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MÖSSBAUER STUDIES OF FERRITIN-LIKE IRON IN RED BLOOD CELLS OF THALASSEMIA SICKLE-CELL ANEMIA AND HEMOGLOBIN HAMMERSMITH

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HAL Id: jpa-00218552

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Submitted on 1 Jan 1979

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MÖSSBAUER STUDIES OF FERRITIN-LIKE IRON IN RED BLOOD CELLS OF THALASSEMIA SICKLE-CELL ANEMIA AND HEMOGLOBIN

HAMMERSMITH

E. Bauminger, S. Cohen, S. Ofer, E. Rachmilewitz

To cite this version:

E. Bauminger, S. Cohen, S. Ofer, E. Rachmilewitz. MÖSSBAUER STUDIES OF FERRITIN-

LIKE IRON IN RED BLOOD CELLS OF THALASSEMIA SICKLE-CELL ANEMIA AND

HEMOGLOBIN HAMMERSMITH. Journal de Physique Colloques, 1979, 40 (C2), pp.C2-502-C2-

504. �10.1051/jphyscol:19792176�. �jpa-00218552�

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JOURNAL DE PHYSIQUE Colloque C2, suppl6ment au n O 3, Tome 40, mars 1979, page (22-502

MOSSBAUER S T U D I E S OF F E R R I T I N - L I K E I R O N I N RED BLOOD C E L L S OF THALASSEMIA, S I C K L E - C E L L ANEMIA AND HEMOGLOBIN HAMMERSMITH (+)

E.R. Bauminger, S.G. Cohen, S. Ofer and E.A. ~achmilewitz*

Racah Institute of Physics, The Hebrew University, Jerusalem, Israel

s Hadassah University Hospital Mount Scopus, Hebrew University-Hadassh Medical School, JerusaZem, Israel

Rbsum6.- De grandes quantitbs de fer sous forme de compos6s du type ferritine ont Ct6 d6tect6es et estim6es quantitativement 5 l'aide de la technique Mijssbauer dans des globules rouges intactes de

17 patients affligss de thalassdmie majeure a et 0, de 2 autres affligbs d'anCmie et d'un autre souffrant d'instabilitd de Hammersmith de lth6moglobine. Les quantit6s de fer du type ferritine sont comparables 2 celles du fer Hb et sont particuligrement blevbes dans les rdticulocytes. Aucune quan- tit6 de fer du type ferritine n'a btC ddtectbe chez des patients souffrant d'anbmie h6molytique auto-immune et d'anbmie pernicieuse. Les hautes quantit6s de fer du type ferritine prdsentes dans les hbmoglobinopathies sont probablement la cons&quence d'une dbnaturation intra-cellulaire du Hb suivie d'une ddcharge de fer excbdentaire.

Abstract.- Large amounts of ferritin-like iron were detected and quantitatively estimated, using the Mgssbauer technique, in intact red blood cells of 17 patients with a and 0 thalassemia major, 2 with sickle-cell anemia and one with unstable hemoglobin (Hb) Hammersmith. The amounts of ferritin-like iron were comparable to those of Hb iron and were particularly large in reticulocytes. No ferritin- like iron was detected in patients with severe autoimmune hemolytic anemia and pernicious anemia.

The large quantities of ferritin-like iron in hemoglobinopathies are probably a consequence of intra- cellular Hb denaturation and the release of excess iron.

The present work deals with the application of the Mgssbauer effect to the study of blood diseases resulting from changes in hemoglobin (Hb) structure and composition (thalassemia, sickle-cell anemia and Hb Hammersmith).

In an earlier study by the present authors / 1 / on the iron present in whole thalassemic red blood cells (RBC) using the technique of recoil-free absorption, an iron-containing compound, not present in normal RBC, was found. The iron Gssbauer spec- tra at various temperatures of this additional com- pound, were found in the present work to be identi- cal to spectra obtained from isolated ferritin or hemosiderin. This shows that the physical state of the iron in this compound is very similar to that of the iron cores in ferritin. Because of this and additional.arguments presented, it is very likely that the additional compound is a storage protein, ferritin or hemosiderin.

The present study was carried out on periphe- ral RBC from 13 patients with 6-thalassemia, 4 with hemoglobin H disease, 2 with sickle-cell anemia and one with unstable Hb Hammersmith. In all these ca- ses, a third compone,lt, in addition to the subspec- tra corresponding to oxy- and deoxy-Hb, could be '+)supported in part by the Stiftung Volkswzgenwerk.

distinguished in the spectra. This component was not observed in the samples of frozen RBC from 3 normal controls, two patients with 0-thalassemia minor, one with pernicious anemia and two with Coomb's positi- ve autoimmune hemolytic anemia. Figures I and 2 display the spectra obtained at various temperatu- res between 4.1 and 263 K of RBC from a patient with 0-thalassemia major. Spectra A and B obtained

at 8 2 K and 200 K, respectively, clearly show a new

component, c, whose peaks are situated between the peaks of the two quadrupole doublets of oxy- and deoxy-Hb. At 2 6 3 K only the component c remains and the Hb peaks are not evident. The temperature depen- dence of the spectra shows that the recoil-free efficiency (f-value) of the c component drops off much more slowly with rising temperature than the f-value of Hb and that at a sufficiently high tempe- rature, only the f-value of the former is apprecia- bly different from zero. The spectrum at 4.1 K is displayed in figure 2. At this temperature one can see the peaks of the two quadrupole doublets of Hb, while khe additional component yields a spectrum split by the magnetic hyperfine interaction.

The parameters of the c component, as obtained from least squares computer fits are identical to those of ferritin and hemosiderin in the whole tem- perature range /2/. The quantitative estimates of

Article published online by EDP Sciences and available at http://dx.doi.org/10.1051/jphyscol:19792176

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the relative amounts of the Hb iron to ferritin iron in RBC are based on the ~Essbauer spectra taken at 82 K, at which temperature the f-values were found to be the same for Hb iron and ferritin iron. Whe- reas the ratio of ferritin iron to the Hb iron (R value) in RBC of the controls was less than I % , it varied between 3% and 50% in the cases of thalasse- mia, sickle-cell anemia and Hb Hammersmith. It was considered of great interest to determine the rela- tive concentrations of ferritin-like iron, separa- tely, in RBC at different stages of maturation To this effect, R values were determined for samples containing significantly different concentrations of reticulocytes and mature RBC separated by diffe- rential centrifugation. It was found that in the same patient the amount of ferritin-like iron in a reticulocyte is between 2.5 to 8 times that of fer- ritin-like iron in a mature RBC.

-2 -1 0 1 2 3

V E L O C I T Y ( m m / s )

Fig. 1 : 5 7 ~ e &ssbauer spectrum in RBC obtained from a patient with 0-thalassemia intermedia;

A

-

spectrum obtained at 82 K, B

-

at 2 0 0 K and

C

-

at 263 K. Subspectra a correspond to deoxy-Hb, subspectra b to oxy-Hb and subspectra c to the ferritin-like compound.

In four cases the absorption spectra of frozen hemolysates of thalassemic RBC were also measured at 82 K. All these spectra showed the c component with about the same relative intensities as in the RBC.

V E L O C I T Y ( m m / s )

Fig. 2 : 5 7 ~ e Gssbauer spectra in RBC at 4 . 1 K, obtained from a patient with 0-thalassemia interme- dia. Subspectrum a corresponds to deoxy-Hb, subspec- trum b to oxy-Hb and subspectrum c to the ferritin- like compound.

The main arguments for the identification of the compound responsible for the c component as fer- ritin or hemosiderin are : (i) Identity of the hy- perfine parameter of the c component with those of iron in isolated ferritin or hemosiderin. (ii) The presence of the compound in large amounts in hemo- lysates of thalassemic RBC. To our knowledge, the only soluble compound with a magnetic iron core found in mammals, is ferritin. (iii) Preliminary ra- dio imunoassay studies on hemolysates of thalasse- mic RBC, confirm the presence of ferritin / 3 / .

(iv) The previous observations of Eylar and Matioli / 4 / , who have shown that the rate of apoferritin synthesis is increased substantially in the thalas- semic reticulocytes. (v) Ultrastructural studies of Polliack et al. / 5 / , which demonstrated the presence of ferritin and hemosiderin granules in thalassemic reticulocytes and normoblasts.

The reason for the large difference in the con- centration of ferritin iron in bhe two different types of hemolytic anemias studied, one resulting from changes in Hb structure and composition (tha- lassemia, sickle-cell anemia and Hb Hammersmith) and the other resulting from extracellular causes (per- nicious anemia and autoimmune hemolytic anemia) is not clear. The large amounts of ferritin iron detec- ted in RBC and patients with thalassemia, sickle- cell anemia, or Hb Hammersmith may be a consequence of the high rate of intracellular denaturation of Hb during the accelerated and ineffective erythro- poieses which takes place in these diseases. It is possible that following intracellular Hb denatura- tion, heme is separated from globin, and iron even- tually comes off the heme molecule. This iron could be a factor that triggers intracellular apoferritin

synthesis.

(4)

c2-504 JOURNAL DE PHYSIQUE

In all cases investigated, for each patient, the amount of ferritin iron in the mature RBC is smaller by a factor of about three than the amount in the reticulocytes. Two alternative hypotheses may account for this large difference :

a) The mature thalassemic and sickle-cell RBC, as old surviving cells, contain Hb which is more stable, and therefore, there is less iron relea- sed from denatured Hb and less ferritin iron accumulated in these cells. On the other hand, significant fractions of the reticulocytes, which contain large amounts of ferritin-like iron, are destroyed before reaching maturation.

b) Appreciable amounts of ferritin iron are somehow removed from the RBC during the life span of the RBC

.

References

/ 11 Ofer, S . , Cohen, S.G., Bauminger, E .R. and Ra- chmilewitz, E.A., J. Physique Colloq.

37

(1976)

C6-199-202.

/2/ Fischbach, F.A., Gregory, D.W., Harrison, P . M . , Hoy, T.G. and Williams, J . M . , U. Ultrastruct.

Res.

37

(1971) 495-503.

131 Hershko, C., private communication.

/ 4 / Eylar, E.H. and Matioli, G., Nature

208

(1965)

661-664.

/5/ Polliack, A , , Yataganas, X., Thorell, B. and Rachmilewitz, E.A., Brit. J. Haemat.

6

(1974)

201-204.

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