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782 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 783

instances of de novo mutations without evidence of the variant in par- 6. Gormley M: The first “molecular disease”: A story of Linus Pauling, the intellectual
ents of an affected individual. Many of the 146 known unstable variants patron. Endeavour 31(2):71–77, 2007.
are found in a single individual or in a limited number of instances. 7. Haller JO, Berdon WE, Franke H: Sickle cell anemia: The legacy of the patient (Walter
Clement Noel), the interne (Ernest Irons), and the attending physician (James Herrick)
However, some unstable variants like Hb Koln (β98Val→Met) and Hb Zurich and the facts of its discovery. Pediatr Radiol 31(12):889–890, 2001.
(β67His→Arg) have been found in many populations around the world. 8. Serjeant GR: The emerging understanding of sickle cell disease. Br J Haematol 112(1):
3–18, 2001.
9. Williams VL: Pathways of innovation: A history of the first effective treatment for sickle
Laboratory Features cell anemia. Perspect Biol Med 47(4):552–563, 2004.
Patients with unstable Hb variants may have varying degrees of anemia. 10. Goldsmith JC, Bonham VL, Joiner CH, et al: Framing the research agenda for sickle
Generally, the anemia is mild and does not require therapeutic inter- cell trait: Building on the current understanding of clinical events and their potential
implications. Am J Hematol 87(3):340–346, 2012.
vention. However, exacerbation of anemia during exposure to oxidant 11. Serjeant GR, Serjeant BE, Forbes M, et al: Haemoglobin gene frequencies in the Jamai-
stress (such as infections and the use of oxidant drugs) is a common can population: A study in 100,000 newborns. Br J Haematol 64(2):253–262, 1986.
feature. Features of a hemolytic state (reticulocytosis, indirect hyper- 12. Hassell KL: Population estimates of sickle cell disease in the U.S. Am J Prev Med
38(4 Suppl):S512–S521, 2010.
bilirubinemia, elevated LDH, decreased or undetectable haptoglobin) 13. Okumura MJ, Campbell AD, Nasr SZ, et al: Inpatient health care use among adult sur-
are present. Red cell morphology shows polychromasia, anisocytosis, vivors of chronic childhood illnesses in the United States. Arch Pediatr Adolesc Med
poikilocytosis, and occasionally basophilic stippling. A typical feature 160(10):1054–1060, 2006.
of this disorder is the presence of Heinz bodies, best visualized with 14. Kauf TL, Coates TD, Huazhi L, et al: The cost of health care for children and adults with
sickle cell disease. Am J Hematol 84(6):323–327, 2009.
supravital staining with brilliant cresyl blue as membrane attached 15. Kan YW, Dozy AM: Polymorphism of DNA sequence adjacent to human beta-glo-
inclusion bodies in red cells. Hb electrophoresis reveals the presence bin structural gene: Relationship to sickle mutation. Proc Natl Acad Sci U S A 75(11):
of an additional abnormal Hb band. The quantity of the variant Hb is 5631–5635, 1978.
variable and inversely proportional to the degree of instability of the 16. Nagel RL, Fabry ME, Pagnier J, et al: Hematologically and genetically distinct forms
of sickle cell anemia in Africa. The Senegal type and the Benin type. N Engl J Med
abnormal Hb (e.g., the more unstable the variant, the less the quantity). 312(14):880–884, 1985.
More accurate quantification can be achieved with cation exchange or 17. Pagnier J, Mears JG, Dunda-Belkhodja O, et al: Evidence for the multicentric origin of
reversed phase HPLC. The presence of an unstable variant in the hemo- the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci U S A 81(6):1771–1773,
1984.
lysate can be demonstrated by simple tests of stability. The most com- 18. Powars DR: Sickle cell anemia: Beta s-gene-cluster haplotypes as prognostic indicators
monly used tests are heat denaturation and isopropanol precipitation. of vital organ failure. Semin Hematol 28(3):202–208, 1991.
The heat denaturation test is more cumbersome and time consuming 19. Dykes GW, Crepeau RH, Edelstein SJ: Three-dimensional reconstruction of the 14-fila-
ment fibers of hemoglobin S. J Mol Biol 130(4):451–472, 1979.
and is seldom used in practice. The isopropanol precipitation test is a 20. Fronticelli C, Gold R: Conformational relevance of the beta6Glu replaced by Val muta-
simple screening test for unstable variants and involves the incubation tion in the beta subunits and in the beta(1–55) and beta(1–30) peptides of hemoglobin
of the hemolysate with a 17 percent solution of isopropanol; hemoly- S. J Biol Chem 251(16):4968–4972, 1976.
sates containing unstable Hb variants will form a precipitate, whereas a 21. Wishner BC, Ward KB, Lattman EE, et al: Crystal structure of sickle-cell deoxyhemo-
globin at 5 A resolution. J Mol Biol 98(1):179–194, 1975.
normal hemolysate will remain clear. 22. Ferrone FA, Hofrichter J, Eaton WA: Kinetics of sickle hemoglobin polymerization.
I. Studies using temperature-jump and laser photolysis techniques. J Mol Biol 183(4):
591–610, 1985.
HEMOGLOBINS WITH ALTERED 23. Ferrone FA, Hofrichter J, Eaton WA: Kinetics of sickle hemoglobin polymerization. II.
A double nucleation mechanism. J Mol Biol 183(4):611–631, 1985.
OXYGEN AFFINITY 24. Huang Z, Hearne L, Irby CE, et al: Kinetics of increased deformability of deoxygenated
sickle cells upon oxygenation. Biophys J 85(4):2374–2383, 2003.
M Hbs result from mutations around the heme pocket that disrupt the 25. Carragher B, Bluemke DA, Gabriel B, et al: Structural analysis of polymers of sickle cell
hydrophobic nature of this structure with resultant oxidation of the iron hemoglobin. I. Sickle hemoglobin fibers. J Mol Biol 199(2):315–331, 1988.
in the heme moiety from ferrous (Fe ) to ferric (Fe ) state and cause 26. Padlan EA, Love WE: Refined crystal structure of deoxyhemoglobin S. II. Molecular
3+
2+
interactions in the crystal. J Biol Chem 260(14):8280–8291, 1985.
methemoglobinemia (Chap. 50). Mutations in certain critical areas of 27. Vekilov PG: Sickle-cell haemoglobin polymerization: Is it the primary pathogenic event
the globin molecule alter the affinity of the globin for oxygen. In general, of sickle-cell anaemia? Br J Haematol 139(2):173–184, 2007.
mutations that stabilize the molecule in the T state lead to low O -affin- 28. Ferrone FA: Polymerization and sickle cell disease: A molecular view. Microcirculation
2
ity variants, which can clinically manifest as cyanosis or mild anemia. 11(2):115–128, 2004.
Mutations that stabilize the R state or destabilize the T state result in 29. Ballas SK, Mohandas N: Sickle red cell microrheology and sickle blood rheology. Micro-
circulation 11(2):209–225, 2004.
high O -affinity variants. These variants will cause secondary polycythe- 30. Eaton WA, Hofrichter J: Hemoglobin S gelation and sickle cell disease. Blood
2
mia (Chap. 57). The mutations that affect the ligand binding affinity of 70(5):1245–1266, 1987.
the Hb molecule are mostly in the α β interface. Rarely, mutations in 31. Kaul DK, Fabry ME, Nagel RL: Microvascular sites and characteristics of sickle cell
adhesion to vascular endothelium in shear flow conditions: Pathophysiological impli-
1 2
the α β interface lead to altered O affinity. Another mechanism in the cations. Proc Natl Acad Sci U S A 86(9):3356–3360, 1989.
2
1 1
generation of high O affinity mutants involves mutations that alter the 32. Noguchi CT, Schechter AN: The intracellular polymerization of sickle hemoglobin and
2
binding of 2,3-BPG. its relevance to sickle cell disease. Blood 58(6):1057–1068, 1981.
33. Embury SH: The not-so-simple process of sickle cell vasoocclusion. Microcirculation
11(2):101–113, 2004.
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