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Unstable hemoglobin variants

Martin H Steinberg, MD
Section Editor
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


Some mutations of globin genes decrease the solubility of the molecule in the red cell. Substitutions in the primary sequence of globin in these unstable hemoglobins can alter the tertiary or quaternary structure of the molecule and result in a globin polypeptide/hemoglobin tetramer that is unstable and precipitates intracellularly. These intraerythrocytic precipitates are detectable with the aid of supravital staining as dark globular aggregates called Heinz bodies (picture 1). The affected red cells have a reduced life span, producing a hemolytic syndrome of varied severity called the congenital Heinz body hemolytic anemia syndrome.

This topic reviews the evaluation and management of unstable hemoglobins (hemoglobin mutations associated with the Heinz body hemolytic anemia syndrome).

Separate topic reviews discuss other causes of hemolytic anemia associated with Heinz body formation and general approaches to the evaluation of patients with hemolytic anemia:

G6PD deficiency – (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency".)

Thalassemia – (See "Clinical manifestations and diagnosis of the thalassemias".)

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Literature review current through: Nov 2017. | This topic last updated: Sep 25, 2017.
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  1. Nagel RL. Unstable hemoglobins; hemoglobins with altered O2 affinity; Hb M. In: Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, Steinberg MH, Forget BG, Higgs DR, et al. (Eds), Cambridge University Press, Cambridge 1999.
  2. Miller DR, Weed RI, Stamatoyannopoulos G, Yoshida A. Hemoglobin Köln disease occurring as a fresh mutation: erythrocyte metabolism and survival. Blood 1971; 38:715.
  3. Levine RL, Lincoln DR, Buchholz WM, et al. Hemoglobin Hasharon in a premature infant with hemolytic anemia. Pediatr Res 1975; 9:7.
  4. de la Fuente-Gonzalo F, Baiget M, Badell I, et al. Study of three families with Hb Agrinio [α29(B10)Leu→Pro, CTG>CCG (α2)] in the Spanish population: three homozygous cases. Hemoglobin 2012; 36:526.
  5. Srivastava P, Kaeda JS, Roper D, et al. Severe hemolytic anemia associated with the homozygous state for an unstable hemoglobin variant (Hb Bushwick). Blood 1995; 86:1977.
  6. Moo-Penn WF, Jue DL, Johnson MH, et al. Hemoglobin Brockton [beta 138 (H16) Ala----Pro]: an unstable variant near the C-terminus of the beta-subunits with normal oxygen-binding properties. Biochemistry 1988; 27:7614.
  7. Williamson D. The unstable haemoglobins. Blood Rev 1993; 7:146.
  8. Schlüter K, Drenckhahn D. Co-clustering of denatured hemoglobin with band 3: its role in binding of autoantibodies against band 3 to abnormal and aged erythrocytes. Proc Natl Acad Sci U S A 1986; 83:6137.
  9. Eisinger J, Flores J, Tyson JA, Shohet SB. Fluorescent cytoplasm and Heinz bodies of hemoglobin Köln erythrocytes: evidence for intracellular heme catabolism. Blood 1985; 65:886.
  10. Verhovsek M, Henderson MP, Cox G, et al. Unexpectedly low pulse oximetry measurements associated with variant hemoglobins: a systematic review. Am J Hematol 2010; 85:882.
  11. Tucker PW, Phillips SE, Perutz MF, et al. Structure of hemoglobins Zürich [His E7(63)beta replaced by Arg] and Sydney [Val E11(67)beta replaced by Ala] and role of the distal residues in ligand binding. Proc Natl Acad Sci U S A 1978; 75:1076.
  12. Virshup DM, Zinkham WH, Sirota RL, Caughey WS. Unique sensitivity of Hb Zürich to oxidative injury by phenazopyridine: reversal of the effects by elevating carboxyhemoglobin levels in vivo and in vitro. Am J Hematol 1983; 14:315.
  13. Zinkham WH, Houtchens RA, Caughey WS. Relation between variations in the phenotypic expression of an unstable hemoglobin disorder (hemoglobin Zürich) and carboxyhemoglobin levels. Am J Med 1983; 74:23.
  14. Coleman MB, Steinberg MH, Adams JG 3rd. Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis. J Biol Chem 1991; 266:5798.
  15. Adams JG 3rd, Boxer LA, Baehner RL, et al. Hemoglobin Indianapolis (beta 112[G14] arginine). An unstable beta-chain variant producing the phenotype of severe beta-thalassemia. J Clin Invest 1979; 63:931.
  16. Honig GR, Shamsuddin M, Zaizov R, et al. Hemoglobin Petah Tikva (alpha 110 ala replaced by asp): a new unstable variant with alpha-thalassemia-like expression. Blood 1981; 57:705.
