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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3624-3629
RED CELLS
The importance of erythroid expansion in determining the extent
of apoptosis in erythroid precursors in patients with
 -thalassemia major
Filippo Centis,
Laura Tabellini,
Guido Lucarelli,
Ornella Buffi,
Paola Tonucci,
Barbara Persini,
Mauro Annibali,
Roberto Emiliani,
Anca Iliescu,
Simona Rapa,
Raffaella Rossi,
Lisa Ma,
Emanuele Angelucci, and
Stanley L. Schrier
From the Unità Operativa Ematologia e Centro
Trapianto di Midollo Osseo, Ospedale di Muraglia, Azienda Ospedale 'S.
Salvatore' Pesaro, Italy; and the Division of Hematology,
Stanford University School of Medicine, Stanford, CA.
Beta-thalassemia major is characterized by ineffective
erythropoiesis leading to severe anemia and extensive erythroid
expansion. The ineffective erythropoiesis is in part due to accelerated
apoptosis of the thalassemic erythroid precursors; however, the extent
of apoptosis is surprisingly variable. To understand this variability as well as the fact that some patients undergoing allogeneic marrow transplantation are resistant to the myeloablative program, we attempted more quantitative analyses. Two groups of patients totaling 44 were studied, along with 25 healthy controls, and 7 patients with hemolysis and/or ineffective erythropoeisis. By 2 flow cytometric methods, thalassemic erythroid precursors underwent apoptosis at a rate
that was 3 to 4 times normal. Because thalassemic marrow has between 5- to 6-fold more erythroid precursors than healthy marrow, this
translated into an absolute increase in erythroid precursor apoptosis
of about 15-fold above our healthy controls. In searching for the
causes of the variability in thalassemic erythroid precursor
apoptosis, we discovered tight direct correlations between the
relative and absolute extent of apoptosis and the extent of erythroid
expansion as measured either by the absolute number of marrow erythroid
precursors or by serum soluble transferrin receptor levels. These
results could mean that the most extreme rates of erythroid
proliferation lend themselves to cellular errors that turn on apoptotic
programs. Alternatively, extreme rates of erythroid hyperplasia and
apoptosis might be characteristic of more severely affected patients.
Lastly, extreme erythroid hyperplasia could generate such numbers of
apoptotic erythroid precursors that marrow macrophages are overwhelmed,
leaving more apoptotic cells in the sample.
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