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RED CELLS
From the Thalassemia Research Center, Institute of
Sciences and Technology for Research and Development, Mahidol
University, Salaya Campus, Nakornprathom; the Faculty of Medicine,
Siriraj Hospital, Mahidol University; the Faculty of Tropical Medicine,
Mahidol University, Bangkok, Thailand; and the Division of Hematology,
Department of Medicine, Stanford University School of Medicine,
Stanford, CA.
The variety of patients with thalassemia in Thailand offers an
opportunity to fully characterize the kinetic causes of the anemia and
to study apoptosis of marrow erythroid precursors as a possible factor
contributing to its severity. Kinetic studies showed that in hemoglobin
H (HbH) disease, the extent of hemolysis, as well as the minimally
ineffective erythropoiesis, usually falls within the compensatory
capacity of normal erythropoiesis; therefore, anemia in patients with
HbH partly represents a failure to expand erythropoiesis adequately.
Hemoglobin Constant Spring (HbCS), a common variant of As a consequence of globalization and decreases in
neonatal and childhood mortality, the severe The primary kinetic lesion in HbH disease, a moderately severe form of
An In both HbH and HbH/CS, the pathophysiologic mechanism is determined
partly by the accumulation of excess, partly oxidized The We previously reported that accelerated apoptosis occurs in marrow
erythroid precursors in patients with Kinetic studies
Patients.
Twenty-seven patients ranging in age from 16 to 46 years, with
approximately equal numbers of patients of each sex with the genotypes
of interest, were studied at the Thalassemia Research Center and
Division of Hematology, Department of Medicine, Siriraj Hospital. Study
protocols were approved by the Ethical Clearance Committee on Human
Rights Related to Research Involving Human Subjects Research, Mahidol
University, Bangkok, Thailand. There were 4 patients with classic HbH
disease (  4 with HbH, 5 with
HbH/CS, 4 with HbCS/CS, and 10 with  -thal/HbE. Marrow samples were
shipped on ice to Stanford University, Stanford, CA, and arrived 36 to
48 hours later. Initially, patient samples were coded and the genotype,
diagnosis, and CBC results were provided only after measurements of
apoptosis were completed. These samples were concentrated by Ficoll
separation (Isoprep 1077; Robbins Scientific Corp, Sunnyvale, CA),
which also removed most RBCs. The nucleated cells
(2 × 107 in 80 µL) were then incubated with 20 µL
mouse monoclonal antihuman CD45 antibody linked to magnetic beads
(Miltenyi Biotech, Auburn, CA). The suspension was then passed through
magnetic columns that bound the CD45-positive cells and allowed the
erythroid precursors, which are negative for CD45, to pass through
unimpeded. Cytospin preparations showed that more than 95% of cells
were erythroid precursors representing all 4 stages. Magnetic-bead
separation provided a better yield in cells and in morphologic features
than separation using panning.25 The erythroid precursors
were counted and assayed for the extent of apoptosis.
The results obtained in the patients in group I showed that there were
potentially interesting differences in the extent of apoptosis in the
several clinical categories. However, we were concerned about the
possible effects that shipment and storage might have had on abnormal
erythroid precursors, and we were particularly interested in repeating
studies of samples that seemed to be discrepant or to have a shipping
artifact. Therefore, 2 of us (L.M. and S.L.S.) traveled to Bangkok,
where 14 patients (group II) were studied2 with HbH, 3 with HbH/CS, 2 with HbCS/CS, 6 with -thal/HbE, and 1 with HbEE. The procedures for
bone marrow aspiration and sample preparation were identical to those
described above except that the marrow samples were processed within
minutes and the entire experiment, including fluorescence-activated
cell sorter (FACS) analysis, was completed the same day. Five patients
in group I were also in group II so that results from fresh and shipped
samples could be compared directly.
Two patients had values that seemed likely to be erroneous. Patient 25 (with 0-thal/HbE) had a very high value for dead cells
(8%) on propidium iodide (PI) assay, and therefore we suspected an
artifact. On restudy in Bangkok, this patient had 0.6% PI-positive
cells. Patient 5 (with HbH/CS) was restudied because the value on the
annexin V assay was 12.4%, which was twice as high as that of the 4 other patients with the same diagnosis. On restudy in Bangkok, the
annexin V value was 4.9%. Three other patients were available for
restudy: patient 4 (with HbH/CS), whose annexin V value was 5.3% at
Stanford and 4.0% in Bangkok; patient 18 (with HbH), whose annexin V
value was 7.5% at Stanford and 5.3% in Bangkok; and patient 8 (with HbCS/CS), whose annexin V value was 12.7% at Stanford and 12.8% in
Bangkok. The 2 apparently aberrant values (patient 5 and patient 25)
were censored.
Control samples consisted of erythroid precursors harvested from
allogeneic bone marrow transplantation donors at Stanford and collected
with institutional review board approval, as described previously.25
Measurement of apoptosis In the patients in group I, 2 methods based on flow cytometry were used to assess apoptosis. During the apoptotic process, phosphatidylserine (PS) moves from the inner leaflet to the outer leaflet of the plasma membrane phospholipid bilayer.39 Externally oriented PS can be detected by annexin V labeled with fluorescein isothiocyanate-conjugated (FITC).39,40 Three microliters of annexin V-FITC (Annexin V Kit; R&D Systems, Minneapolis, MN) was added to 106 erythroid precursors suspended in 0.5 mL binding buffer and incubated for 10 minutes at room temperature. The samples were immediately placed on ice, and just before the flow cytometry, 10 µL PI (R&D Systems) was added. The addition of PI allowed us to determine the number of live (PI excluded) and dead (PI fluorescent) cells.39 At Stanford, we used a FACSTAR (Becton Dickinson, San Jose, CA) to determine the number of annexin V-positive erythroid precursors in 20 000 cells counted.To confirm our results using a different method, we used the Hoechst 33342 dye technique,41 which kinetically labels the nuclei of cells undergoing apoptosis. We further standardized this method on human erythroid precursors induced to undergo apoptosis by incubating them in medium devoid of erythropoietin (data not shown). To a 0.5-mL erythroid precursor suspension, we added 10 µL Hoechst 33342 (10 µg/mL; Molecular Probes, Eugene, OR) and incubated the mixture for exactly 4 minutes at 37°C, after which the mixture was immediately placed on ice. PI was added just before FACS analysis. The results were analyzed by using Flow-Jo software (Treestar, San Carlos, CA). Group II patients were studied at the Siriraj Hospital, where the FACS scanner did not have ultraviolet capabilities; therefore, only the annexin V-FITC method and PI were used to identify apoptotic and dead cells, respectively. Otherwise, the cell separation and incubation techniques were identical. Statistical analyses were performed by using the Student t test (Microsoft Excel statistical function; Microsoft Corp, Redmond, WA).
Erythrokinetics Comparison between HbH disease, HbH/CS, and HbCS/CS.
We studied 4 patients with HbH disease and compared them with 6 patients with HbH/CS (Table 1). The MCV
in HbH/CS disease is almost normal because of the well-described
hyperhydration20,22 and the RBCs contain many
inclusions.21 Values for iron-binding capacity and
transferrin saturation were not different; however, the serum iron
level in the patients with HbH/CS was 60% higher. Even though the 2 groups of patients were comparably anemic, the PITR, an index of
erythropoiesis, was 3 times the control value in patients with HbH and
5 times the control value in those with HbH/CS (P < .02).
Patients with HbH had a minimal reduction in utilization of radioiron,
whereas patients with HbH/CS had a mean value of 59%
(P < .01; Table 1 and Figure
1), indicating considerable ineffective
erythropoeisis.30,38 The radiochromium RBC survival was
much shorter in patients with HbH/CS (P < .05;
Table 1).
These results suggested that the contribution of HbCS might be to increase both ineffective erythropoiesis and hemolysis. Accordingly, 6 patients with homozygous HbCS/CS were studied (Table 2). There was a mild anemia with a normal MCV20,22 and a distinct reticulocytosis. RBCs were hypochromic, with basophilic stippling. Radiochromium RBC survival curves showed evidence of hemolysis (Table 2). The PITR was 3 times the normal level, whereas the mean RBC radioiron utilization value was low at 58% similar to the 59% in patients with HbH/CS (Table 1 and
Figure 1).
0-thal/HbE. We
studied these patients to provide contrast with patients with  thalassemia (Table 1 and 2) and to try to understand why only some of
these patients are severely anemic. There were 6 patients with mild disease (mean hemoglobin value, 93 g/L) and 5 with severe disease (mean
hemoglobin value, 64 g/L; Table 3). The
MCV value was higher in the severe-disease group, probably reflecting
the greater reticulocytosis (Table 3). The increase in transferrin
saturation in the severe-disease group was significant. RBC utilization
of radioiron was greatly but equally decreased, at about 35% for both
mild and severe cases, and these values were much lower than comparable
values in patients with variant forms of thalassemia (Figure 1 and
Tables 1-3). There were 2 striking differences between severe and mild
cases: the PITR was 2 times higher in severe cases
(P < .0001), with values 9 to 10 times those of controls,
and the radiochromium survival assay showed a much increased rate of
hemolysis in severe cases (P < .005; Table 3).
Studies of apoptosis of erythroid precursors Patients.
Thirty-seven analyses were carried out in 32 patients who were typical
of the diagnostic categories. The 23 patients in group I underwent
analysis of apoptosis of marrow erythroid precursors by 2 methods, the
annexin V-FITC and the Hoechst 33342 techniques, which generally
yielded values within 3% of each other (Figure 2). Because of our concerns regarding
possible shipping artifacts and to explore several interesting
findings42 (such as the apparent increase in apoptosis in
HbCS/CS), 14 additional analyses (group II) were done in Bangkok,
including 5 in patients also in group I. Analysis of the 2 groups
revealed no significant differences (data not shown). Therefore, the
results obtained in the 2 groups by using the annexin V-FITC method
were pooled (Table 4). The results of all
assays using both methods are shown in Figure 2. A single patient with
HbEE was studied (data not shown) and the values for apoptosis and cell
death were entirely normal.
-thalassemic erythroid precursors
undergo enhanced apoptosis. The stage of erythropoiesis at which
apoptosis occurs can be determined by using flow cytometry to measure
forward scatter and thereby identify the size of the cells undergoing
apoptosis (cells positive on annexin V-FITC assessment). The
larger erythroid precursors are the least mature forms.43 In samples of normal marrow (Figure 3),
most of the erythroid apoptosis occurred at the smallest, or late
orthochromic normoblast, stage. We analyzed 2 patients with
0-thal/HbE in whom erythroid precursors showed
substantial apoptosis and determined the stage at which apoptosis was
detected (Figure 3). Most of the erythroid precursors in one patient
were polychromatophilic erythroblasts, whereas orthochromic
erythroblasts predominated in the other patient; however, in both
patients, there was little apoptosis in proerythroblasts and basophilic
erythroblasts and an increase in the extent of apoptosis with
increasing erythroid maturity (Figure 3).
Kinetic studies In our patients with HbH disease, the mean radiochromium survival was about 16 days (Table 1); therefore, like others,9,12-14,44 we identified hemolysis as the major kinetic feature of the anemia. The PITR30,38 was increased about only 3 fold (Table 1), not the expected 5-fold increase in normal marrow. This erythropoiesis is only minimally ineffective, with radioiron utilization of about 75% (Table 1 and Figure 1). This lack of a full compensatory erythropoiesis in HbH has not previously been emphasized and we do not have an explanation for it.We believe that these are the first studies showing that RBC survival times in patients with HbH/CS were much shorter than those in comparably anemic patients with HbH (Table 1). The PITRs in the patients with HbH/CS were increased to more than 5 times the control values, thereby achieving the anticipated level of erythroid compensation (not seen in HbH). Furthermore, this erythropoiesis was clearly ineffective, since the RBC radioiron utilization rate was less than 60% (Table 1 and Figure 1). Thus, to maintain the same hemoglobin levels as in HbH, erythropoiesis in patients with HbH/CS increased almost 2 fold (PITR = 3.7 versus 2.0) to overcome more ineffective erythropoiesis and more hemolysis. Table 2 shows the important contribution of HbCS to this
pathophysiologic mechanism. Mildly anemic patients with homozygous HbCS
(HbCS/CS) had increased hemolysis, which is perhaps
pathophysiologically related to the extreme RBC
rigidity.22 The membrane accumulation of
The patients with severe cases of Studies of apoptosis In murine thalassemia,31 the extent of
ineffective erythropoiesis correlates directly with the extent of
erythroid apoptosis. We hypothesized that there would be a similar
correlation in human and thalassemia and studied this issue in
both Stanford and Bangkok. The results were consistent, so the annexin
V results were pooled (Table 4) and all results are shown in
Figure 2.
Compared with healthy controls, patients with HbH and HbH/CS had
perhaps a doubling in apoptosis detected by at least one of our
methods, whereas patients with HbCS/CS had a further significant doubling in apoptosis to 4 times the control value (Figure 2 and Table
4). The increased apoptosis in HbCS/CS suggests that the The
Stage of erythropoiesis at which apoptosis occurs. The stage
of erythropoiesis at which accelerated apoptosis occurred in severe
Measurements made to detect apoptosis in living human tissues (unlike
studies in cell cultures) represent the extent of apoptosis at a single
moment. In living tissues, cells undergoing apoptosis signal this state
to macrophages, which rapidly attack and remove such
cells.46 A reliable marker of apoptosis, cell-surface
exposure of PS, is such a signal.39,40 Thus, the value for
apoptosis in our studies represented a composite of cells entering
apoptotic programs and their removal by macrophages. Macrophages in
patients with These studies further clarified critical differences in the kinetics of
the anemia in
We thank the Faculty of Medical Technology for the blood chemistry analyses and the Division of Hematology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, for the hematologic and hemoglobin analyses.
Submitted February 1, 2000; accepted June 1, 2000.
Supported by Seameo Tropmed, National Research Council of Thailand, and US Public Health Service grants HL ROI-34408 and RO1-DK13682.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Presented in part at the XXI Congress of the International Society of Hematology, Sydney, Australia, May 1985, and the Annual Meeting of the American Society of Hematology, San Diego, CA, December 1997. Reprints: Stanley L Schrier, Division of Hematology, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Room S-161, Stanford, CA, 94305.
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| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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Abstract
Introduction
G-globin gene all
modify the severity of the anemia; however, the extreme variation
remains unexplained.