  17. Kano G, Morimoto A, Hibi S, et al. Hb Bristol-Alesha presenting thalassemia-type hyperunstable hemoglobinopathy. Int J Hematol 2004; 80:410.
  18. Rees DC, Rochette J, Schofield C, et al. A novel silent posttranslational mechanism converts methionine to aspartate in hemoglobin Bristol (beta 67[E11] Val-Met->Asp). Blood 1996; 88:341.
  19. Crowley MA, Mollan TL, Abdulmalik OY, et al. A hemoglobin variant associated with neonatal cyanosis and anemia. N Engl J Med 2011; 364:1837.
  20. Rachmilewitz EA, Harari E. Intermediate hemichrome formation after oxidation of three unstable hemoglobins (Freiburg, Riverdale-Bronx and Köln). Hamatol Bluttransfus 1972; 10:241.
  21. Winterbourn CC, Carrell RW. Studies of hemoglobin denaturation and Heinz body formation in the unstable hemoglobins. J Clin Invest 1974; 54:678.
  22. Fischer S, Nagel RL, Bookchin RM, et al. The binding of hemoglobin to membranes of normal and sickle erythrocytes. Biochim Biophys Acta 1975; 375:422.
  23. Low P. Interaction of native and denatured hemoglobins with band 3: Consequences for erythrocyte structure and function. In: Red Blood Cell Membranes: Structure, Function, Clinical Implications, Agre P, Parker JC (Eds), Marcel Dekker, New York 1989.
  24. Walder JA, Chatterjee R, Steck TL, et al. The interaction of hemoglobin with the cytoplasmic domain of band 3 of the human erythrocyte membrane. J Biol Chem 1984; 259:10238.
  25. Greenberg MS. Heinz body hemolytic animea. "Bite cells" -a clue to diagnosis. Arch Intern Med 1976; 136:153.
  26. Lee-Potter JP, Deacon-Smith RA, Simpkiss MJ, et al. A new cause of haemolytic anaemia in the newborn. A description of an unstable fetal haemoglobin: F Poole, alpha2-G-gamma2 130 trptophan yeilds glycine. J Clin Pathol 1975; 28:317.
  27. Zinkham WH, Winslow RM. Unstable hemoglobins: influence of environment on phenotypic expression of a genetic disorder. Medicine (Baltimore) 1989; 68:309.
  28. Bisconte MG, Caldora M, Musollino G, et al. α-Thalassemia associated with hb instability: a tale of two features. the case of Hb Rogliano or α1 Cod 108(G15)Thr→Asn and Hb Policoro or α2 Cod 124(H7)Ser→Pro. PLoS One 2015; 10:e0115738.
  29. Lode HN, Krings G, Schulze-Neick I, et al. Pulmonary hypertension in a case of Hb-Mainz hemolytic anemia. J Pediatr Hematol Oncol 2007; 29:173.
  30. Kato GJ, Taylor JG 6th. Pleiotropic effects of intravascular haemolysis on vascular homeostasis. Br J Haematol 2010; 148:690.
  31. Kumar MK, Judd C, Hoyer JD, et al. Hb Manukau [β67(E11)Val → Gly; HBB: c.203T>G]: the role of genetic testing in the diagnosis of idiopathic hemolytic anemia. Hemoglobin 2014; 38:211.
  32. Li R, Wang T, Xie XM, Li DZ. Case report: prenatal diagnosis of Hb Hammersmith [β42(CD1)Phe→Ser; HBB: c.128T > C] in a family with an adult male patient. Hemoglobin 2014; 38:142.
  33. Yates AM, Mortier NA, Hyde KS, et al. The diagnostic dilemma of congenital unstable hemoglobinopathies. Pediatr Blood Cancer 2010; 55:1393.
  34. Milner PF, Wrightstone RN. The unstable hemoglobins: a review. Prog Clin Biol Res 1981; 51:197.
  35. http://www.bu.edu/sicklecell/diagnostics/.
  36. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9095.
  37. http://www.questdiagnostics.com/testcenter/TestDetail.action?ntc=29385.
  39. Nagel RL, Jaffe E. Dyshemoglobins. In: Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, Steinberg MH, Forget BG, Higgs DR, et al. (Eds), Cambridge UP, Cambridge 1999.
  40. Richards FM. Protein stability: still an unsolved problem. Cell Mol Life Sci 1997; 53:790.
  41. Perutz MF. Electrostatic effects in proteins. Science 1978; 201:1187.
  42. Paglietti ME, Sollaino MC, Loi D, et al. First detection of Hb Taybe [α38(C3) or α39(C4) Thr→0 (α1)] in an Italian child. Hemoglobin 2012; 36:299.
  43. Fairbanks VF. A pitfall in hemoglobin electrophoresis. Artefactual minor unstable hemoglobin results from improper specimen handling. Am J Clin Pathol 1980; 73:245.
  44. Rose C, Bauters F, Galacteros F. Hydroxyurea therapy in highly unstable hemoglobin carriers. Blood 1996; 88:2807.
  45. Loovers HM, Tamminga N, Mulder AB, Tamminga RY. Clinical Course of Two Children with Unstable Hemoglobins: The Effect of Hydroxyurea Therapy. Hemoglobin 2016; 40:341.
  46. Crary SE, Buchanan GR. Vascular complications after splenectomy for hematologic disorders. Blood 2009; 114:2861.