Download Management_of_sickle_cell_disease

Management of sickle cell disease last revised December 20, 2000
Management of Patients with Sickle Cell Disease
An Overview
Contents
Background
Nature of the Problem
Modulators of SCD Severity
Origin of the Sickle Mutation
Management of Acute Problems
Pain
Acute chest syndrome
Infection
Bone marrow necrosis
Stroke
Splenic sequestration crisis
Aplastic crisis
Hepatic sequestration crisis
Priapism
Management of Chronic Problems
Pain
Anemia
infection prophylaxis
Avascular bone necrosis
Osteomyelitis
skin ulcers
Renal dysfunction
Retinopathy
Heart
Pregnancy
Newer Therapies
Hydroxyurea
Erythropoietin
Butyrate
Clotrimazole
Nitric Oxide
FluocorTM
Bone marrow transplantation
Gene replacement therapy
References
Background
Nature of the Problem
Sickle cell disease (SCD) results from the substitution of a valine residue for
glutamic acid at position 6 in the beta-subunit of hemoglobin (Ingram, 1956).
With a few minor exceptions, people with only one gene for hemoglobin S (Hb S)
are phenotypically normal (sickle trait). People who inherit two Hb S genes from
their parents have sickle cell disease. Deoxygenated Hb S tends to polymerize
non-covalently into long strands that deform the erythrocyte, giving the
characteristic "sickle cell" morphology (Eaton and Hofrichter, 1990). Hb S with
bound oxygen (e.g., in the arterial circulation) does not polymerize.
The mechanism by which these changes in the physical properties of the
hemoglobin molecule produce the clinical manifestations of the disease is not
unequivocally proven. The most widely accepted hypothesis is that erythrocytes
deform as they release their oxygen in the capillaries and are trapped in the
microcirculation (Eaton et al., 1976) (Kaul et al., 1989). The blockade of blood
flow produces areas of tissue ischemia, leading to the myriad of clinical
problems seen with sickle cell disease. Although a good deal of indirect
evidence supports this theory, definitive proof that this is the
pathophysiologic mechanism in sickle cell disease is lacking.
Recently, investigators have focused on other factors outside the red cell that
could contribute to the manifestations of sickle cell disease. Hebbel and
colleagues first showed that sickle erythrocytes adhere abnormally to vascular
endothelial cells. Their observations were confirmed and extended by other
workers. The endothelial cells may abnormally express adhesion receptors,
perhaps in response to activators released from sickle red cells (e.g., reactive
oxygen species). Other investigators have focused on leucocytes and platelets
which might also contribute to disturbed blood flow in sickle cell disease. The
involvement of multiple components of the blood in the manifestations of sickle
cell disease makes understanding the pathophysiology more difficult. On the
other hand, these additional modulators could be targeted by new therapies, with
diminution in the severity of sickle cell symptoms.
Sickle cell disease is extremely varied in its manifestations (Ballas, 1991)
(Wethers, 1982). This includes both the organ systems that are affected as well
as the severity of the affliction. A study of the natural history of sickle cell
disease indicated that about 5% of patients account for nearly one-third of
hospital admissions (Platt et al., 1991). A significant number of patients with
the disease have few admissions and live productive and relatively healthy
lives. The average life-span of people with sickle cell disease is shorter than
normal, however, reflecting increased mortality due to the complications of the
disease.
Modulators of SCD Severity
Fetal Hemoglobin
Variations in the severity of sickle cell disease between individuals usually
defy explanation. Some factors have been identified that ameliorate the severity
of the condition, however. The most important of these is a high level of
hemoglobin F (Hb F) in the erythrocytes (Platt et al., 1991). The first insight
into the role of fetal hemoglobin in the clinical manifestations of SCD was made
by a pediatrician, Janet Watson (Watson, et al., 1948). She and her colleagues
at a New York hospital noted that babies with SCD rarely had manifestations of
the condition in the first year of life. They proposed that the high level of
fetal Hb in the red cells, which persists during the first year of life, somehow
protects the infant. Fetal Hb levels decline to their routinely low steady-state
level between the ages of one to two years. The childhood manifestations of SCD
are seen thereafter.
Patients with sickle cell disease who also have hereditary persistence of fetal
hemoglobin (HPFH) often have few if any symptoms (Stamatoyannopoulos et al.,
1975). In these individuals, Hb F usually comprises greater than 20% of the
hemoglobin in the erythrocytes. Patients may be partially protected from the
ravages of sickle cell disease with even lower levels of Hb F. Unfortunately,
few patients with SCD have Hb F levels of greater than 10 or 11% in the absence
of HPFH.
Fetal Hb disrupts the polymerization of deoxy-Hb-S (Goldberg et al., 1977).
Since polymerization of deoxy-Hb-S is the signal event in the pathogenesis of
SCD, fetal Hb effectively prevents disease manifestation. The distribution of Hb
F among RBCs is also important. In hereditary persistence of fetal hemoglobin
(HPFH), Hb F exists at high levels in all red cells. All red cells are equally
protected from sickling. In the absence of HPFH, patients with high levels of Hb
F have a heterogeneous distribution of fetal hemoglobin between cells. An over
simplified example is a patient in whom half the cells have 30% Hb F and half
have 0%. The patient would have 15% Hb F overall. However, half the cells would
sickle and occlude flow through the microcirculation. These deformed cells would
block the flow of the normally shaped high Hb F cells. The patient would
experience all the manifestations of sickle cell disease.
Alpha-thalassemia
Relative to patients with straightforward sickle cell disease, the rate of
hemolysis is lower in people who also have two-gene deletion alpha-thalassemia
(Embury et al., 1982). The mechanism by which alpha-thalassemia ameliorates red
cell destruction is unknown. Polymerization of sickle hemoglobin is
exponentially related to its concentration in the cell. The red cell hemoglobin
concentration in patients with two gene deletion alpha-thalassemia and sickle
cell disease is no different from that of patients with ordinary sickle cell
disease, however (Steinberg and Embury, 1986). The Hb F concentrations often is
higher in the red cells of these patients and may contribute partially to the
reduction in the rate of hemolysis.
Harbingers of Ill
The advent of therapies that can significantly ameliorate the clinical course of
sickle cell disease opens the possibility of early intervention. If physicians
could predict which children will fall victim to recurrent severe pain crises or
bouts of acute chest syndrome, they could intervene before the clinical episodes
thereby preventing the associated morbidity and possible mortality. This is
particularly relevant for treatments such as bone marrow transplantation that
can cure sickle cell disease but also carry the risk of significant morbidity
and even mortality.
Table 1. Factors that Correlate with a Severe Clinical Course in Sickle Cell
DiseaseAn episode of dactylitis prior to one year of age.
A hemoglobin level of less than 7 g/dl before age 2 years.
Persistent leucocytosis in the absence of infection
Miller and colleagues (2000) examined the records of nearly 400 children
followed at comprehensive sickle cell centers. Their multivariate analysis of
the clinical courses of these children between infancy and 10 years of age
uncovered several factors that augured severe complications, including recurrent
severe pain episodes, stroke and acute chest syndrome. As seen in Table 1, the
variables can be easily identified. Children who manifest these characteristics
can be considered for aggressive early treatment of their sickle cell disease. A
smaller study that tracked the course of adult and pediatric patients over a
7-year period found that adults with an elevated white count experienced more
frequent hospital admissions for painful vaso-occlusive crises than did those
with lower white counts (Olatunji, et al., 2000). Interestingly, none of the
assessed variables correlated with severity in the children. The smaller size of
the study and the the greater age range of the children evaluated likely account
for the difference from the report by Miller and colleagues (2000). Together,
these reports point to high white count as a significant risk factor of adverse
events in patients with sickle cell disease.
The relationship of stroke risk to high blood velocity in the intracranial
arteries is discussed below.
Origin of the Sickle Mutation
Beta-globin haplotypes
The beta-globin gene exists in a region of chromosome 11 called the "beta globin
locus." Random mutations occur in the non-coding regions of the beta-globin
locus which are neither selected for or against. When a gene mutation occurs in
the coding region of the beta-globin gene (for instance, the conversion of
glutamic acid to valine at postion 6 in sickle hemoglobin), the surrounding
non-coding region is not affected. The genetic background of the surrounding
region is called the "haplotype" of that particular mutation. The chance is
extreme small that another radom mutation will occur in the non-coding region.
Therefore, the haplotype of a particular gene mutation event is fixed. Analysis
of the genomic structure of the beta-globin gene shows consistent patterns of
base substitutions in the non-coding regions of the Hb S gene (Bouhassira et
al., 1989). The structural regions of the Hb S genes are identical. The
substitutions in the flanking regions of the gene (the haplotypes) show that Hb
S arose separately at least four times in Africa, and once in Asia, probably in
India (Nagel and Fleming, 1992). The four African haplotypes show broad trends
in disease severity. The Central African Republic haplotype tends to have the
least favorable clinical course, followed by the Benin and Senegal haplotypes
(Powars and Hiti, 1993). The ranking of the more recently described fourth
haplotype, Cameroon, is uncertain.
No clear explanation exists for the differences in average severity between the
haplotypes. The mutations in the flanking region could secondarily affect
severity by altering Hb F expression in the cells. This is only a hypothesis,
however. The patterns of severity apply only to populations. Broad overlap in
the clinical patterns prevents the use of haplotypes to predict the clinical
course in a particular person. Usually, people with sickle cell disease outside
Africa (e.g., blacks in the United States) or India have mixed haplotypes for
their sickle cell genes. Analysis of haplotype in this setting is even less
likely to provide clinically useful information.
Hb S is common in some areas of the Mediterranean basin, including regions of
Italy, Greece, Albania and Turkey (Boletini et al., 1994) (Schiliro et al.,
1990). Haplotype analysis shows that the Hb S in these areas originated in
Africa. The genes probably moved along ancient trading routes between wealthy
kingdoms in western Africa and the trade centers in the Mediterranean basin. The
high levels of Hb S attained in some areas reflects partial protection against
protection against malaria provided by sickle cell trait (see below).
The Hb S mutation arose independently a fifth time in southwest Asia (Miller et
al., 1987). The area of the Middle East near the head of the Persian Gulf is
very marshy. In the past the area was swampy and harbored malaria. Malaria
remains endemic to much of the Indian subcontinent. The fact that the Hb S
mutation apparently arose in response to malaria in southwest Asia supports the
"malaria explanation" of the prevalence of the gene. The identity of the
hemoglobin S haplotype in India and the Persian Gulf region suggests that it
arose in one area and moved to the other with trade or migration (Ramasamy et
al., 1994) (Kar et al., 1986). Although we cannot be certain of the origin of
the Asian haplotype of the sickle cell gene, the very high prevalence of the
gene in tribal peoples of India suggest that the subcontinent was the place of
origin. This Asian variety of Hb S may on average produce fewer complications
than its African counterparts (Perrine et al., 1978).
The Sickle Gene and Malaria
The high representation of the hemoglobin S gene in some populations reflects
the protection it provides against malaria (Gendrel et al., 1991) (Carlson et
al., 1994). The malaria parasite does not survive as well in the erythrocytes of
people with sickle trait as it does in the cells of normals (Orjih et al.,
1985). The basis of the toxicity of sickle hemoglobin for the parasite is
unknown. One possibility is that the malarial parasite produces extreme hypoxia
in the red cells of people with sickle trait. These cells then sickle and are
cleared (along with the parasites they harbor) by the reticuloendotheila system
(Roth, et al, 1978). Another possible mechanism is that low levels of
hemichromes are formed in sickle trait erythrocytes. Hemichromes are complexes
that contain heme moieties that have dissociated from the hemoglobin.
Hemichromes catalize the formation of reactive oxygen species, such as the
hydroxyl radical, which can injury or even kill the malarial parasites
(Anastasi, 1984).
The malaria hypothesis maintains that during prehistory, on average, people
without the sickle gene died of malaria at a high frequency. On the other hand,
people with two genes for sickle hemoglobin died of sickle cell disease. In
contrast, the heterozygotes (sickle trait) were more resistant to malaria than
normals and yet suffered none of the ill-effects of sickle cell disease. This
selection for heterozygotes is termed "balanced polymorphism". Support for this
concept comes from epidemiological studies in malaria-endemic regions of Africa.
The frequency of sickle cell trait is lower in people coming for treatment to
malaria clinics than is seen in the general population (Wilcox, et al., 1983).
The reasonable assumption is that relative protection form malaria is at work in
this situation.
Although malaria remains a major health problem in many tropical regions of the
world, the disease is not a significant threat to people in the temperate zones.
Consequently, the protection afforded by sickle trait no longer has a survival
advantage for many groups of people in whom the sickle cell gene is common. This
has left sickle cell disease as the major health issue in these populations.
Management of Acute Problems
Pain
Vaso-occlusive pain episodes experienced by patients with sickle cell disease
vary tremendously in frequency and severity. Some patients rarely have painful
crises, while others spend the greater part of a given year in the hospital
receiving analgesics. The cooperative study of the natural history of sickle
cell disease showed that about 5% of patients accounted for one-third of
hospital days devoted to pain control (Platt et al., 1991). To complicate
matters further, the pattern of pain varies over time, so that a patient who has
a particularly severe year may later have a prolonged period characterized by
only minor pain. The frequency and severity of vaso-occlusive pain episodes
often change as a person moves from childhood to being an adult. The
"breakpoint" often occurs during the late teens or early 20's. Changes in
hormonal status that occur during these years could contribute to the changes in
severity of sickle cell disease. However, no causal relationship has been
established, so the association remains only temporal.
The mode of onset of sickle cell pain crises likewise varies. Patients can
develop agonizingly severe pain in as little as 15 minutes. In other instances,
the pain gradually escalates over hours or even days. Patients manage most
episodes of pain at home. Oral analgesics, combined with rest and fluids often
allows a person to "ride out" the pain episode. Some patients report that warm
baths or warm compresses applied to aching joints ameliorates the severity of
the pain.
The sites affected in acute painful crises vary for each patient. Pain occurs
commonly in the extremities, thorax, abdomen, and back (Ballas and Delengowski,
1993). Pain tends to recur at the same site for a particular person. For each
person, the quality of the crisis pain is usually similar from one crisis to
another. During the evaluation, the provider should question the patient as to
whether the pain feels like "typical" sickle cell pain. Most patients can
distinguish back pain due to pyelonephritis or abdominal pain due to
cholecystitis, for instance, from their typical sickle cell pain. If the quality
of the pain is not typical of their sickle cell disease, other causes should be
investigated before ascribing it to vaso-occlusion.
No reliable objective index of pain exists. The provider depends solely on the
patient's report. One of the most difficult problems that patients with sickle
cell disease face is seeking treatment for pain in a setting in which they are
unknown. The typical scenario is one in which a patient is brought to a busy
emergeny room complaining of pain. Some patients writh with severe pain while
others are stoic. The person who bears the pain with as much poise as possible
runs the risk of not being believed by the staff. Some providers mistakenly
believe that the number of deformed sickle cells on the peripheral blood smear
reflects the degree of pain that a patient is experiencing. Other providers look
to parameters such as blood pressure and heart rate. Although these measures
provide more information than the peripheral smear, they do not reliably reflect
pain severity. Trust in the patient report is key to the management of sickle
cell pain crises.
Opiods
The pain experienced with an acute painful crisis typically is quite severe.
Most patients describe a full blown crisis as the most intense pain that they
have ever experienced. The pain sometimes increases in severity slowly over a
couple of days. At other times, a crescendo is reached in less than 15 minutes.
Pain control often requires large quantities of opiod analgesics. The exact
amount varies, and depends in part on the frequency with which the person
requires opiods. For many patients, 4 to 8 mg of hydromorphone can be given as
an intravenous bolus over 15 to 20 minutes followed by another 4 mg in 30
minutes if pain control is inadequate.
Patients often feel that one analgesic, such as hydromorphone for example,
controls pain more effectively than others. Therefore, they should be questioned
about the kind of medication that has worked best in the past. Also, some
patients may experience reactions with one analgesic (e.g., itching with
meperidine) but not with others (Pegelow, 1992).
Pain relief occurs more slowly with intramuscular injections, and the injections
themselves can produce substantial discomfort. Consequently, intravenous
administration of analgesics is usually preferable. As pain control improves,
the analgesia should be maintained to prevent the patient from slipping back
into a painful cycle. The "prn" administration of analgesics should be avoided,
if possible (Robieux et al., 1992). Following stabilization in the emergency
situation with intravenous boluses of opiods, the patient should be transferred
to the floor and placed a maintenance regimen. "Patient-controlled analgesia"
(PCA) often works well for pain relief (Holbrook, 1990) (McPherson et al.,
1990). With these infusion devices, patients can administer small doses of
additional medication over their continuous infusion (to a fixed maximum) to
control flares of pain.
Patients can become drowsy as their pain is controlled. Often, this reflects the
fatigue that comes with one or more sleepless nights with pain at home. The
analgesics should not be discontinued automatically for somnolence as long as
the patient is easily aroused. A common misconception is that if a person is
sleeping, the analgesics are controlling the pain. Patients often sleep despite
severe pain. The quantity of analgesia can be slowly reduced as the patient's
symptoms improve. While the tapering of intravenous analgesics can require only
two or three days, control of a full blown crisis often requires 10 to 14 days.
Less commonly, bouts of sickle vaso-occlusive pain require several weeks to
control.
Meperidine can present problems for pain control in patients with sickle cell
disease. The half-life of the drug in the circulation is about 4 hours. The
liver converts meperidine to normeperidine, a derivative that has analgesic
activity but which also is toxic. Grand mal seizure is a particularly serious
complication that occurs with the administration of large amounts of meperidine.
Normeperidine likely is the primary culprit in this situation. Other opiod
analgesics, therefore, are preferable to meperidine. The American Pain Society
recommends that meperidine no longer be used for control of pain in people who
require long-term analgesic treatment.
Eventually the patient should be switched to oral opiod analgesics, which may
be necessary for a week or more after discharge (Friedman et al., 1986). The
parenteral analgesics should be tapered after the oral medication is started.
Abrupt termination of parenteral analgesics when oral medications are begun can
cause a rebound in sickle cell crisis pain. Most patients with sickle cell
disease manage their analgesics responsibly. If possible, they should have a
supply of analgesics at home to control less severe episodes of pain. In
addition to analgesia, patients with painful crises should also receive
supplemental oxygen and intravenous fluids. Once the pain is under control, oral
hydration can replace the intravenous fluids.
Epidural analgesia has been used for pain control in some patients with sickle
cell disease (Tobias, 1993) (Yaster et al., 1994). This approach is most
effective when the major discomfort is below the level of the chest. Although
some patients receive good relief with epidural analgesia alone, others continue
to require systemic analgesics, albeit at lower doses. Some patients have a
psychological aversion to having needles introduced into their backs and balk at
epidural analgesia, despite its superior pain relief relative to systemic
analgesics.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Recently, NSAIDs have been added to the management algorithm of acute sickle
cell pain (Sanders et al., 1992). The drug that has been used most often in this
context is ketorolac tromethamine. The reports of the use of this agent to
control acute painful episodes in patients with sickle cell disease have been
largely anecdotal (Perlin et al., 1994). While some reports are positive, others
show no effect of ketorolac in the treatment of acute vaso-occlusive pain crises
(Wright et al., 1992). Ketorolac comes in a preparation that is designated for
intramuscular injection. However, the medication can be diluted into normal
saline and infused as an intravenous bolus. Ketorolac alone usually will not
control an episode of acute sickle cell pain. However, the medication appears to
operate synergistically with opiod analgesics. Patients often recover more
rapidly and require less opiods when ketorolac is added to the treatment
regimen. A single 30 mg intravenous bolus is usually administered for
supplemental pain control. Ketorolac can produce gastritis and bleeding. The
drug should be used cautiously in patients with peptic ulcer disease or a
history of gastrointestinal bleeding. NSAIDs can impair kidney function and
accelerate the renal injury produced by sickle cell disease itself. For these
reasons, many specialists avoid NSAIDs in patients with sickle cell disease.
Transfusion
Transfusion therapy appears intuitively reasonable for a disorder that results
from polymerization of deoxygenated hemoglobin in the red cells. The complex
pathophysiology of sickle cell disease confounds the picture, however.
Vaso-occlusive sickle cell crises are probably fueled, at least in part, by
sluggish blood flow through the microcirculation (Clark et al., 1980). Slow
blood flow promotes deoxygenation of hemoglobin and polymerization of the
molecules. Although the oxygen carrying capacity of blood increases with
hematocrit, so does viscosity. As the hematocrit rises beyond the range of the
low-30's, increased viscosity may outweigh enhanced oxygen delivery and swing
the dynamics of the situation toward sickling.
In areas where tissues are poorly perfused due to vaso-occlusion, the ability of
additional red cells to reverse local hemoglobin S polymerization is
questionable. Transfused erythrocytes will not improve blood flow through
regions of the microcirculation that are occluded by deformed red cells.
Although the transfused red cells do not sickle in the microcirculation even
with slow flow, the overwhelming predominant sickle erythrocytes in the
circulation is decisive in the development of local vaso-occlusion.
Simple transfusion is not an effective intervention for the management of acute
painful episodes in patients with sickle cell disease. Exchange transfusion has
been used in attempts to alleviate bouts of severe, intractable pain with better
effect, overall (Davies and Brozovic, 1989). In addition, chronic transfusion
therapy has been used to decrease the frequency of pain in patients with
recurrent debilitating painful crises (Keidan et al., 1987). While sometimes
effective, this approach as a number of problems, as detailed below.
Corticosteroids
A recent report described the use of corticosteroids in a cohort of children
with severe sickle cell pain crises (Griffin et al., 1994). The patients
received large doses of intravenous steroids on each of the first two days of
their painful sickle crises. The treatment group required narcotic analgesics
for approximately half as long as the control patients. The rate of pain relapse
was significantly higher in patients who received the steroid treatment. This
intriguing observation awaits confirmation, particularly in adults with sickle
cell disease.
Acute Chest Syndrome
Acute chest syndrome (ACS) is difficult to diagnose because its etiology varies
and its manifestations are variegate. Common characteristics include fever,
dyspnea, cough, and pulmonary infiltrates (Haynes Jr and Kirkpatrick, 1993)
(Poncz et al., 1985). The infiltrates can have a lobar distribution, but often
are bilateral. Sometimes, the pulmonary picture is one of diffuse, hazy
opacities that resemble adult respiratory distress syndrome. In other instances,
ACS looks like a simple pneumonia. This problem in diagnosis is aggravated by
the fact that infectious agents such as viruses, bacteria, and mycoplasma can
trigger the syndrome (Charache et al., 1979) (Kirkpatrick et al., 1991) (Miller
et al., 1991). Bone marrow infarction with secondary pulmonary fat emboli also
can trigger the acute chest syndrome (Vichinsky et al., 1994) (Gelfand et al.,
1993). In most instances, the etiology of ACS is a mystery.
The arterial blood oxygen saturation commonly falls with ACS to a greater degree
than occurs with a simple pneumonia of the same magnitude. Patients with the
acute chest syndrome often have progressive pulmonary infiltrates despite
treatment with antibiotics (Koren et al., 1990). Infection may set off a wave of
local ischemia that produces focal sickling, deoxygenation and additional
sickling.
The microcirculatory vessels in the lung tend to constrict with hypoxia rather
than dilate, as occurs with vessels in other parts of the body. Regions of
vascular constriction could worsen the occlusion of the microcirculation.
Unchecked, ACS can produce cardiovascular collapse and death. ACS occurs more
commonly in children than adults (Sprinkle et al., 1986) (Gill et al., 1995).
People who survive an episode of ACS are more likely than the general sickle
cell population to have future attacks. Patients who suffer recurrent episodes
of ACS are prone to develop chronic lung insufficiency.
Given the baseline anemia in SCD, pulmonary compromise is a serious
complication. The most important step in the treatment of ACS is to recognize
the disorder. Potential bacterial infections should be treated with appropriate
antibiotics. When symptoms progress, particularly with a worsening of the chest
roentgenogram, ACS must be considered. Sometimes, the pulmonary pattern mimics
congestive heart failure. However, congestive heart failure is uncommon in
patients with SCD who are in the 15 to 30 year age range, making the presumptive
diagnosis of ACS more likely. A relentless decline in arterial oxygenation is
often a harbinger of ACS, and demands prompt action.
Exchange transfusion is the treatment of choice for ACS (Lanzkowsky et al.,
1978) (Emre et al., 1995). The procedure involves exchange of the total blood
volume and is done most efficiently using an apheresis machine. When an
apheresis machine is not available, sequential transfusion/phlebotomy can be
performed. A hemoglobin electrophoresis should be sent prior to the exchange
transfusion. A second should be sent after the procedure. The object is to
ensure that the exchange has reduced the percentage of Hb S cells to under 30%.
Patients often improve substantially within hours of an exchange. Rising
arterial oxygenation and decreasing dyspnea usually augur recovery. The chest
roentgenogram typically lags behind the clinical status. Since a bacterial
pneumonia rarely can be excluded in these patients, most receive concomitant
broad-spectrum antibiotics.
A serious potential problem with exchange transfusion is delayed transfusion
reaction (Diamond et al., 1980). Most patients with SCD are of African ancestry.
Most of the blood available for transfusion comes from people of European
descent. A number of minor red cell antigens are expressed at different
frequencies in these two groups. Repeated transfusion of any African-American
can, therefore, induce antibodies directed against these minor antigens.
Should years pass between transfusions, the titers of antibody can fall to
levels that are undetectable by routine cross matching. Transfusion with blood
containing the offending antigen often rekindles antibody production to high
levels in only a few days. In a person who has received exchange transfusion, a
large fraction of the circulating red cells can be destroyed in a deadly delayed
transfusion reaction.
The transfusion records of any exchange transfusion candidate should be
searched thoroughly for any history of antibodies to minor red cell antigens.
Antibody screening should be repeated three to four weeks after the exchange
transfusion to look for new alloantibodies to minor antigens.
Infection
Patients with sickle cell disease are susceptible to overwhelming infection
(Olopoenia et al., 1990) (Overturf et al., 1977) (Landesman et al., 1982). The
most significant factor is splenic autoinfarction during childhood (Fernbach and
Burdine Jr, 1970). Functional asplenia leaves patients vulnerable to infections
with encapsulated organisms such as Streptococcus pneumoniae and Hemophilus
influenzae. Further, some studies suggest that neutrophils do not function
properly in patients with sickle cell disease (Humbert et al., 1990). How the
mutation in sickle cell disease might lead to a defect in neutrophil function is
unclear.
Patients with SCD and unexplained fever should be cultured thoroughly. If the
clinical condition suggests septicemia, the best action is to start broad
spectrum antibiotics after complete culturing. Signs of systemic infection
include fever, shaking chills, lethargy, malaise, and hypotension. Patients with
septicemia can expire in only a few hours. Therefore, observation is not a good
option when sepsis is suspected.
Acute Bone Marrow Necrosis
Acute bone marrow necrosis is now recognized more often as a complication of
sickle cell disease, in part due to improved methods of detection (Johnson et
al., 1994) (Shapiro and Hayes, 1984). In the past, the diagnosis could only be
made by bone marrow biopsy or inferred from the complications that resulted. If
the necrosis occurred in regions of the marrow that were not easily biopsied,
the diagnosis was almost impossible to confirm. This has changed with the
introduction of magnetic resonance imaging (MRI) techniques (Mankad et al.,
1990) (Rao et al., 1989). Bone marrow should have the density of other body
tissues on MRI scans. With bone marrow necrosis, marrow liquefaction is easily
detected on scan.
Patients with bone marrow necrosis often suffer excruciatingly severe pain. Some
patients require drastic measures, such as epidural anesthesia for control of
wrenchingly intense pain. Patients often describe acute bone marrow necrosis as
producing "the worst pain I've ever experienced." The necrosis frequently occurs
in the marrow of the ribs, femur or tibia.
Pulmonary fat emboli can complicate bone marrow necrosis (Johnson et al., 1994).
Fat emboli can trigger respiratory insufficiency or even acute chest syndrome.
Making the diagnosis of fat emboli to the lungs is difficult. In some cases,
sputum samples stained with Oil Red O will show fat-laden macrophages. Exchange
transfusion has been used with success in some patients with acute bone marrow
necrosis. The experience is anecdotal, since the ability to document bone marrow
necrosis in patients is a relatively recent development.
Stroke
Strokes are much more common in children than in adults. The average age of
stroke victims is about 4 years (Ohene-Frempong, 1991). Frequently, large
arteries such as the internal carotid or the middle cerebral are occluded
(Balkaran et al., 1992) (Earley, et al., 1998). The mechanism of occlusion of
these vessels is not clear, despite necropsy examination of a number of children
who succumbed to the condition. Imaging procedures such as angiography and the
non-invasive magnetic resonance angiography (MRA) have provided information on
the sequence of events that proceed a stroke (Adams et al., 1992) (DeBaun et
al., 1995) (Wang et al., 1992). Narrowing of arteries near sharp turns often are
seen. A common finding is narrowing at the separation of the middle cerebral and
the internal corotid arteries. Paradoxically, the higher rate of blood flow
produced by arterial narrowing is believed to contribute to the risk of complete
arterial occlusion. A complete occlusion at this critical location produces
massive strokes.
A key question is whether medical intervention can prevent a stroke in a child
with an arterial lesion. The Stroke Prevention Trial in Sickle Cell Anemia
(STOP), sponsored by the NHLBI, was conducted at several institutions (Adams, et
al., 1998) to address this question.
Between February, 1995 and October, 1996, the trial, coordinated through the
Medical College of Georgia (Dr. Robert Adams) and the New England Research
Institutes (Dr. Donald Brambilla), enrolled 130 subjects, ages 2 to 16, who were
at high risk for stroke on the basis of elevated cerebral blood flow measured by
transcranial doppler (TCD) screening tests (greater than or equal to 200 cm/sec
time averaged mean velocities). The patients, drawn from 13 US clinical centers
and one in Canada, were randomized to receive either standard supportive care or
periodic blood transfusions. The primary endpoint was the rate of stroke rates
in the treated and control groups.
The primary data analysis in the STOP Trial compared stroke rates in 63
children randomized to receive repeated exchange or simple transfusions and 67
children who received standard supportive care. A stroke was defined as
clinically significant neurologic impairment and physical findings, supported by
an abnormal magnetic resonance imaging (MRI) study. The clinical records and
MRI's were analyzed by a panel that was blinded to the treatment assignment of
the study subjects.
The patients in the transfusion arm received simple or exchange transfusions
every 3-to- 4 weeks in an effort to maintain the Hb S level below 30%. After one
year, 10 of the children in the standard care group had suffered a cerebral
infarction, compared with one child in the transfusion group. This difference
represents a 90% relative decrease in the stroke rate in the transfused
patients. These results were so compelling that the study's Data and Safety
Monitoring Board, composed of independent, outside experts in the fields of
pediatric hematology, neurology, radiology, statistics, and ethics recommended
that the trial be terminated early so that the children who had been receiving
standard supportive care could be offered an effective treatment to prevent
first-time stroke. On September 2, 1997, the study was halted, and the
investigators in the 14 participating centers were notified of the results and
the efficacy of transfusion therapy.
The STOP Trial confirmed that TCD can identify children with sickle cell anemia
at high risk for first-time stroke. Since the greatest risk of stroke occurs in
early childhood, the NHLBI recommends that children ages 2-16 receive TCD
screening. Screening should be conducted at a site where clinicians have been
trained to provide TCDs of comparable quality and information content to those
used in the STOP Trial. The clinicians should also be able to read them in a
manner consistent with what was done in STOP. To apply the predictive and
therapeutic information developed in the STOP Trial, two abnormal
STOP-comparable TCDs are needed to identify patients at high risk of stroke
(velocity greater than 200 cm/sec on two separate occasions).
During follow-up, some children in the large screening population, who
initially had normal or ambiguous TCD readings developed frankly abnormal TCD
readings. These data suggest that children with normal TCDs should be
re-screened at an interval which depends on their age and the prior result of
TCD. Although the optimal timing is not known, re-screening approximately every
6 months is a reasonable objective.
Stroke in SCD is a medical emergency. The deficits are often profound, although
many children recover substantial function. Exchange transfusion followed by
maintenance hypertransfusion is mandatory (Cohen et al., 1992) (Pegelow et al.,
1995). This action improves recovery and reduces the risk of recurrent stroke.
In the absence of this intervention, as many as two-thirds of children will
suffer subsequent events (Wang et al., 1991). The optimal duration of therapy is
unclear. Several studies have shown that as many of 50% of children on
maintenance therapy for as long as 5 years suffer new strokes within months of
stopping treatment.
A newly recognized area of concern in patients with sickle cell disease is
"silent stroke" (White and DeBaun, 1998). Recent technological advances,
including MRI, MRA, and PET scanning have been combined with neuropsychiatric
testing to gain a new window into the effect of silent strokes in children with
sickle cell disease. Analysis of 42 children followed as part of the Cooperative
Study of Sickle Cell Disease showed that nearly 20% had suffered silent cerebral
infarction, as detected by MRI (Kinney, et al., 1999). Multivariate analysis
showed a number of associations, including a greater risk of silent infarctions
with lower hematocrits. This association was found in another study of 50
patients (Steen, et al., 1999). One-third of the latter children showed evidence
of mild intellectual impairment on cognitive testing. Positron emission scans
and magnetic resonance angiography could be useful adjuncts in the effort to
diagnose children with silent cerebral infarction (Powars, et al., 1999),
(Gilliams, et al., 1998). Clearly this is an area of major concern that deserves
much more investigation.
In adults, hemorrhagic stokes occur more frequently than arterial occlusive
strokes (Van Hoff et al., 1985). Subarachnoid hemorrhages are most common.
Bleeds that involve deep structures in the brain, such as the thalamus, also
occur, however. In some instances, this reflects the development of "moya-moya"
syndrome years after an earlier thrombotic stroke. A network of delicate
capillaries can form, often in the area of the old infarction. Angiography
reveals the complex filamentous structure of the moya-moya lesion (Peerless,
1997). Should these capillaries rupture, disastrous intracranial hemorrhage
occurs. Easily accessible lesions are sometimes surgically excised. Thrombotic
strokes in adults are as mysterious as those in children. Nonetheless, exchange
transfusion followed by maintenance hypertransfusion is a prudent course of
action.
Splenic Sequestration Crisis
Splenic sequestration crisis results from the acute entrapment of large amounts
of blood in the spleen (Sears and Udden, 1985). The manifestations are left
upper quadrant pain, exacerbated anemia and, often, hypotension. In children, a
large fraction of the circulating blood volume is frequently sequestered.
Splenic sequestion crisis is a medical emergency that demands prompt and
appropriate treatment. Parents should be familiar with the signs and symptoms of
splenic sequestion crisis. Children should be seen as speedily as possible in
the emergency room.
Circulatory collapse and death can occur in less than thirty minutes. Splenic
autoinfarction makes splenic sequestration crisis uncommon in adults with
homozygous Hb S sickle cell disease. The condition can occur in adults with
sickle beta-thalassemia or sickle-hemoglobin C (SC) disease since autoinfarction
does not occur in these syndromes (Roshkow and Sanders, 1990) (Solanki et al.,
1986). The most prominent symptom is left upper quadrant pain. The larger blood
volumes of adults make hypotension and circulatory collapse much less common
than in children.
The treatment of splenic sequestration crisis includes intravenous fluids and
transfusion as necessary to maintain the intravascular volume. A child who
suffers one episode of splenic sequestration crisis is at greater risk of a
second attack (Kinney et al., 1990). Specialists debate whether children who
survive an episode of splenic sequestration crisis should undergo prophylactic
splenectomy after their recovery (Szwed et al., 1980). Less is known about the
condition in adults. Given the lower morbidity and mortality in adults,
splenectomy is rarely a consideration.
Aplastic Crisis
Aplastic crisis is a potentially deadly complication of sickle cell disease that
develops when erythrocyte production temporarily drops. Infection with
parvovirus B-19 frequently causes aplastic crises (Saarinen et al., 1986). This
adeno-associated virus causes "Fifth Disease", a normally benign childhood
disorder associated with fever, malaise, and a mild rash. The virus has a
trophism for erythroid progenitor cells, and impairs cell division for a few
days during the infection. Normal people experience, at most, a slight drop in
hematocrit since the half-life of erythrocytes in the circulation is 40 to 60
days. The picture is different in patients with hemolytic anemias, who maintain
reasonable hematocrits only through prodigious production of new red cells. A
shut-down in erythroid production for a few days in these patients can lead to
potentially deadly declines in hematocrit (Mallouh and Qudah, 1993). Often, but
not always, aplastic crises coincide with a painful crises. The reticulocyte
count should be checked on admission to the emergency room or to the hospital in
patients with SCD. The treatment of aplastic crisis is purely supportive, with
transfusions to maintain an acceptable hematocrit until marrow activity is
restored.
Hepatic Sequestration Crisis
Sickled cells can become lodged in the liver obstructing blood flow through the
organ (Davies and Brozovic, 1989). The result is painful hepatic enlargement
accompanied by an increase in the plasma levels of hepatic synthetic enzymes
(e.g., ALT, AST). The serum bilirubin levels often skyrocket to levels in the
range of 30 to 40 mg/dl. Acute hepatic failure can ensue. Fluids, oxygen and
analgesia are the usual management interventions taken. The benefit of more
aggressive measures such as exchange transfusion is unknown.
Priapism
Priapism is a potentially serious problem for young men with sickle cell
disease. The condition is believed to result from impaired blood egress from the
corpus spongiosum of the penis, leading to prolonged erections (Fowler Jr et
al., 1991). The affliction often occurs in association with spontaneous
nocturnal erections. Episodes of priapism can last from several hours to several
days. One group of investigators reported a ninety percent actuarial probability
of at least one episode of priapism by age twenty-one years (Mantadakis, et al.,
1999).
Stuttering priapism is common. Here, the (typically) young man develops
erections lasting one to two hours, initially, that resolve spontaneously. The
condition then progresses to a point where the erections are quite prolonged and
painful. Priapism lasting more than three or four hours is a medical emergency
since it can produce impotence (Mykulak and Glassberg, 1990) (Emond et al.,
1980).
The most commonly used intervention in the past was irrigation of the ventral
vein of the penis by a urologist in an attempt to remove the blockage to blood
flow. Since the problem is one of microvascular occlusion, the results of this
approach were generally poor. Not only does the surgery often fail to resolve
the priapism, but the procedure itself risks inducing impotence (Yang et al.,
1990). More recently, exchange transfusion has been used in some of these
patients with mixed results (Seeler, 1973). Non-acute cases of priapism are
sometimes treated with conjugated estrogens (Serjeant et al., 1985) or
vasodilators (Baruchel et al., 1993). While there is some clinical data to
support the short-term use of estrogens, the opinions of specialists in sickle
cell disease remain divided.
Management of Chronic Problems
Pain
Chronic pain is a major problem for many patients with sickle cell disease. The
etiology of chronic pain in sickle cell disease is uncertain. Organ injury and
necrosis produced by years of intermittent ischemia from vaso-occlusion likely
plays a large role. Radiographs of bones show characteristic deformities of the
ribs, for instance. The damage that produced the deformities likely produces
chronic pain. The severity of the pain varies greatly and can change over time.
Some patients control their pain by intermittently using mild analgesics, such
as non-steroidal anti-inflammatory agents. Others require frequent doses of
opiod analgesics. Consequently, no universally applicable formula exists for
management of chronic pain. The patients who frequently present the greatest
management challenges for physicians, are those with persistent severe pain
controlled by chronically administered opiod analgesics.
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) can control chronic pain in many
patients with sickle cell disease (Sanders et al., 1992). The agents can be used
alone or in conjunction with opiod analgesics. Most commonly, NSAIDs are used
intermittently to control flairs of pain. One potential problem with these
agents is renal damage. Patients with sickle cell disease are more susceptible
than normal people to renal injury. Since renal damage can be compounded by
NSAIDs, physicians must closely monitor renal function in patients on these
drugs. Cox-2 inhibitors allegedly produce less nephrotoxicity than do standard
NSAID's. Limited experience exists with the use of these agents to control
chronic pain in people with sickle cell disease. They are nonetheless worth
serious consideration in these patients.
Opiod analgesics
Most patients who require large or frequent doses of opiods to control pain are
not seeking drugs for recreational purposes. Often, these patients become
tolerant to opiods. Consequently, the quantity of medication needed to control
severe pain exceeds that of an individual with a severe but self-limited painful
episode, such as torn knee ligaments. Most patients report accurately the
quantity of analgesics needed to control their pain (Gil et al., 1994). In some
instances, long-acting opiod analgesics can blunt the severity of the pain,
allowing patients to use less of the shorter acting agents. Unfortunately, no
objective measure of pain exists. Appropriate treatment of pain irrespective of
the cause requires an on-going dialogue between the doctor and patient
(Armstrong et al., 1992).
Whenever possible, patients should start taking their analgesics before the pain
becomes extremely severe. Maintaining pain at a tolerable level is easier than
reducing it from a high level of intensity. A typical episode of severe sickle
pain can require a patient to consume 4 to 8 mg of oral hydromorphone every
three hours to achieve relief. Many "severe" sickle crises can be managed at
home with analgesics, fluids, and rest. If the pain progresses despite the use
of reasonable quantities of medication, the patient should seek emergency
medical care.
Pain due to sickle cell disease is typically viewed as episodic bouts secondary
to occlusion of the microcirculation. Many health care providers do not realize
that severe chronic pain is also a consequence of sickle cell disease. Chronic
sickle cell pain occurs more commonly in adults than in children. Permanent
damage to the microcirculation secondary to years of recurrent sickle injury
likely is the basis of this syndrome. Bony abnormalities on x-ray, such as
vertebral body compression, attest to the injury that occurs over the years.
Other tissues, by inference, suffer similar problems.
One of the obstacles to control of chronic pain is the short duration of action
common to many analgesics, such as hydromorphone and meperidine. A number of
longer acting formulations are available. One of the most effective drugs for
the control of chronic sickle cell pain is methadone. Although best know for its
use in narcotic detoxification programs, methadone is a highly effective
analgesic when given three times per day. Methadone for control of narcotic
addiction can be dispensed only at certified detoxification centers. Methadone
for pain control can be given at other facilities in accordance with the
guidelines for use of any opiod.
Meperidine can present problems for pain control in patients with sickle cell
disease. The half-life of the drug in the circulation is about 4 hours. The
liver converts meperidine to normeperidine, a derivative that has analgesic
activity but which also is toxic. Grand mal seizure is a particularly serious
complication that occurs with the administration of large amounts of meperidine.
Normeperidine likely is the primary culprit in this situation. Other opiod
analgesics, therefore, are preferable to meperidine. The American Pain Society
recommends that meperidine no longer be used for control of pain in people who
require long-term analgesic treatment.
Drug-seeking behavior
Addiction is a concern for for medical providers and patients alike when chronic
pain require long-term use of opiods for control. The magnitude of the problem
is less than is often imagined, however. Those who develop an addiction or
drug-seeking behavior are seen frequently in emergency rooms and as hospital
inpatients. This overrepresentation of a small number of patients in the health
care system leads many providers to conclude that drug-seeking behavior is a
problem for most patients with sickle cell disease. Opiods used for pain
control, even when given in relatively high doses, usually do not lead to
addiction. As with any other group of people, some patients with sickle cell
disease have a propensity to develop addictive disorders. The "easier access"
that these patients have to narcotics brings out a problem that might have
developed in any event.
An important first step in managing this problem is to define drug-seeking
behavior. The use of large quantities of oral opiods or frequent visits to the
emergency room do not de facto signify drug-seeking behavior. Drug-seeking
behavior is the use of opiods in the absence of pain sufficiently severe to
justify these medications. Since no objective measure of pain exists, reaching
this conclusion is difficult. Drug-seeking behavior can be established only by
getting to know the patient and by observing the pattern of drug usage. This
means that over a period of months, frequent and heavy use of opiods by the
patient may need to be tolerated in order to establish the pattern of drug
consumption. Only then can the medical care provider reasonably say on the basis
of subtle signs such as facial expression, vocal inflexion, pulse rate, etc.,
that drug-seeking behavior is likely. At this point, the patient can be
approached to discuss what appears to be unwarranted use of drugs.
These patients can respond positively. Drug-seeking behavior can be a very
psychologically painful experience. Many patients are relieved when they are
confronted and given an option of help. Counseling or sessions with a
psychologist or social worker can be useful. In establishing drug-seeking
behavior, allowing a few patients to succeed in taking extra medication for a
while outweighs punishing patients who have a legitimate need by placing
arbitrary limits on everyone.
A few patients demonstrate incorrigible and sometimes frankly sociopathic
behavior. In these instances, the best approach is to limit opiod availability.
The patient should be informed that a limit is being imposed and the reason for
its implementation. Excuses for requesting additional medication fit a pattern
that can be a clue to drug-seeking behavior. Common pretexts include, (a)
forgetting to fill the prescription before expiration, (b) losing the drug after
the prescription is filled, (c) being robbed of the prescription or the
medication, (d) having a friend or relative abscond with the medication after
having the prescription filled. The limit should be followed strictly. Tracking
patterns of medication use is aided by keeping a log of all opiod prescriptions
issued. Photocopys of prescriptions provide excellent documentation. If
possible, a single provider at the institution should write the prescriptions
and maintain the record. Covering staff and ER physicians should be alerted to
the arrangement and should not supply additional prescriptions. The arrangement
is not punitive. Rather it allows the staff to better assess and treat
legitimate sickle cell pain. Health providers should document their efforts to
monitor and control excess use of opiods by their patients. Scrupulous
record-keeping also helps avoid entanglements with medical practice oversight
agencies.
Patients with extreme drug seeking behavior or sociopathic personality disorders
often acquire medication from other hospitals or medical facilities. Sometimes
this is done under the cover of an alias. Health-care providers have limited
ability to control such activity. The provider must be sure that the pattern of
drug use at his or her institution is reasonable, but cannot police the entire
region.
Support Groups/Psychiatric Support
The psychosocial dynamics of sickle cell disease are complex. As with any other
chronic, and often debilitating, illness, patients face a plethora of social
problems that greatly influence their clinical condition (Whitten and Fischhoff,
1974). Loneliness, isolation, self-resentment, loss of self-esteem, and simple
anger are common in patients with sickle cell disease. These factors can
profoundly influence the patient's ability to cope with pain. Patient support
groups and psychological counseling often are very useful. The positive results
in studies in which children were taught psychological coping skills for pain,
reinforce the importance of this component of patient care (Gil et al., 1991).
Anemia
Vitamin Supplementation
Patients with sickle cell disease, like other people with hemolytic anemias,
require daily folic acid replacement. Folate is rapidly consumed by the
proliferating erythroid precursors. The normal daily intake of this vitamin
sometimes is insufficient to maintain a balance. One mg of supplemental folate
per day is more than enough to satisfy the needs of the erythron. A patient with
sickle cell disease whose hematocrit begins to fall unexpectedly should be
checked for folate deficiency as a part of the general work-up.
Sporadic Transfusion
Patients with sickle cell disease are anemic, by definition. The degree of the
anemia varies. The hematocrit frequently is in the mid- 20's. Some patients have
hematocrits in the low 30's while others have values in the high teens. The
baseline hematocrit remains relatively stable in a given patient, however.
Patients with Hemoglobin SC disease tend to run hematocrits in the low to mid
30's. Most patients are conditioned to tolerate their degree of anemia, and
routine transfusion is not necessary. Raising the hematocrit provides no
clinical benefit, unless the baseline value has fallen into the mid-teens, at
which point oxygen carrying capacity can be compromised. Hematocrits in such a
low range leave little leeway for further decline. On the other hand,
transfusing patients with sickle cell disease to hematocrits in the mid- to
upper-30's can be dangerous, since blood viscosity increases substantially at
higher hematocrits (Kaul et al., 1983). The increase in viscosity can worsen the
sickling propensity by increasing the time during which the cells remain in the
low oxygen tension regions of the circulation.
Chronic Transfusion Therapy
The best established use of chronic transfusion therapy is in patients who have
suffered strokes and have had initial exchange transfusions. Chronic transfusion
therapy is less well established for the treatment of other complications of
sickle cell disease. This modality has been advocated as a means of treating
recurrent severe episodes of sickle pain, priapism, and as a prophylactic
measure inpregnant patients. Variable improvement in these condition occurs. The
utility of transfusion therapy is limited by complications, most notably
alloimmunization and iron overload (Rosse et al., 1990) (Wang et al., 1986) .
Clinically significant iron overload can occur after as few as 30 red cell
transfusions. The only treatment for transfusional iron overload is chelation
therapy with desferrioxamine (Cohen and Schwartz, 1979). Marginal iron
mobilization with this drug is a frequent problem.
A major hurdle to the use of desferrioxamine is non-compliance. This is a
particular problem for young people, and occurs in other disorders that require
chelation therapy for transfusional iron overload, including beta-thalassemia
and congenital sideroblastic anemia. Investigation of other chelators, including
some orally active drugs, is ongoing. Approval is imminent for no agent,
however.
Alloimmunization
Alloimmunization against minor red cell antigens is a major problem for patients
with sickle cell disease who receive frequent transfusions (Rosse et al., 1990).
The representation of minor antigens, such as Kell, Duffy, and Kidd, differs
between African-Americans and European- Americans (Issitt, 1994). For patients
who receive only a few transfusions, the problem is not serious. With repeated
transfusion, however, antibodies develop against these minor determinants
complicating typing and jeopardizing further transfusion.
Blacks are substantially underrepresented as blood donors, compounding the
problem of alloimmunization for patients with sickle cell disease. In addition,
patients with sickle cell disease appear to develop alloantibodies more rapidly
than other black patients who are transfused (Vichinsky et al., 1990). Some
institutions perform extended panel matching which includes the most clinically
significant minor antigens in an effort to delay the development of
alloantibodies. Some patients develop such severe problems with alloantibodies
that transfusion becomes nearly impossible. A number of institutions have active
programs to recruit blood donors from the black community to lessen the impact
of alloimmunization.
Routine use of blood from black donors for black patients with sickle cell
disease is not warranted. The likelihood of finding matched units for patients
with sickle cell disease is greater when black people are in the donor pool.
Matching is necessary nonetheless since antigen variation among black people,
like all other humans, is great. An expanded donor pool substantially improves
the chance of a match with antigen testing.
Age and severity of anemia
Sometimes, the severity of the anemia in patients with sickle cell disease
gradually increases as they age. The reason for this marrow "burn-out"
phenomenon is unknown. The clinical situation is complicated by the fact that
many of the patients have end-organ damage, such as a dilated cardiomyopathy,
that may limit their ability to tolerate such severe anemia. Data from the
national cooperative study of sickle cell disease indicates that on average
patients with sickle cell disease survive until the mid 5th decade of life. Bone
marrow "burn-out" will be a greater issue as better general medical care and new
therapies prolong the lives of patients with sickle cell disease.
Infection Prophylaxis
Infection is a leading cause of death in patients with sickle cell disease.
Hyposplenism, due to splenic autoinfarction, is a major contributor.
Hyposplenism is not the sole cause of the defective host defense as evidenced by
the fact that overwhelming sepsis is the leading cause of death of children
under three years of age (Gill et al., 1995). Splenic autoinfarction is less
common in these very young children.
Antibiotics
A double-blind study of the use of penicillin prophylaxis for children between
the ages of six months and three years was terminated before the expected time
of completion (Gaston et al., 1986). The trend indicated clearly that penicillin
protected patients from infection or death due to overwhelming infection by
Streptococcus pneumoniae. The recommendation now is that all children be placed
on prophylactic penicillin at a dose of 250 mg twice a day. Patients with
allergies to penicillin should be treated with erythromycin. No recommended
duration of treatment with prophylactic penicillin exists.
A second study looking at the role of prophylactic penicillin in older children
was recently completed. No difference in the incidence of severe infection was
found in this cohort of children between the ages of 5 and 12 years (Falletta,
et al., 1995). The implication is that penicillin plays an important
prophylactic role only in young children. One caveat to the interpretation of
this study is that the incidence of pneumoccocal infection was strikingly low in
both groups. This could have been a clinical fluke. As such, a true difference
in infection rate between the two groups could possibly have been missed.
The role of prophylactic penicillin in adults with sickle cell disease is
unclear. Adults develop overwhelming sepsis, but at a much lower frequency than
do children. No controlled study to determine whether prophylactic antibiotics
are useful in adults has been done. The recently completed trial in older
children suggest that prophylactic antibiotics may not benefit adults.
