Stiller, CA, et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood. 1995;85:1742–1750.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×