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First Report of Reversal of Organ Dysfunction in Sickle Cell Anemia by the
Use of Hydroxyurea: Splenic Regeneration
By Susan Claster and Elliott Vichinsky
Much of the morbid* associated with sickle cell anemia
(SCA) is due to ongoing infarction resulting in organ dysfunction. Because the spleen is often the first organ damaged in this illness. there is a significant impairment of the
immune system in thesepatients.Hydroxyurea (HU) has
beenshown to increase fetal hemoglobin (HbF) anddecrease painful episodes in patients with this disease. It is
unclear whether HU can prevent organ damage.We treated
two SCA patients with HUfor several years and found evidence of reversal of previously documented splenic dysfunction. Patient no. 1 was treated for 30 months with an increase in HbF to 30%. HU was stopped becauseof cytopenia.
She developedleft upper quadrant pain. A splenectomy
was
performeddue to the possibility of splenicabscesses. A
pathologic review found no evidence of infection and an
enlarged spleen that showed active germinal centers. Patient no. 2 was treated for 24 months with HUbefore developing splenomegaly. His HbF levels were 25% to 30%. his
pit counts averaged2%, and his liver spleen scans showed
uptake. Thesetwo cases show that chronic HU therapy may
reverse splenic dysfunctionin certain patients and suggest
that this drug may have efficacy beyond the elimination of
pain in SCA.
0 7996 by The American Society of Hematology.
M
occasions, beginning in May 1977. Seven months later, her
spleen wasno longer palpable. A liver-spleen &can performed in early 1979 showed no splenic activity. She received 5 U of blood over a 4-month period in mid 1979,
and her spleen became palpable for approximately 6 months.
In 1980, a pit count was 8.0%. She received transfusions
again between 1984 and 1986, including a 7-U exchange
transfusion in 1985; however, her spleen never again became
palpable. A repeat liver-spleen scan in 1984 was unchanged.
A bone scan in 1987 showed splenic activity consistent with
splenic fibrosis and cal~ification.’~
She was started on HU therapy in 1987 at the age of 20.
At that time, her hemoglobin level was 6.3 g/dL and her
HbF was 4.1%. Thirty months later, her HbF had increased
to 30%. However, several months later, her HU therapy was
discontinued because of cytopenia. Her hemoglobin level
decreased to 6.0 g/dL from 9.4 g/dL. Her platelet count
decreased to 35,000. Her absolute neutrophil count was
2,000. She was admitted to the hospital. During that admission, she presented with left upper quadrant pain and fever.
No splenomegaly was noted on exam.A computer tomography (CT) scan of her abdomen showed an enlarged spleen
with focal lesions, consistent with either nodular regeneration or abscesses. Splenectomy was performed because of
the concern about the latter. Her spleen weighed 294 g.
Microscopic examination showed cords filled with RBCs.
Reactive germinal centers were also seen, consistent with
UCH OF THE MORBIDITY associated with sickle
cell anemia (SCA) is the result of progressive organ
damage due to sickling-induced infarction. One of the earliest organs to be damaged is the spleen.’ As the level of fetal
hemoglobin (HbF) decreases to less than 15% to 20% during
early childhood, the corresponding increase in hemoglobin
S causes progressive dysfunction in this organ.* Youngchildren with SCA often have an enlarged but poorly functioning
spleen. Eventually, the spleen completely autoinfarcts and
becomes nonfunctional, resulting in significant impairment
of the patient’s immune ~ y s t e m . ~ . ~
MATERIALSANDMETHODS
There are two commonly used methods for evaluating splenic
function. The first, radionuclide scanning, uses the uptake ofthe
technetium-99 isotope, attached to a sulphur colloid particle, to show
.~
the functioning of the reticuloendothelial cells of the ~ p l e e n The
other method measures splenic function by quantitation of pitted red
blood cells (RBCs) using phase contrast microscopy to show surface
pits6 A normally functioning spleen removes these imperfections.
In sickle cell disease, the level of pitted RBCs is inversely related
to HbF and increases withage.’ A pit count greater than 3.5%
has been determined to indicate splenic dysfunction.’ Using these
techniques, previous studies have shown that transfusion therapy as
well as bone marrow transplantation can reverse splenic dysfunction
in certain individuals.’”’
Hydroxyurea (HU) has been administered to sickle cell patients
because of its ability to increase HbF levels and thereby retard
sickling.’* Previous studies have shown this drug has the ability to
decrease the number of painful episodes in SCA patient^.'^ The
ability of HU to sustain elevations of HbF as high as 20% to 30%
in some patients suggests that the use of this drug may offer some
potential reversal of organ damage without the attendant risks of
transfusion. Wenow report the return of splenic function in two
patients who were treated with long-term HU therapy. This is the
first evidence this drug may, in fact, reverse organ dysfunction in
some sickle cell patients.
RESULTS
Patient nu. I. Patient no. 1 is a 27-year-old woman with
SCA who has had a severe clinical course. Her previous
history has been characterized by multiple episodes of vasoocclusion, acute chest syndrome, and sepsis. Her spleen remained consistently palpable until the age of 10 (1977).
Between the ages of 10 and 19, she was transfused on seven
Blood, Vol 88, No 6 (September 15). 1996: pp 1951-1953
From the Department of Medicine, Highland General Hospital,
Oakland, CA: and the Department of Hematology/Oncology Sickle
Cell Program, Children’s Hospital of Northern California, Oakland,
CA.
Submitted December 18, 1995; accepted April 29, 19%.
Supported in part by the Northern California Comprehensive
Sickle Cell Cenber, a program of the Sickle Cell Disease Branch of
the National Heart, Lung and Blood Institute (Grant No, HL-20985).
Address reprint requests to Susan Claster, MD, The Department
of Hematology, Children’s Hospital Oakland, 747 52nd St, Oakland,
CA 94609.
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.
0 19% by The American Society of Hematology.
0006-4971/96/8806-04$3.00/0
1951
From www.bloodjournal.org by guest on December 22, 2014. For personal use only.
1952
CLASTER AND VlCHlNSKY
active immune function. There was diffuse fibrosis. No extramedullary hematopoiesis was seen and neither was there
any evidence of infection. HU therapy was not restarted.
Patient no. 2. Patient no. 2 is a 21-year-oldmanwith
SCA who was first seen at our institution at the age of 5.
At that time, a 3-cm
spleen was noted on physical exam.
HbF was measured at the age of 7 and found to be 13.6%.
Pit counts performed at this time were 4.7%. In 198 I , at the
age of 8, the HbF wasnoted to be 10.4% and a liver-spleen
scan showed absent uptake of tracer. He received his first
transfusion that same year and his spleen became somewhat
smaller. He underwent two exchange transfusions in 1983
for priapismwithout significant change in his splenomegaly.
His splenomegaly persisted until late 1988 (age 15).By January1989, his spleen was no longer palpable. He received
transfusions from January through May 1989 for priapism,
as well as exchange transfusions in 1990 and 1991 for acute
chest syndrome.Hislast course of transfusions was from
May through November 1991 foraseptic necrosis of his hips.
Despite these transfusions, his spleen remained undetectable
by physical exam. A bone scan performed in 199 1 showed
minimal splenic activity, consistent with splenic fibrosis and
calcification.I4
In January 1992, he was started on HU therapy. His pretreatment hemoglobin level was 7.0 g/dL and his HbF was
7.0%. Within 6 months, his total hemoglobin level had increased to 1 1.0 g/dL and his HbF had increased to 25% to
30%. He was maintainedon a dose of 17.0 mg/kg. His spleen
was not palpableon multiple occasions. Twenty-fourmonths
after starting therapy, he was noted to have palpable splenomegaly,which haspersisted for36 months.Liver-spleen
scans have shown splenic uptake, and pit counts have averaged 2.0%.
DISCUSSION
The morbidity associated with splenic autoinfarction is of
great concern to providers who care for youngpatients with
SCA. Although the use of prophylactic penicillin decreases
the risk of overwhelming sepsis from encapsulated organi s m ~ ,there
' ~ are now ominous
reports of prophylaxis failures
due to penicillin-resistant strains."
Splenic dysfunction in SCA patients has previously been
reported to be reversible. Pearson showed that five children
with splenomegaly showed uptake on spleen scans after the
level of hemoglobin S was reduced toless than 50% by
transfusions.' Wethersand Grover"' reported twoyoung
adults with elevated pit counts that transiently normalized
aftertransfusions.Buchanan
et al' found thatpatientson
an intensive hypertransfusion regimen had normal or only
slightlyincreased pitcountsandevidence
of uptake on
spleen scans. Recently, correction of splenic dysfunction in
threesicklecellpatientswho
underwentsuccessful bone
marrow transplantation has also been shown."
The exact mechanism of the HU-inducedeffecton
the
spleen is unclear. It is probably related to the chronic elevation of HbF and the resultantinhibitionofsickling.
This
mechanism is also seen in these patients with SCA who have
genetically elevated levels of HbF and who have splenomegaly as adults." It is unclear what duration of HU therapy
might be required to improve splenic function.Patient no. 2
clearly developed splenomegaly after 24 months on therapy,
and patient no. 1 developedsplenic abnormalitieson CT
scan 29months after the initiation of HU. However, pit
counts and spleenscans werenotprospectivelyobtained
inthesepatients.
Thosepatients with ongoing functional
hyposplenism who receive this drug may require a shorter
period of time to show improvement. It is also possible that
patients with severely fibrosed spleens will not respond at
all to this drug. A prospective study involving a larger group
of patients is clearly warranted to answer these questions.
Transfusions have been the traditional modality for treatment of chronic complications of sickle cell disease. However, it is well known that the use of transfusions is fraught
with problems, including iron overload, alloantibody formation, and infection.18 HU has now been used to treat complications such as leg ulcers and stroke when transfusions were
unable to be administered.'"'" The improvement in splenic
function in response to this drug suggests that other organ
systems that are damaged by the effects of SCA may also
respond favorably to the effects of prolonged elevations in
HbF.
The reversal of splenic dysfunctioninduced by HU in two
young adults suggests that serious consideration should be
given to administering this drug to young children.As in
previous studies withtransfusions, these are thepatients with
the greatest chance of reconstitution of splenic function. In
fact, early HU therapy might potentially prevent functional
hyposplenism in this group of patients. If this were the case,
it might obviate theneed for prophylactic antibiotics. Further
studies of this drug would also be aided by measurements
of immune function before and after therapy.
Finally, as HU use increases in SCA, more patients will
receive the drug chronically. This may result in an increased
incidenceof splenomegalyand functionalhyposplenism.
Therefore, it is important for providers who care for these
patients to evaluate the possibility of splenic infarct or sequestration in thosepatients who present with left upper
quadrant pain. This isespeciallyimportant
in thoseolder
patients who havebeen on long-term therapy and whowould
otherwise not be at risk for this complication.
ACKNOWLEDGMENT
The authors thank R. Vercher for her assistance in preparing this
manuscript.
REFERENCES
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From www.bloodjournal.org by guest on December 22, 2014. For personal use only.
SPLENIC REGENERATION
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1953
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From www.bloodjournal.org by guest on December 22, 2014. For personal use only.
1996 88: 1951-1953
First report of reversal of organ dysfunction in sickle cell anemia by
the use of hydroxyurea: splenic regeneration
S Claster and E Vichinsky
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