Nonetheless, many physicians still prescribe prophylactic antibiotics for
adults.
Immunization
Immunization with the pneumococcal vaccine is standard practice both in adults
and children with sickle cell disease. Several studies suggest that immunization
provides some protection, although incomplete, against pneumoccocal infection
(Ammann et al., 1977) (Ammann, 1982) (Schwartz, 1982). The vaccine appears to be
effective even in adults where splenic function has been lost (Wong et al.,
1992). The more recently available 23-valent vaccine provides broader coverage
than earlier versions. Although the duration of protection is unknown, most
specialists re-innoculate patients once every 5 to 7 years. A noteworthy
contrary voice comes from a broadbased review of pneumococcal vaccine efficacy
that cast doubt on the role of the vaccine in patients with sickle cell disease
(Butler, et al., 1993).
More recently, a vaccine against Hemophilus influenzae has entered the clinical
arena (Rubin et al., 1989). The efficacy of this vaccine in sickle cell disease
is unknown. Given the serious nature of H. influenzae infections in these
patients, many specialists, particularly pediatricians, now routinely immunize
their patients against this organism.
Immunization against viral influenza is common practice. Viral influenza per se
is not a special threat for patients with sickle cell disease. Since influenza
is often complicated by bacterial infection and other problems, prevention of
the disease by immunization is a very practical intervention.
Recently, an effective vaccine against hepatitis B was developed. Since
patients with sickle cell disease are likely to require one or more transfusions
in their lifetime, immunization against hepatitis B is a reasonable precaution
(Mok et al., 1989).
Avascular Necrosis of Bone
Avascular necrosis of bone is a common problem in patients with sickle cell
disease. This process is distinctly different from the acute bone marrow
necrosis discussed earlier. The areas most frequently affected are cortical bone
of the acetabulum, the head of the femur, and the head of the humerus (Hernigou
et al., 1993). The etiology of avascular necrosis of bone is unknown. One
hypothesis posits marrow hyperplasia in the femoral head with tissue crowding
and secondary reduced blood flow to the bone as the inciting factor. Avascular
necrosis also occurs in patients with compound heterozygous conditions such as
Hb SC disease, as well as in patients with homozygous SS disease.
Patients usually report that the quality of the pain associated with avascular
bone necrosis differs substantially from their sickle cell pain. The articular
cartilage thins and often disappears as the process progresses. The joints can
deteriorate to a condition of bone-on-bone interface. Movement of the joint
becomes wrenchingly painful. Early on, non-steroidal anti-inflammatory agents
can be useful. With more severe situations, particularly those that involve the
shoulder, injections of corticosteroids may help. Finally, decompression of the
tissue in the head of the humerus or the head of the femur is used by some
orthopedic surgeons with success. This invasive procedure should be reserved for
patients with more advanced cases of avascular necrosis. The possible efficacy
of femoral head core decompression is currently being investigated in a
multicenter study coordinated by Dr. Elliot Vichinsky at the Children's Hospital
of Oakland, California.
Even with these interventions, the process cannot be completely halted, leading
to joint replacement in some instances. Since most of the patients are in their
20's or 30's when this becomes an issue, the decision to proceed with joint
replacement is difficult. Artificial joints are not well-tolerated by some
patients with sickle syndromes (Moran, 1995). As many as one-third of patients
require a second surgery within four years of joint replacement. Also, these
patients, for unclear reasons, are very vulnerable to infections of their
orthopedic hardware. The unfortunate result sometimes is a destroyed articular
interface and a flail joint which, in the case of the femur, can leave the
patient confined to a wheelchair.
More research is needed to identify patients at risk early in the course of the
degenerative process so that preventive measures can be instituted. One
promising addition to the diagnostic armamentarium is MRI imaging. This
technique can detect very early evidence of damage to the bone, and holds the
hope of improved management of this very debilitating complication of sickle
cell disease.
Osteomyelitis
Osteomyelitis often occurs at the site of necrotic segments of bone. Nearly
three-quarters of cases of osteomyelitis in patients with sickle cell disease
are due to Salmonella species (Anand and Glatt, 1994). Local pain and fever are
the most common indicators of chronic osteomyelitis (Epps Jr et al., 1991). In
the early stages of the disorder, bone roentenograms and even bone scans
frequently are unrevealing. Gallium scans can provide early evidence of the
disorder. Recently, MRI has been added to the diagnostic arsenal, and appears to
be a promising technique (Bonnerot et al., 1994). Definitive diagnosis often
requires bone biopsy. This procedure sometimes is not an option, due to the
location of the infection, however. Once the diagnosis is made, four to six
weeks of intravenous antibiotic therapy are needed.
If a causative organism is not identified, broad- spectrum antibiotics that have
good tissue penetration should be used. Evidence of effectiveness, in these
instances, is an improvement in the pattern of fever and pain. The advent of
home infusion services obviates the need for prolonged hospitalizations in many
cases.
Skin Ulcers
Skin ulcers are relatively infrequent in the United States in comparison to
reports from Jamaica. In that country, about 30% of patients with sickle cell
disease develop skin ulcers. This exceeds by far the incidence in the US, which
is closer to 1% (Koshy et al., 1989). Nonetheless, when skin ulcers occur, the
problems are very serious.
The most common site of skin ulcers is over the lateral malleoli. The
ulcerations often have no clear-cut antecedent trauma and progress over a period
of weeks to the point that the lesions extend into the dermis, and often into
the underlying subcutaneous tissue. With the breakdown in the protection
provided by the integument, patients are susceptible to infections and other
complications.
Treatment of ankle ulcers should be conservative. Rest, elevation, and dry
dressings with antimicrobial ointments are the best approaches to this problem.
Attempts at skin grafting are frequently thwarted by the poor blood flow to the
affected region. Healing usually takes weeks to months. The area should be
protected against trauma when the patient is up and about (Wethers et al.,
1994). Anecdotal reports exist of enhanced healing of ulcers in patients placed
on chronic transfusion therapy. In some instances, patients were begun on
chronic transfusion prior to skin grafting and maintained with monthly
transfusions for two or three months thereafter. Socks or other clothing that
cover the area should be avoided, to reduce friction injury. A simple dry
dressing provides additional protection. At one time, a group of investigators
advocated oral zinc supplementation as a means of speeding the healing of ankle
ulcers (Prasad et al., 1977). The rationale was that patients with sickle cell
disease are often deficient in zinc (which is the second most common metal ion
in red cells and is lost during hemolysis). Zinc is important for wound healing.
The evidence that zinc supplementation aids the healing of ankle ulcers is
controversial. However, the benign nature of zinc supplementation makes it a
reasonable option in patients with this terribly debilitating and often
recalcitrant condition.
Renal Dysfunction
The most common defect in patients with sickle cell disease is impaired urine
concentrating ability, or hyposthenuria (Kontessis, et al., 1992). Hyposthenuria
often occurs by the age of 3 or 4 years. The condition should be considered in
children with sickle cell disease who display bedwetting. Hyposthenuria is seen
in patients with homozygous sickle cell disease as well as in compound
heterozygotes (e.g., sickle-beta thalassemia). The extremely high osmolality in
the distal tubule produces some sickling even of the cells in patients with
sickle trait. As a consequence, hyposthenuria is the most common abnormality
seen that results from sickle cell trait (Gupta, et al., 1991).
The risk of renal dysfunction or failure is substantial in patients with sickle
cell disease (Flanagan et al., 1993). The high osmolality in the renal medulla
increases cell propensity to sickling. As a result, medullary ischemia and
papillary necrosis are common problems (Powars et al., 1991).
Sometimes, the necrotic papillae slough into the collecting system, obstructing
the outflow tract. No specific intervention has been devised that is
particularly effective in these patients. When the BUN and creatinine begin to
rise, limiting protein consumption is reasonable, as is recommended for other
patients with renal dysfunction. One report suggested that angiotensin
converting enzyme inhibitors may also retard the progression of nephropathy in
sickle cell disease (Falk et al., 1992). Further investigation of this promising
lead is needed.
Patients with sickle cell disease usually have low serum creatinine and BUN
levels. This is probably due to the high glomerular filtration rate along with a
high rate of creatinine secretion in the distal tubule. BUN values of 7 and
creatinine values of 0.5 are typical of those seen in patients with sickle cell
disease. A formal evaluation of glomerular filtration rate should be considered
in patients in whom the serum creatinine rises above the level of about 1.0..
Potentially nephrotoxic drugs should be used with extreme caution in patients
with sickle cell disease. Antibiotics such as gentamicin should be avoided when
other agents are available that are less toxic to the kidney. As noted
previously, nonsteroidal anti-inflammatory drugs (NSAIDs) should be used
cautiously in patients with sickle cell disease. Heavy loads of radiographic
contrast agents formerly were a significant problem for patients with sickle
cell disease. The newer agents produce a much lower osmotic load, with less
dehydration of the kidneys, as a result.
Limited experience exists on the efficacy of dialysis in patients with sickle
cell disease (Falk et al., 1983). Reports that hemodialysis is problematic in
patients with sickle cell disease are anecdotal. Every effort to prevent renal
deterioration should be undertaken. Microscopic hematuria is a common problem in
patients with sickle cell disease (as well as some patients with sickle cell
trait). Hematuria per se requires no intervention unless blood loss is massive.
Some patients with sickle cell disease and renal failure have received
allografts (Gonzalez-Carrillo et al., 1982).
People with sickle cell trait sometimes develop massive hematuria (Sears,
1978). Interestingly, the bleeding often comes from the left kidney. Hydration
and alkalization of the urine are commonly used interventions. Anecdotal reports
of the use of DDAVP in this situation are encouraging (Baldree, et al., 1990).
Episilon amino caproic acid (Amicar) has been used in some patients with
refractory bleeding from the kidney (Black, et al., 1976). Bleeding can continue
for weeks. Iron replacement may be necessary in some cases as treatment
interventions continue.
Retinopathy
Retinopathy is a significant problem for 10% to 20% of patients with sickle cell
disease (Moriarty et al., 1988). The peak age of onset is in the 20's. For
unknown reasons, the condition develops more frequently in patients with
hemoglobin SC disease than in those with homozygous sickle cell disease
(Clarkson, 1992). The retinopathy resembles that seen in people with diabetes.
The condition is believed to result from ischemia to the retina. The areas
affected, at least initially, are in the periphery of the retina, so that direct
ophthalmoscopy is rarely revealing (Kimmel et al., 1986). An ophthalmologist
should evaluate the patient using pupillary dilation and indirect
ophthalmoscopy. Patients should be seen at least once a year, and more
frequently if abnormalities are noted. Ischemia can lead to retinal thinning as
well as neovascularization. The fragile vessels formed by neovascularization are
subject to rupture, often leading to disastrous intraorbital hemorrhages. This
complication can produce sudden loss of vision (Pulido et al., 1988). Laser
photocoagulation has been used in an effort to prevent retinal hemorrhage
(Condon and Serjeant, 1980). Another common problem is retinal detachment,
particularly as a sequel to retinal hemorrhage.
Heart
Cardiomegaly is common in patients with sickle cell disease. Usually this
condition reflects sustained state of high cardiac output. While high output
failure occurs in some patients with sickle cell disease, the heart is
hyperdynamic in most (Gerry et al., 1978).
Pulmonary congestion due to fluid overload during hydration for painful crisis
is not a common problem in young patients. The picture changes as patients age.
A distinct minority of patients will develop problems with fluid balance with
the fluid challenge that occurs with hydration (Haynes, Jr and Allison, 1986).
For some patients, the problem is more one of left atrial dysfunction than
impaired ventricular activity. Nonetheless, patients who develop a chest
roentgenographic picture suggestive of "congestive heart failure" during
treatment for painful crisis must be examined carefully to rule out other
complications such as acute chest syndrome.
Pregnancy
Women with sickle cell disease can carry pregnancies to term, but the process
sometimes is complicated (Koshy et al., 1987) (Seoud et al., 1994). The
frequency of painful crises sometimes increases. Physical activity should be
limited, particularly after the mid-second trimester when the intravascular
volume increases substantially. Fetal development is usually normal if the
patient can be coaxed through the pregnancy (Powars et al., 1986). Some
specialists in sickle cell disease advocate simple blood transfusion in these
patients. Others have found no benefit to this intervention (Tuck et al., 1987).
The object is to maintain a hematocrit that allows normal fetal development.
Exchange transfusion has been used in some instances in which patients had
particularly difficult problems during the pregnancy. These reports are
anecdotal.
Women who have painful crises during pregnancy should be treated with analgesics
as necessary, including narcotics. The newborns who have been exposed to opiods
must be withdrawn by administering decreasing doses of these drugs in the
neonatal period. Warned of this issue, neonatologists can easily manage the
problem.
Newer Therapies
Therapies of Proven Benefit
Hydroxyurea
Hydroxyureainhibits ribonucleotide reductase, blocking DNA synthesis and cell
division. The drug also enhances fetal hemoglobin by developing erythroid cells
(Platt et al., 1984) (Stamatoyannopoulos and Nienhuis, 1992). Since fetal
hemoglobin blocks sickling, hydroxyurea has been administered to patients with
sickle cell disease in an effort to enhance fetal hemoglobin production
(Charache, 1991) (Rodgers et al., 1990). Hydroxyurea induces fetal hemoglobin
production, increases the red cell mean corpuscular volume, and reduces the
number of dense cells and irreversibly sickled cells in the circulation
(Goldberg et al., 1992).
On January 31, 1995, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
(MSH) was suspended by the NIH because patients on the hydroxyurea arm of the
study had significantly fewer painful crises than did the controls (Charache et
al., 1995). This made hydroxyurea the first (and only) drug proven to prevent
sickle cell crises. A second major observation was that 50% fewer episodes of
acute chest syndrome occurred in the patients treated with hydroxyurea.
Hydroxyurea does not cure sickle cell disease, nor is it effective in all
patients. A detailed study showed that hydroxyurea modifies the characteristics
of red cells in patients with homozygous HbS disease to resemble those of
patients with HbSC disease (Bridges, et al, 1996). The heterogeneous response
seen in the MSH study is consistent with people with sickle cell disease being
"converted" to a HbSC disease physiognomy. Patients should be carefully screened
and meet certain criteria:
Age - 18 years or older.
Frequent painful vaso-occlusive crises. "Frequent" can reasonably be defined
as three or more crises per year that require hospitalization.
Use of accepted modes of contraception to prevent conception while on the
drug.
Hydroxyurea is not reasonable therapy for many patients with sickle cell
disease. Patients who have relatively few vaso-occlusive pain crises should not
receive hydroxyurea therapy. Other contraindications for hydroxyurea include:
Pregnancy
Allergy to the drug
Thrombocytopenia or neutropenia
Although thrombocytopenia and/or neutropenia are relative contraindications,
some patients can tolerate the medication despite these pre-existing factors
with close monitoring. Bimonthly blood counts are required when patients are
started on hydroxyurea. In some patients on hydroxyurea, the hematocrit rises to
the high 30's or even low 40's. No evidence exists to support hydroxyurea as
prophylaxis against stroke, chronic leg ulcers, priapism, or other complications
of sickle cell disease.
The dose of hydroxyurea needed to prevent painful crises is unknown. In the MSH
study, patients received the maximum tolerated dose (MTD). The dose administered
was increased stepwise until signs of toxicity, such as mild neutropenia,
developed. The dose of hydroxyurea was then reduced slightly. Whether such
intense treatment is required is unknown. Lower doses of hydroxyurea (e.g.,
25mg/Kg/day) are used by some specialists. Most patients treated with
hydroxyurea develop macrocytosis (e.g., MCV=110). Macrocytosis is not a good
treatment gauge, however.
The data on hydroxyurea applies only to patients with homozygous sickle cell
disease (two hemoglobin S genes). Patients with compound heterozygous conditions
(e.g., sickle-beta thalassemia, Hb SC disease) were excluded from the MSH study
to eliminate if possible any response variability in the data. Future trials may
address these issues.
Hydroxyurea is not approved for use in children. The MSH study was restricted to
people 18 years of age or older. An NIH-sponsored trial of the drug in children
is on-going. A number of issues have been raised regarding hydroxyurea in
children, including neurocognitive development and bone maturation. The
pediatric hydroxyurea study will address some of these issues.
Hydroxyurea is teratogenic in mice, but its toxicity to the human fetus is
unknown. The drug has not been associated with carcinogenesis. The carcinogenic
potential with very long-term use is unknown, however. The NIH-sponsored
Follow-up Study of Hydroxyurea in Sickle Cell Disease is designed to monitor the
300 people in the original MSH study for long-term side effects.
Bone Marrow Transplantation
Bone marrow transplantation can cure SCD. This intervention was first used in a
patient with sickle cell disease who also had relapsed acute lymphocytic
leukemia. The transplant was done to treat the leukemia, but cured the sickle
cell disease as well. The largest experience with transplantation for sickle
cell disease comes from Belgium and France, where about 80 patients have
undergone bone marrow transplantation (Apperley, 1993). The results have been
quite promising with cure of the sickle cell disease in every case in which
engraftment occurred.
Concerns about problems such as graft versus host disease and interstitial
pneumonia, two potentially fatal complications of bone marrow transplantation,
have limited the use of this modality in the United States (Kalinyak et al.,
1995) (Davies, 1993). A recently reported trial of bone marrow transplantation
in children from centers in the US reaffirmed that the procedure can cure sickle
cell (Walters et al., 1996). Ten percent of the children died from the
procedure, and some suffered severe complications, such as graph rejection. A
later report by this group includes thirty-four children under the age of 16
years who have received bone marrow transplants (Walters MC, et al., 1997). The
incidence of complications as lower in the children who underwent transplant
subsequent to the initial report.
The questions of when to perform a transplant and which patients should receive
the therapy are difficult. The optimal time for transplantation is during
childhood, since children fare better with transplantation than do adults. The
variable clinical manifestation of sickle cell disease makes it impossible to
predict in childhood which patients will have a more severe course. This issue
is particularly pertinent considering that transplantation is best carried out
prior to the development of end organ damage from the sickle cell disease.
Analysis of data from the Study of the Natural History of Sickle Cell Disease
reported by Platt, et al, suggested that patients with fetal hemoglobin levels
of less than 8.6% tend to have more severe disease over the long run (Platt et
al., 1994). This would seem to provide a guide that could be used in the
decision of which patients to transplant. However, the data are only statistical
values. With rare exceptions, statistical data cannot be applied to a particular
patient to predict the clinical course.
An unresolved ethical question surrounds bone marrow transplantation for
children with sickle cell disease. Sickle cell disease is often a debilitating
condition that makes life miserable for its victims. Although the Natural
History Study indicates that patients with sickle cell disease die earlier than
actuarial projections for other African-Americans, data collected in the 1980's
showed a life span that extends into the 40's. With the nearly universal use of
prophylactic penicillin in children to prevent overwhelming pneumococcal
infections along with other advances in supportive treatment, this figure is
likely to improve.
The question of who should decide to subject a child to this potentially fatal
procedure likewise is complex. Should the decision be left to parents and
physicians? In a study at the University of Chicago, parents were presented with
hypothetical data on cure/mortality rates for their children with sickle cell
disease, and asked to indicate when the risks of the procedure were acceptable
relative to the gravity of the disease (Kodish et al., 1991). About one-third of
the parents indicated that a transplant mortality rate of 15% along with a 15%
incidence of graft-versus-host disease were acceptable odds. However, young
adults older than 18 years were not allowed to participate in the decision
process. Should the patients, the ones with the most to gain and the most to
lose, be excluded from the decision-making loop? Should the courts appoint
advocates for the children, to ensure that the parents and physicians indeed are
acting in the "best interest" of the youngsters?
A program of bone marrow transplantation for beta-thalassemia major has been
successfully initiated in Italy (Lucarelli et al., 1993). Although sickle cell
disease and beta-thalassemia major are both hemoglobinopathies, clear
differences between the diseases exist. The most important is the monotonous
progression to disability and death that occurs with beta-thalassemia major.
Bone marrow transplantation for sickle cell disease offers promise. The jury has
not returned a final verdict, however.
Experimental Therapies
Erythropoietin
Erythropoietin is a hormone produced by the kidneys that stimulates red cell
production (Adamson and Eschbach, 1990). Usually, the hormone is made in
response to hypoxemia (Kario et al., 1992). Erythropoietin also increases fetal
hemoglobin levels in the red cells of many patients (Nagel et al., 1993). A
number of investigators have examined the extent to which erythropoietin will
raise fetal hemoglobin levels in sickle cell disease. The consensus is that the
drug can significantly raise fetal hemoglobin levels, particularly when given in
high doses.
In one report, the drug was used in a dose of over 1,000 U/kg three times per
week (Rodgers et al., 1993). The treatment significantly elevated fetal
hemoglobin levels. The quantity of erythropoietin required for this effect was
enormous, particularly when compared to patients on hemodialysis where the
typical dose is now about 150 U/kg three times per week. The cost of
erythropoietin at the higher dose is prohibitive. Further, while erythropoietin
can increase the fetal hemoglobin content of red cells, no controlled trial has
shown that it alters the clinical course of sickle cell disease.
Butyrate
Arginine butyrate and similar compounds have been tested in patients with sickle
cell disease (Perrine et al., 1989). The use of this agent stemmed from the
observation that babies born to diabetic mothers with poor glucose control had
sustained production of fetal hemoglobin after birth relative to infants born to
normal women. Butyrate produced as a byproduct of the hyperglycemia produced the
phenomenon. A group of investigators subsequently examined the use of butyrate
as a means of inducing fetal hemoglobin synthesis in patients with sickle cells
disease (Perrine et al., 1993).
Arginine butyrate can increase fetal hemoglobin levels, but the effect is
variable (Sher et al., 1995). Unfortunately, the drug must be given
intravenously and has a half-life of only about 5 minutes. Intermittent rather
than continuous infusion of arginine butyrate may induce fetal hemoglobin
synthesis more effectively. Side effects that have been seen in patients who
have received arginine butyrate include anorexia, nausea, vomiting, and abnormal
liver function tests (One patient had a seizure on the medication after
inadvertently receiving 4 times the recommended dose.) For most patients,
arginine butyrate is well-tolerated, however. The requirement for intravenous
administration limits the use of the agent. However, many drugs now are
administered intravenously to patients at home (e.g., desferrioxamine for iron
overload). Creative strategies are being explored to make arginine butyrate a
useful therapeutic option.
An effort is underway to identify orally active agents with longer half-lives.
Several compounds have been identified, and a couple have been placed into early
clinical trials. One of these is sodium phenylbutyrate, a drug that has been
used for patients with urea cycle disorders (Dover et al., 1994). Unfortunately,
patients tolerated the medication poorly, in part due to the fact up to 40
tablets per day are needed to obtain acceptable blood levels. The increase in Hb
F levels produced by the oral agents studied thus far have been significantly
less than that seen with arginine butyrate (Perrine et al., 1994). The butyrates
have a number of hurtles to leap before they are accepted for more general use,
including a demonstration that they consistently alter the red cell profile and,
ultimately, improve the clinical picture in sickle cell disease.
Clotrimazole
Red cell dehydration contributes substantially to polymerization of sickle
hemoglobin in patients with sickle cell disease. The cell membrane is damaged in
part through repeated physical distortion by hemoglobin
polymerization/depolymerization, and in part through oxidant damage from
reactive oxygen species generated by hemichromes and other hemoglobin
byproducts. K-CL co-transport increases, with K+ loss and associated water loss.
Also, sickle cells accumulate Ca2+. As a consequence, the Gardos channel
(Ca2+-activated K+ export) is activated, with further dehydration.
Clotrimazole and other imidazole antimycotics specifically inhibit the
Ca2+-activated K+ channel pathway of normal and sickle erythrocytes. The
original report of Alvarez and colleagues described the inhibition of the normal
human red cell Gardos channel by clotrimazole (CLT) and other imidazole
antimycotics. Dr. Carlo Brugnara showed in sickle erythrocytes that CLT blocks
K+ transport via the Gardos channel, prevents the change in membrane potential
observed when the Gardos channel is activated by internal Ca2+, and inhibits
dehydration induced by either the Ca2+ ionophore A 23187 or cyclic
oxygenation-deoxygenation.
Initial work by Dr. Brugnara and colleagues at Children's Hospital, Boston
showed that clotrimazole reduces the number of dense cells and the number of
irreversibly sickled cells in patients with sickle cell disease (Brugnara, et
al, 1996). A study of the agent at Children's Hospital and Brigham and Women's
Hospital evaluated the combined effects of clotrimazole and hydroxyuea in
patients with sickle cell disease. The hope was that the agents, which have
different mechanisms of action on sickle cells, would work at least
cooperatively, and perhaps synergistically, to reduce sickling. Clotrimazole
proved to have a number of side-effects that limited its success, including
severe dysuria in many men. A newer imidazole with fewer side-effects has
recently come available. Enrollment in the clotrimazole study has be suspended
in anticipation of this newer agent.
Nitric Oxide
Nitric oxide is one of the newest agents to enter testing for possible treatment
of patients with sickle cell disease. It is an inhaled gas that has been used in
a variety of investigational conditions, including neonatal pulmonary
hypertension and adult respiratory distress syndrome.
Nitric oxide is know primarily for its ability to relax smooth muscle
relaxation. However, the compound also forms a covalent link with hemoglobin,
particularly attaching as an S-nitroso group to the ß-93 cysteine (Gow and
Stamler, 1998). This amino acid residue is near the "acceptor pocket" on the
ß-subunit of hemoglobin where the ß-6 valine of Hb S forms a non-covalent
interaction. The hydrophilic S-nitroso cysteine at the ß-93 residue could
destabilize the interaction between deoxy-Hb S molecules in polymerized sickle
hemoglobin.
Dr. C. Alvin Head, of Massachusetts General Hospital, and Dr. Carlo Brugnara,
of Children's Hospital, studied the interaction of nitric oxide both in vitro
and in vivo in normal volunteers and patients with sickle cell disease (Head, et
al., 1997). Their data suggested that nitric oxide breathed at a concentration
of 80 ppm reduces the polymerization tendency of sickle hemoglobin. Reduced
polymerization was inferred by a fall in the P50 of sickle hemoglobin (no effect
occurred with Hb A). Nitric oxide for acute painful vaso-occlusive crisis is
being studied in an ongoing multicenter trial. Other investigators were unable
to reproduce the P50 effect (Gladwin, et al., 1999). Further work is needed to
determine whether nitric oxide has a role in the treatment of patients with
sickle cell disease.
FluocorTM
FluocorTM is a drug manufactured by the CytRx Corporation of Norcross, Georgia.
A phase III clinical trial of the drug for patients with acute sickle cell pain
crisis was recently completed. FluocorTM is a more highly purified version of
the drug, RheothRxTM which went through phase II clinical studies several years
ago. Fifty patients were followed in a placebo-control pilot study designed to
evaluate safety and efficacy of the compound (Adams-Graves, et al., 1997). The
investigators infused the drug continuously for 48 hours at the beginning of a
sickle cell crisis. The treated patients required less narcotic analgesic and
showed a net reduction in hospital length-of-stay relative to placebo control
patients. The multicenter study of FluocorTM failed to confirm these preliminary
results. The future of the drug in the treatment of sickle cell disease is
unclear.
Gene Replacement Therapy
The beta-globin gene was cloned a number of years ago, fueling interest in the
possibility of gene replacement therapy for sickle cell disease. While the idea
of simply replacing the defective gene with a normal one is appealing, a number
of major difficulties must be surmounted. The first is to engineer a construct
in which the beta-globin gene is expressed at high levels. Our understanding of
the factors that control globin gene expression has advanced significantly over
the past few years, but many of the nuances are yet to be worked out. A large
segment of DNA upstream of the beta-globin gene cluster, called the locus
control region, is necessary for efficient transcription of beta-globin mRNA.
Any attempt at gene therapy must include the large locus control region.
Another problem is that the inserted gene must be regulated in its expression so
that it produces beta-globin chains at a level roughly equal to the production
of endogenous alpha- globin chains. Failure to achieve such a balance would
produce a thalassemia. Further, the endogenous sickle beta-globin gene likely
would have to be silenced, so that it does not continue to produce sickle globin
chains.
Finally, the cloned gene would have to be introduced into pluripotent stem cells
so that the patient would continue to make normal beta-globin in perpetuity. The
retroviral vectors that have been used to this point infect dividing cells,
while pluripotent stem cells divide very slowly. To overcome this difficulty, a
number of researchers have turned to adeno-associated viruses (AAV) as vehicles
for gene therapy since these viruses can infect resting cells. Here a new
barrier, namely immune response to the viral vector, has appeared. In any event,
gene therapy for sickle cell disease, the ultimate cure for the disorder, is not
imminent.
Concluding Thoughts
Without major breakthroughs in gene therapy or bone marrow transplantation that
make these treatments applicable to a large number of patients, drug
intervention will remain the major therapeutic option for sickle cell disease.
The likelihood is low of finding a "magic bullet" medication that substantially
improves sickle cell disease for all or even most patients. Treatment likely
will involve the use of different agents alone or in combination to produce
optimal results. Most chronic illnesses, in fact, require combination drug
therapy. Hypertension, for instance, cannot be managed solely with diuretics.
Physicians test combinations of diuretics, beta blockers, calcium channel
blockers, and angiotensin converting enzyme (ACE) inhibitors to acheive opitmal
control of hypertension while producing the fewest side-effects.
Table 2. Future therapies for sickle cell diseaseTreatment
GoalCureMaintenanceAcute Pain Management
Bone Marrow Transplanthydroxyureanitric oxide
Gene TherapyclotrimazoleFluocorTM
magnesium pitolateInibitiors of endothelial cell adhesion
arginine butyrateAntiinflammatory agents
Combination therapy currently is not an option for sickle cell disease, since
only hydroxyurea has been proven to alter the course of the condition. Many, if
not most of the agents currently under investigation likely will fall short of
investigators' hopes. If a few survive the rigors of testing and joint the
clinical armamentarium, however, we could mix and match drugs for patients with
sickle cell disease. Ideally, the treatment regimens would include drugs with
differing modes of action. Hydroxyurea, for instance, combined with clotrimazole
would team a drug that enhances fetal hemoglobin production (hydroxyurea) with
one that reduces erythrocyte dehydration (clotrimazole). For a particular
patient, sickle cell symptoms might be improved substantially by neither drug
alone. The combination, however, might significantly ameliorate the condition.
Table 2 shows how therapies might be combined, using as examples some of the
agents currently under investigation. We cannot say whether the therapeutic
algorithm that eventually evolves will include these approaches or modalities
not yet conceived. The only statement that can be made with confidence is that
new vistas in the treatment of sickle cell disease will usher in better and more
fulfilling lives for these patients.
A major goal of investigation should be development of interventions that can be
used in very young patients. Many of the problems experienced by adults and
adolescents with sickle cell disease reflect incremental organ damage by bouts
of hypoxia. The affected areas may initially be microscopic. With time, these
foci of injury colasce to form regions of macroscopic injury, such as avascular
necrosis of the femur. Prevention must be the watchword as we seek to improve
the management of patients with sickle cell disease.
References
Adams, R., Mckie, V., Nichols, F., Carl, E., Zhang, D., Mckie, K., Figueroa,
R., Litaker, M., Thompson, W., and Hess, D. (1992). The use of transcranial
ultrasonography to predict stroke in sickle-cell disease. The New England
Journal of Medicine 326, 605-610.
Adams RJ, McKie VC, Brambilla D, Carl E, et. al. (1998). Stroke prevention in
sickle cell anemia. Control Clin Trials 19:110-129.
Adams-Graves P, