Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1967 Nov;46(11):1795–1811. doi: 10.1172/JCI105670

Pathogenesis of Hemolytic Anemia in Homozygous Hemoglobin C Disease*

Samuel Charache 1,2, C Lockard Conley 1,2, David F Waugh 1,2, Richard J Ugoretz 1,2,‡, J Richard Spurrell 1,2
PMCID: PMC292930  PMID: 6061750

Abstract

Hemoglobin C is less soluble than hemoglobin A in red cells, in hemolysates, and in dilute phosphate buffer. Its relative insolubility may be explained by electrostatic interactions between positively charged β6-lysyl groups and negatively charged groups on adjacent molecules. Red cells from patients with homozygous hemoglobin C (CC) disease exhibit aberrant physical properties which suggest that the cells are more rigid than normal erythrocytes. They pass through membrane filters less readily than normal red cells do, and their viscosity is higher than that of normal cells. Differences from normal cells are exaggerated if mean corpuscular hemoglobin concentration (MCHC) is increased, by suspension in hypertonic salt solution. Increased rigidity of CC cells, by accelerating their fragmentation, may be responsible for formation of microspherocytes. These small dense cells are exceptionally rigid, and probably are even more susceptible to fragmentation and sequestration. Rigidity of CC cells can be attributed to a “precrystalline” state of intracellular hemoglobin, in which crystallization does not occur, although the MCHC exceeds the solubility of hemoglobin in hemolysates.

Full text

PDF
1795

Images in this article

1798Image
on p.1798
1800Image
on p.1800
1801Image
on p.1801

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. AGER J. A., LEHMANN H. Intra-erythrocytic haemoglobin crystals. J Clin Pathol. 1957 Nov;10(4):336–338. doi: 10.1136/jcp.10.4.336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. ALLISON A. C. Properties of sickle-cell haemoglobin. Biochem J. 1957 Feb;65(2):212–219. doi: 10.1042/bj0650212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. BESSIS M., NOMARSKI G., THIERY J. P., BRETON-GORIUS J. Etude sur la falciformation des globules rouges au microscope polarisant et au microscope électronique. II. L'intérieru du globule; comparaison avec les cristaux intra-globulaires. Rev Hematol. 1958 Apr-Jun;13(2):249–270. [PubMed] [Google Scholar]
  4. BORUN E. R., FIGUEROA W. G., PERRY S. M. The distribution of Fe59 tagged human erythrocytes in centrifuged specimens as a function of cell age. J Clin Invest. 1957 May;36(5):676–679. doi: 10.1172/JCI103468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. CONLEY C. L. PATHOPHYSIOLOGICAL EFFECTS OF SOME ABNORMAL HEMOGLOBINS. Medicine (Baltimore) 1964 Nov;43:785–787. doi: 10.1097/00005792-196411000-00023. [DOI] [PubMed] [Google Scholar]
  6. DERVICHIAN D. G., FOURNET G., GUINIER A., PONDER E. Structure submicroscopique des globules rouges contenant des hémoglobines anormales. Rev Hematol. 1952;7(4):567–574. [PubMed] [Google Scholar]
  7. DINTENFASS L. Considerations of the internal viscosity of red cells and its effect on the viscosity of whole blood. Angiology. 1962 Aug;13:333–344. doi: 10.1177/000331976201300801. [DOI] [PubMed] [Google Scholar]
  8. DINTENFASS L. RHEOLOGY OF PACKED RED BLOOD CELLS CONTAINING HEMOGLOBINS A-A, S-A, AND S-S. J Lab Clin Med. 1964 Oct;64:594–600. [PubMed] [Google Scholar]
  9. ERSLEV A. J., ATWATER J. EFFECT OF MEAN CORPUSCULAR HEMOGLOBIN CONCENTRATION ON VISCOSITY. J Lab Clin Med. 1963 Sep;62:401–406. [PubMed] [Google Scholar]
  10. GUEST M. M., BOND T. P., COOPER R. G., DERRICK J. R. RED BLOOD CELLS: CHANGE IN SHAPE IN CAPILLARIES. Science. 1963 Dec 6;142(3597):1319–1321. doi: 10.1126/science.142.3597.1319. [DOI] [PubMed] [Google Scholar]
  11. HARRIS J. W., BREWSTER H. H., HAM T. H., CASTLE W. B. Studies on the destruction of red blood cells. X. The biophysics and biology of sickle-cell disease. AMA Arch Intern Med. 1956 Feb;97(2):145–168. doi: 10.1001/archinte.1956.00250200021002. [DOI] [PubMed] [Google Scholar]
  12. HUISMAN T. H., VAN DER SCHAAF P. C., VAN DER SAR A. Some characteristic properties of hemoglobin C. Blood. 1955 Nov;10(11):1079–1091. [PubMed] [Google Scholar]
  13. HUNT J. A., INGRAM V. M. Allelomorphism and the chemical differences of the human haemoglobins A, S and C. Nature. 1958 Apr 12;181(4615):1062–1063. doi: 10.1038/1811062a0. [DOI] [PubMed] [Google Scholar]
  14. ITANO H. A. Solubilities of naturally occurring mixtures of human hemoglobin. Arch Biochem Biophys. 1953 Nov;47(1):148–159. doi: 10.1016/0003-9861(53)90444-5. [DOI] [PubMed] [Google Scholar]
  15. JANDL J. H., JONES A. R., CASTLE W. B. The destruction of red cells by antibodies in man. I. Observations of the sequestration and lysis of red cells altered by immune mechanisms. J Clin Invest. 1957 Oct;36(10):1428–1459. doi: 10.1172/JCI103542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. JANDL J. H., SIMMONS R. L., CASTLE W. B. Red cell filtration and the pathogenesis of certain hemolytic anemias. Blood. 1961 Aug;18:133–148. [PubMed] [Google Scholar]
  17. Jacob H. S. Abnormalities in the physiology of the erythrocyte membrane in hereditary spherocytosis. Am J Med. 1966 Nov;41(5):734–743. doi: 10.1016/0002-9343(66)90034-9. [DOI] [PubMed] [Google Scholar]
  18. KRAUS A. P., DIGGS L. W. In vitro crystallization of hemoglobin occuring in citrated blood from patients with hemoglobin C. J Lab Clin Med. 1956 May;47(5):700–705. [PubMed] [Google Scholar]
  19. Koyama S., Aoki S., Deguchi D. Electron microscopic observations of the splenic red pulp with special reference to the pitting function. Mie Med J. 1964 Sep;14(2):143–188. [PubMed] [Google Scholar]
  20. MURAYAMA M. A MOLECULAR MECHANISM OF SICKLED ERYTHROCYTE FORMATION. Nature. 1964 Apr 18;202:258–260. doi: 10.1038/202258a0. [DOI] [PubMed] [Google Scholar]
  21. Murayama M. Molecular mechanism of red cell "sickling". Science. 1966 Jul 8;153(3732):145–149. doi: 10.1126/science.153.3732.145. [DOI] [PubMed] [Google Scholar]
  22. Nathan D. G., Gunn R. B. Thalassemia: the consequences of unbalanced hemoglobin synthesis. Am J Med. 1966 Nov;41(5):815–830. doi: 10.1016/0002-9343(66)90039-8. [DOI] [PubMed] [Google Scholar]
  23. PONDER E. Globules rouges normaux, paracristallins et falciformes. Rev Hematol. 1958 Apr-Jun;13(2):129–131. [PubMed] [Google Scholar]
  24. PONDER E. The specific heat and the heat of compression of human red cells, sickled red cells, and paracrystalline rat red cells. J Gen Physiol. 1955 May 20;38(5):575–580. doi: 10.1085/jgp.38.5.575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. PROTHERO J. W., BURTON A. C. The physics of blood flow in capillaries. III. The pressure required to deform erythrocytes in acid-citrate-dextrose. Biophys J. 1962 Mar;2:213–222. doi: 10.1016/s0006-3495(62)86850-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. RAND P. W., LACOMBE E. HEMODILUTION, TONICITY, AND BLOOD VISCOSITY. J Clin Invest. 1964 Nov;43:2214–2226. doi: 10.1172/JCI105095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. RIGAS D. A., KOLER R. D. Ultracentrifugal fractionation of human erythrocytes on the basis of cell age. J Lab Clin Med. 1961 Aug;58:242–246. [PubMed] [Google Scholar]
  28. Rifkind R. A. Destruction of injured red cells in vivo. Am J Med. 1966 Nov;41(5):711–723. doi: 10.1016/0002-9343(66)90032-5. [DOI] [PubMed] [Google Scholar]
  29. Rifkind R. A. Heinz body anemia: an ultrastructural study. II. Red cell sequestration and destruction. Blood. 1965 Oct;26(4):433–448. [PubMed] [Google Scholar]
  30. SMITH E. W., KREVANS J. R. Clinical manifestations of hemoglobin C disorders. Bull Johns Hopkins Hosp. 1959 Jan;104(1):17–43. [PubMed] [Google Scholar]
  31. Teitel P. Disk-sphere transformation and plasticity alteration of red blood cells. Nature. 1965 Apr 24;206(982):409–410. doi: 10.1038/206409a0. [DOI] [PubMed] [Google Scholar]
  32. VAN GASTEL, VAN DEN BERG D., DE GIER J., VAN DEENEN L. SOME LIPID CHARACTERISTICS OF NORMAL RED BLOOD CELLS OF DIFFERENT AGE. Br J Haematol. 1965 Mar;11:193–199. doi: 10.1111/j.1365-2141.1965.tb06577.x. [DOI] [PubMed] [Google Scholar]
  33. WESTERMAN M. P., PIERCE L. E., JENSEN W. N. ERYTHROCYTE LIPIDS: A COMPARISON OF NORMAL YOUNG AND NORMAL OLD POPULATIONS. J Lab Clin Med. 1963 Sep;62:394–400. [PubMed] [Google Scholar]
  34. WHEBY M. S., THORUP O. A., LEAVELL B. S. Homozygous hemoglobin C disease in siblings: further comment on intraerythrocytic crystals. Blood. 1956 Mar;11(3):266–272. [PubMed] [Google Scholar]
  35. Weed R. I., Reed C. F. Membrane alterations leading to red cell destruction. Am J Med. 1966 Nov;41(5):681–698. doi: 10.1016/0002-9343(66)90030-1. [DOI] [PubMed] [Google Scholar]
  36. Weed R. I., Weiss L. The relationship of red cell fragmentation occurring within the spleen to cell destruction. Trans Assoc Am Physicians. 1966;79:426–438. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES