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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3022-3026
Hydroxyurea as an Alternative to Blood Transfusions for the
Prevention of Recurrent Stroke in Children With Sickle Cell Disease
By
Russell E. Ware,
Sherri A. Zimmerman, and
William H. Schultz
From the Duke Pediatric Sickle Cell Program and the Division of
Hematology-Oncology, Department of Pediatrics, Duke University Medical
Center, Durham, NC.
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ABSTRACT |
Children with sickle cell disease (SCD) and stroke receive chronic
transfusions to prevent stroke recurrence. Transfusion risks including
infection, erythrocyte allosensitization, and iron overload suggest a
need for alternative therapies. We previously used hydroxyurea (HU) and
phlebotomy in two young adults with SCD and stroke as an alternative to
transfusions. We have now prospectively discontinued
transfusions in 16 pediatric patients with SCD and stroke. Reasons to
discontinue transfusions included erythrocyte alloantibodies or
autoantibodies, recurrent stroke on transfusions, iron overload,
noncompliance, and deferoxamine allergy. HU was started at 15 mg/kg/d
and escalated to 30 mg/kg/d based on hematologic toxicity. Patients
with iron overload underwent phlebotomy. The children have been off
transfusions 22 months, (range, 3 to 52 months). Their average HU dose
is 24.9 ± 4.2 mg/kg/d, hemoglobin concentration is 9.4 ± 1.3 g/dL, and mean corpuscular volume (MCV) is 112 ± 9 fL. Maximum percentage fetal hemoglobin (%HbF) is
20.6% ± 8.0% and percentage HbF-containing erythrocytes (%F cells) is 79.3% ± 14.7%. Fourteen patients
underwent phlebotomy with an average of 8,993 mL (267 mL/kg)
removed. Serum ferritin has decreased from 2,630 to 424 ng/mL, and 4 children have normal ferritin values. Three patients (19%) had
neurological events considered recurrent stroke, each 3 to 4 months
after discontinuing transfusions, but before maximal HU effects. These
preliminary data suggest some children with SCD and stroke may
discontinue chronic transfusions and use HU therapy to prevent stroke
recurrence. Phlebotomy is well-tolerated and significantly reduces iron
overload. Modifications in HU therapy to raise HbF more rapidly might
increase protection against stroke recurrence.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
STROKE IS one of the most devastating
clinical complications that occurs in children with sickle cell disease
(SCD) and is an important cause of death in this patient
population.1-3 Approximately 5% to 10% of children with
SCD will develop a stroke, most often in the first decade of
life.4,5 The pathological event is usually infarctive and
results from stenosis or occlusion of the large vessels, especially the
internal carotid and proximal cerebral arteries.6,7 Despite
prompt aggressive medical intervention, including complete blood
exchange, many children with SCD and stroke have residual physical and
neuropsychological deficits.8-10
Several studies have documented a high rate of stroke recurrence in
children with SCD who receive no specific preventive therapy. A report
from the Jamaican pediatric cohort described stroke recurrence in 6 of
13 children (46%), with a median interval to recurrence of 9 months
after the first stroke.4 Powars et al11
reported a recurrence rate of 67% in 15 long-term survivors of stroke, with a temporal clustering of additional neurological events in the
first 24 to 36 months after the initial stroke. Russell et al12 reported stroke recurrence in 9 of 10 (90%) of
untransfused pediatric patients with SCD and stroke.
Because of this high risk of stroke recurrence, affected children are
typically treated with monthly erythrocyte transfusions designed to
reduce the concentration of sickled erythrocytes.13,14 A
chronic transfusion regimen is at least 80% to 90% successful in
preventing stroke recurrence,12,15-18 although the optimal duration of transfusions is not known. A 70% stroke recurrence rate
was observed after the prospective discontinuation of a short-term (1- to 2-year) transfusion regimen,19 and a 50% recurrence
rate was observed after prospective discontinuation of a long-term (5- to 12-year) transfusion regimen.20 Most pediatric
hematologists, therefore, recommend indefinite chronic transfusions to
prevent recurrent stroke, despite the long-term risks of transfusions, including the possible transmission of infectious agents, erythrocyte allosensitization, and iron overload.
We recently reported two young adults with SCD and stroke who were
unable to continue chronic transfusion therapy; transfusions were
discontinued, and the patients were treated with oral hydroxyurea (HU)
as prophylaxis against stroke recurrence.21 A phlebotomy program was used to reduce iron overload and stimulate endogenous erythropoiesis. Both patients responded to the HU therapy with elevated
levels of fetal hemoglobin (HbF) and HbF-containing erythrocytes (F
cells) and had no stroke recurrence during nearly 3 years of HU
therapy. In addition, each patient tolerated phlebotomy well and had
diminution in serum ferritin values, suggesting a reduction in total
body iron stores. Based on this anecdotal success, we prospectively
discontinued erythrocyte transfusions in a new and larger cohort of
pediatric patients with SCD and stroke. We used daily oral HU therapy
to help prevent stroke recurrence and an aggressive periodic phlebotomy
regimen to reduce iron overload. Our preliminary results suggest that
some children with SCD and stroke may be able to discontinue chronic
transfusions and use daily oral HU therapy as stroke prophylaxis.
Phlebotomy is well-tolerated and significantly reduces serum ferritin values.
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MATERIALS AND METHODS |
Patient selection.
A total of 25 patients with SCD and stroke who were followed by the
Duke University Pediatric Sickle Cell Program (Durham, NC) were
considered for this protocol. Sixteen patients were identified who had
clinical events or sequelae that suggested they would be unable to
tolerate indefinite chronic erythrocyte transfusion therapy. Reasons to
consider discontinuing transfusions included erythrocyte
alloimmunization, erythrocyte autoantibody formation, recurrent stroke
on transfusion therapy, iron overload (serum ferritin >2,000 ng/mL),
and noncompliance with transfusion or chelation regimens. The remaining
9 patients were not offered enrollment, because they had received blood
transfusions for less than 2 years or had no clinical or laboratory
contraindications to continuing chronic transfusion therapy. The study
protocol was approved by the Duke University Medical Center
Institutional Review Board, and the consent form described the high
risk of recurrent stroke once transfusions were stopped. In all cases, at least two different health care providers independently discussed the risks and benefits with each family before enrollment.
Discontinuation of transfusions and initiation of hydroxyurea
therapy.
Before discontinuing transfusions, patients were screened for abnormal
hepatic or renal function, and also for exposure to hepatitis A, B, and
C, as well as the human immunodeficiency virus. Approximately 2 weeks
after the last transfusion, at a time when endogenous erythropoiesis
was recovering, oral HU therapy was started at a dose of 15 mg/kg/d.
The dose of HU was escalated by 5 mg/kg/d every 8 weeks as tolerated,
up to a maximum of 30 mg/kg/d. If a patient developed hematologic
toxicity, defined as a hemoglobin concentration <5.0 g/dL, an
absolute neutrophil count of <1.5 × 109/L, or a
platelet count <80 × 109/L, HU therapy was held
until blood counts normalized.
Phlebotomy regimen.
Patients with laboratory evidence of iron overload were started on a
periodic phlebotomy program designed to remove excess iron and
stimulate erythropoiesis. Phlebotomy was typically performed in the
outpatient setting by the Duke pediatric hematology/oncology nursing
staff. Five children also had phlebotomy periodically performed at home
by trained pediatric nurses from a home health care agency. Using
peripheral access, 5 to 10 mL/kg of venous blood was removed over 20 to
40 minutes and discarded. Vital signs were monitored every 10 minutes.
Intravascular volume was replaced using an equivalent volume of normal
saline given intravenously over 30 minutes. Phlebotomy was initially
performed every 4 weeks, but an interval of 2 weeks was tolerated well
by most patients.
Quantitation of HbF and F cells.
Measurement of HbF and F cells was performed every 8 weeks. The %HbF was determined using the 2-minute alkali denaturation procedure, and the %F cells using an immunophenotype assay as previously described.22
Statistical analysis.
All clinical and laboratory data were maintained in a Microsoft Excel
database (Redmond, WA). Descriptive statistics were calculated using the Primer of Biostatistics (McGraw-Hill, New York,
NY). The Wilcoxon Signed Rank Test (Statview, SAS
Institute, Cary, NC) was used to compare serum ferritin values before
and after phlebotomy.23
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RESULTS |
Characteristics of the patients.
Each of the 16 eligible patients (11 males, 5 females) chose to enroll
in this study. Clinical characteristics are summarized in
Table 1. Fifteen of the children have a
diagnosis of homozygous sickle cell anemia (HbSS), whereas one child
has a diagnosis of HbS/OArab. The mean age
(±1 standard deviation [SD]) at first stroke was 7.1 ± 4.4 years, with a median of 6.4 years. In all cases, the initial
stroke was infarctive, including 7 presenting with right hemiparesis (4 with concomitant aphasia), 4 with left hemiparesis, 4 with focal
neurological deficitis, and 1 with coma and seizures.
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Table 1.
Clinical Characteristics of 16 Pediatric Patients With
SCD and Stroke Who Discontinued Chronic Transfusions and Received Oral
Hydroxyurea Therapy to Prevent Stroke Recurrence
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Each patient had previously received erythrocyte tranfusions to prevent
stroke recurrence, mean duration of 56 ± 36 months, median 51 months (Table 1). Fifteen children had received transfusions for at
least 1 year; one (#3) discontinued transfusions after 7 months because
of erythrocyte autoantibody and alloantibody formation. All 16 children
had received blood via simple erythrocyte transfusions, but 7 also
received partial exchange transfusions and 10 had erythrocytapheresis
as previously described.24 One patient (#16) was
seropositive to hepatitic C. Nine patients were prescribed deferoxamine
(DFO) chelation therapy; 2 were compliant, 5 were noncompliant, and 2 were allergic. Patient #8 developed a generalized pruritic rash with
periorbital edema; DFO desensitization was attempted, but was
unsuccessful. Patient #12 had significant pain and swelling at the DFO
infusion site with a maculopapular rash on the arms and chest;
desensitization was not attempted.
The reasons to consider discontinuing transfusions varied among the 16 patients (Table 1). Four developed erythrocyte autoantibodies, as
recently described.25 Two of these patients also developed multiple erythrocyte alloantibodies; patient #1 developed
alloantibodies to the public Dib antigen and to a variant D
antigen, whereas patient #5 developed alloantibodies to C,
Jsa, and Lea antigens.25 Additional
reasons to consider discontinuing transfusions included recurrent
stroke while on transfusions (n = 1), iron overload (n = 11), and
noncompliance with the transfusion regimen (n = 4) or chelation therapy
(n = 5). At the time that transfusions were stopped, the patients had a
mean age of 12.1 ± 4.9 years, median 11.8 years.
Hydroxyurea therapy.
The patients have received oral HU therapy for a mean duration of 22 ± 14 months, median 22 months (Table
2). The current average HU dose is 24.9 ± 4.2 mg/kg/d, range 19.1 to 32.7 mg/kg/d. Hematologic toxicity has been mild, with only
occasional episodes of transient, reversible myelosuppression (not
shown).
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Table 2.
Laboratory Parameters for 16 Pediatric Patients With SCD
and Stroke Who Discontinued Chronic Transfusions and Began Oral HU
Therapy to Prevent Stroke Recurrence
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Representative data illustrating the hematologic effects of HU therapy
are shown in Table 2. Recent laboratory values include a mean
hemoglobin concentration of 9.4 ± 1.3 g/dL (median 9.3 g/dL) and a
mean corpuscular volume (MCV) of 112 ± 9 fL
(median 110 fL). Using the maximal laboratory values for
each patient during HU therapy, the mean %HbF is 20.6% ± 8.0%
(median 21.7%), whereas the mean %F cells is 79.3% ± 14.7%
(median 85.7%).
Phlebotomy regimen.
Fourteen of the children had laboratory evidence of iron overload and
have received phlebotomy for a mean duration of 18 ± 12 months,
median 18 months (Table 2). The total volume of blood removed has
ranged from 1,835 to 19,825 mL, with a median volume of 8,993 mL. When
calculated in milliliters of blood removed per kilogram of body weight,
the phlebotomy volume has ranged from 48 to 405 mL/kg, with a median
volume of 267 mL/kg (Table 2).
Serum ferritin values before and after phlebotomy are also shown in
Table 2. The 14 children who received phlebotomy had an initial median
ferritin value of 2,630 ng/mL, and their most recent median ferritin
value has fallen to 424 ng/mL. Seven of the 14 phlebotomized patients
currently have a serum ferritin value under 500 ng/mL (Table 2). A
comparison of initial and latest serum ferritin values shows a
significant diminution in response to phlebotomy, P = 0.0015 by
Wilcoxon Signed Rank Test.
Clinical events.
No patient developed acute chest syndrome or other non-neurological
vaso-occlusive events requiring transfusions while on HU therapy. Six
children (38%) had minor painful events requiring outpatient
analgesia; patients #1 and #6 were hospitalized once for management of
pain. Three patients had new neurological events consistent with
recurrent stroke. Patient #13 had a severe occipital headache 13 weeks
after discontinuing transfusion therapy. Magnetic resonance imaging
(MRI) showed a new occipital infarction, and monthly
transfusion therapy was restarted. Patient #15 developed right
hemiparesis 16 weeks after discontinuing transfusion therapy, and MRI
showed a recurrent left cortical infarction. Her symptoms resolved
after double-volume exchange transfusion, and she resumed monthly
erythrocytapheresis. Patient #16 had isolated left-hand weakness 11 weeks after starting HU therapy; brain MRI was normal, but diffusion
studies were consistent with a new left cortical infarct. His symptoms
quickly resolved after exchange transfusion, and he also resumed
monthly transfusions. No patient has experienced a hemorrhagic
neurological event while on HU therapy.
| |
DISCUSSION |
Our results provide the first preliminary data to suggest that
hydroxyurea may be effective in the clinical setting of cerebrovascular disease in patients with SCD. The 16 pediatric patients with stroke who
enrolled in this protocol discontinued transfusions prospectively after
receiving blood for an average of almost 5 years, presumably with a
substantial ( 50%) risk of stroke recurrence.20 The
reasons to discontinue blood transfusions varied among our patients
(Table 1) and included an inability to find compatible blood because of
severe erythrocyte alloimmunization or autoantibody
formation,24 recurrent stroke while on transfusions,
noncompliance with the transfusion or chelation regimen, and severe
iron overload with DFO allergy. Several of our patients had a very high
risk for recurrence, including one child (#4) who had a second stroke
while on transfusions and 2 others (#3, #14) who had received
transfusions for less than 24 months (Table 1). With a median follow-up
of 22 months, our patients had a stroke recurrence rate of only 19%, suggesting that HU therapy may have helped to prevent recurrent stroke.
In comparison, the stroke recurrence rate at our institution for
patients receiving chronic transfusion therapy is approximately 11%,
similar to that recently reported by Pegelow and
colleagues.18
The mechanisms by which HU might provide protection against stroke
recurrence are not known, but the increase in HbF parameters (%HbF and
%F cells) likely is important in the prevention of in vivo sickling
within the stenotic cerebral vessels. Our patients achieved an average
%HbF of approximately 20% and %F cells of approximately 80% (Table
2), values that should inhibit intracellular sickling.26
Additional possible mechanisms include reductions in total white blood
cell count and absolute neutrophil count that accompany HU
therapy,27-29 as well as improved rheological characteristics of the erythrocytes caused by changes in erythrocyte morphology, adhesiveness, and cation content.30,31
Each of the recurrent neurological events occurred approximately 3 to 4 months after discontinuing transfusion therapy. This is likely the
period of highest risk for stroke recurrence, during which endogenous
HbS-containing erythrocytes are replacing the transfused
erythrocytes, but before the maximal beneficial hematologic effects of
HU therapy. The recently completed pediatric HU safety trial (HUG-KIDS), using the same HU dose escalation schedule, showed
that the hemoglobin concentration, MCV, %HbF, and %F cells increase
during the first 6 months of HU therapy, but continue to increase
between 6 and 12 months of therapy.29 At the time of their
stroke recurrence, our 3 children had an average %HbF level of only
10.4%, well below the %HbF levels achieved by the other patients
after prolonged HU therapy. More rapid escalation of the HU dose, or
initiating HU therapy several months before discontinuing transfusions,
might lead to a more rapid rise in HbF parameters and help prevent
these cases of early stroke recurrence. Importantly, no patient
experienced a hemorrhagic neurological event as was previously
described in a 20-year-old male with cerebrovascular disease receiving
HU therapy.32
The phlebotomy program was designed to reduce the iron burden and
stimulate erythropoiesis, thereby increasing the number of
HbF-containing reticulocytes and preventing stroke recurrence. The
phlebotomy regimen has been very well tolerated, and most patients have
10 mL/kg blood removed every 2 weeks while maintaining a hemoglobin
concentration above 8 g/dL (Table 2). Phlebotomy has led to steady
reductions in the total body iron stores, with substantial diminution
in the serum ferritin of all 14 patients who received phlebotomy. Seven
of the 14 patients who received phlebotomy currently have a serum
ferritin <500 ng/mL, and phlebotomy has been discontinued in 4 children whose ferritin values decreased to approximately 200 ng/mL.
These results compare favorably with those reported for patients with
beta-thalassemia, who received phlebotomy after curative allogeneic
bone marrow transplantation and had eventual mobilization of tissue
iron and reduction in liver iron concentration.33 Although
we have not performed a quantitative liver biopsy for iron burden on
our patients, one had superconducting susceptometry (SQUID) analysis
performed after stopping phlebotomy and was found to have normal
hepatic iron stores. SQUID analysis or liver biopsy may be necessary in
selected patients to confirm normalization of hepatic iron.
HU has been shown to be effective in reducing the number of painful
events, transfusions, and episodes of acute chest syndrome in adults
with sickle cell anemia.34 Similar clinical benefits have
been reported in small groups of pediatric patients.35-39 Based on our encouraging preliminary single-institution results, we
believe that larger multicenter trials may be warranted to determine
the clinical efficacy of HU in pediatric patients with sickle cell
disease, especially in the setting of cerebrovascular disease. To test
formally the efficacy of HU in preventing recurrent stroke, children
could receive prophylactic erythrocyte transfusions for 2 to 3 years
after the initial event, then randomize to either (1) continued
transfusions with iron chelation or (2) HU and phlebotomy to alleviate
iron overload. The study end points should include not only recurrent
clinical neurological events and changes in brain MR
imaging and angiography, but also financial costs, quality of life, and
the possible sequelae of continued transfusion therapy such as
transmission of infection, erythrocyte allosensitization, and iron
overload. Improved testing of blood units for infectious pathogens and
the use of antigen matching has reduced much of the morbidity
associated with chronic erythrocyte transfusion therapy, but iron
overload remains a serious long-term problem.40 Finally, HU
could also be considered for the prevention of primary stroke. Adams et
al41 have recently shown that transcranial doppler (TCD)
can identify children with SCD who have an increased risk of primary
stroke, and that transfusion therapy can prevent primary stroke in this
clinical setting.42 As additional children with SCD and
elevated TCD values become identified, perhaps HU therapy should be
considered as an alternative to chronic transfusions in this
asymptomatic population of patients.
| |
NOTE ADDED IN PROOF |
Patient 11, who was originally noncompliant with transfusions, became
noncompliant with hydroxyurea after 17 months and refused further
therapy. Four months later he developed a recurrent left hemiplegia.
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ACKNOWLEDGMENT |
The authors thank Dr Thomas R. Kinney and Erin O'Branski for support
of this clinical protocol and Dr Gary Brittenham for SQUID analysis.
The authors are also grateful to the nurses in the Duke Pediatric
Hematology/Oncology out-patient clinic, especially Jayne Cash, Anne
Fitzgerald, and Karen Lewis, and to the nurses at Pediatric Services of
America; without their dedication, the phlebotomy regimen could not
have been successfully completed.
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FOOTNOTES |
Submitted February 16, 1999; accepted June 28, 1999.
Supported in part by the Duke Children's Miracle Network Telethon.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Russell E. Ware, MD, PhD, PO Box 2916, Duke University Medical Center, Durham, NC 27710; e-mail:
ware0005{at}mc.duke.edu.
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REFERENCES |
1.
Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug P, Rida W:
Mortality in children and adolescents with sickle cell disease.
Pediatrics
84:500, 1989[Abstract/Free Full Text]
2.
Gray A, Anionwu EN, Davies SC, Brozovic M:
Patterns of mortality in sickle cell disease in the United Kingdom.
J Clin Pathol
44:459, 1991[Abstract/Free Full Text]
3.
Serjeant GR:
The clinical features of sickle cell disease.
Baillieres Clin Haematol
6:93, 1993[Medline]
[Order article via Infotrieve]
4.
Balkaran B, Char G, Morris JS, Thomas PW, Serjeant BE, Serjeant GR:
Stroke in a cohort of patients with homozygous sickle cell disease.
J Pediatr
120:360, 1992[Medline]
[Order article via Infotrieve]
5.
Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow CH, Gill FM:
Cerebrovascular accidents in sickle cell disease: Rates and risk factors.
Blood
91:288, 1998[Abstract/Free Full Text]
6.
Stockman JA, Nigro MA, Mishkin MM, Oski FA:
Occlusion of large cerebral vessels in sickle-cell anemia.
N Engl J Med
287:846, 1972
7.
Adams RJ, Nichols FT, McKie V, McKie K, Milner P, Gammal TE:
Cerebral infarction in sickle cell anemia: Mechanism based on CT and MRI.
Neurology
38:1012, 1988[Abstract/Free Full Text]
8.
Ohene-Frempong K:
Stroke in sickle cell disease: Demographic, clinical and therapeutic considerations.
Semin Hematol
28:213, 1991[Medline]
[Order article via Infotrieve]
9.
Craft S, Schatz J, Glauser TA, Lee B, DeBaun MR:
Neuropsychologic effects of stroke in children with sickle cell anemia.
J Pediatr
123:712, 1993[Medline]
[Order article via Infotrieve]
10.
Cohen MJ, Branch WB, McKie VC, Adams RJ:
Neuropsychological impairment in children with sickle cell anemia and cerebrovascular accidents.
Clin Pediatr
33:517, 1994
11.
Powars D, Wilson B, Imbus C, Pegelow C, Allen J:
The natural history of stroke in sickle cell disease.
Am J Med
65:461, 1978[Medline]
[Order article via Infotrieve]
12.
Russell MO, Goldberg HI, Hodson A, Kim HC, Halos J, Reivich M, Schwartz E:
Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease.
Blood
63:162, 1984[Abstract/Free Full Text]
13.
Milner PF:
Chronic transfusion regimens in sickle cell disease.
Prog Clin Biol Res
98:97, 1982[Medline]
[Order article via Infotrieve]
14.
Piomelli S:
Chronic transfusions in patients with sickle cell disease.
Am J Pediatr Hematol/Oncol
7:51, 1985[Medline]
[Order article via Infotrieve]
15.
Lusher JM, Haghighat H, Khalifa AS:
A prophylactic transfusion program for children with sickle cell anemia complicated by CNS infarction.
Am J Hematol
1:265, 1976[Medline]
[Order article via Infotrieve]
16.
Russell MO, Goldberg HI, Reis L, Friedman S, Slater R, Reivich M, Schwartz E:
Transfusion therapy for cerebrovascular abnormalities in sickle cell disease.
J Pediatr
88:382, 1976[Medline]
[Order article via Infotrieve]
17.
Sarnaik S, Soorya D, Kim J, Ravindranath Y, Lusher J:
Periodic transfusions for sickle cell anemia and CNS infarction.
Am J Dis Child
133:1254, 1979[Abstract/Free Full Text]
18.
Peglow CH, Adams RJ, McKie V, Abboud M, Berman B, Miller ST, Olivieri N, Vichinsky E, Wang W, Brambilla D:
Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions.
J Pediatr
126:896, 1995[Medline]
[Order article via Infotrieve]
19.
Wilimas J, Goff JR, Anderson HR Jr, Langston JW, Thompson E:
Efficacy of transfusion therapy for one to two years in patients with sickle cell disease and cerebrovascular accidents.
J Pediatr
96:205, 1980[Medline]
[Order article via Infotrieve]
20.
Wang WC, Kovnar EH, Tonkin IL, Mulhern RK, Langston JW, Day SW, Schell MJ, Wilimas JA:
High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease.
J Pediatr
118:377, 1991[Medline]
[Order article via Infotrieve]
21.
Ware RE, Steinberg MH, Kinney TR:
Hydroxyurea: An alternative to transfusion therapy for stroke in sickle cell anemia.
Am J Hematol
50:140, 1995[Medline]
[Order article via Infotrieve]
22.
Marcus SJ, Kinney TR, Schultz WH, O'Branski EE, Ware RE:
Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle cell disease.
Am J Hematol
54:40, 1997[Medline]
[Order article via Infotrieve]
23.
Hollander M, Wolfe D:
Nonparametric Statistical Methods. New York, NY, Wiley, 1973
24.
Adams DM, Schultz WH, Ware RE, Kinney TR:
Erythrocytapheresis can reduce iron overload and prevent the need for chelation therapy in chronically transfused pediatric patients.
Am J Pediatr Hematol/Oncol
18:46, 1996
25.
Castellino SM, Combs MR, Zimmerman SA, Issitt PD, Ware RE:
Erythrocyte autoantibodies in paediatric patients with sickle cell disease receiving transfusion therapy: Frequency, characteristics, and significance.
Br J Haematol
104:189, 1999[Medline]
[Order article via Infotrieve]
26.
Noguchi CT, Rodgers GP, Serjeant GR, Schechter AN:
Levels of fetal hemoglobin necessary for treatment of sickle cell disease.
N Engl J Med
318:96, 1988[Medline]
[Order article via Infotrieve]
27.
Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG:
Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.
J Clin Invest
74:652, 1984
28.
Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, Milner PF, Orringer EP, Phillips G Jr, Platt OS, Thomas GH:
Hydroxyurea: Effects on hemoglobin F production in patients with sickle cell anemia.
Blood
79:2555, 1992[Abstract/Free Full Text]
29. Kinney TR, Helms RW, O'Branski EE, Ohene-Frempong K, Wang W,
Daeschner C, Vichinsky E, Redding-Lallinger R, Gee B, Platt OS,
Ware RE: Safety of hydroxyurea in children with sickle
cell anemia: Results of the HUG-KIDS study, a Phase I/II trial.
Blood, in press
30.
Adragna NC, Fonseca P, Lauf PK:
Hydroxyurea affects cell morphology, cation transport, and red blood cell adhesion in cultured vascular endothelial cells.
Blood
83:553, 1994[Abstract/Free Full Text]
31.
Bridges KR, Barabino GD, Brugnara C, Cho MR, Christoph GW, Dover G, Ewenstein BM, Golan DE, Guttmann CR, Hofrichter J, Mulkern RV, Zhang B, Eaton WA:
A multiparameter analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy.
Blood
88:4701, 1996[Abstract/Free Full Text]
32.
Vichinsky EP, Lubin BH:
A cautionary note regarding hydroxyurea in sickle cell disease.
Blood
83:1124, 1994[Abstract/Free Full Text]
33.
Angelucci E, Muretto P, Lucarelli G, Ripalti M, Baronciani D, Erer B, Galimberti M, Giardini C, Gazier D, Polchi P:
Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation.
Blood
90:994, 1997[Abstract/Free Full Text]
34.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR:
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia.
N Engl J Med
332:1317, 1995[Abstract/Free Full Text]
35.
Scott JP, Hillery CA, Brown ER, Misiewicz V, Labotka RJ:
Hydroxyurea therapy in children severely affected with sickle cell disease.
J Pediatr
128:820, 1996[Medline]
[Order article via Infotrieve]
36.
Jayabose S, Tugal O, Sandoval C, Patel P, Puder D, Lin T, Visintainer P:
Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia.
J Pediatr
129:559, 1996[Medline]
[Order article via Infotrieve]
37.
Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, Fondu P, Toppet M, Sariban E:
Hydroxyurea for treatment of severe sickle cell anemia: A pediatric clinical trial.
Blood
88:1960, 1996[Abstract/Free Full Text]
38.
de Montalembert M, Belloy M, Bernaudin F, Gouraud F, Capdeville R, Mardini R, Philippe N, Jais JP, Bardakdjian J, Ducrocq R, Maier-Redelsperger M, Elion J, Labie D, Girot R:
Three-year follow-up of hydroxyurea treatment in severely ill children with sickle cell disease. The French Study Group on Sickle Cell Disease.
J Pediatr Hematol Oncol
19:313, 1997[Medline]
[Order article via Infotrieve]
39.
Olivieri NF, Vichinsky EP:
Hydroxyurea in children with sickle cell disease: Impact on splenic function and compliance with therapy.
J Pediatr Hematol Oncol
20:26, 1998[Medline]
[Order article via Infotrieve]
40.
Rosse WF, Telen MJ, Ware RE:
Transfusion support for patients with sickle cell disease. Bethesda, MD, AABB Press, 1998
41.
Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, Figueroa R, Litaker M, Thompson W, Hess D:
The use of transcranial ultrasonography to predict stroke in sickle cell disease.
N Engl J Med
326:605, 1992[Abstract]
42.
Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D:
Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography.
N Engl J Med
339:5, 1998[Abstract/Free Full Text]
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|
|
|
|
|
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|
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ABSTRACT
INTRODUCTION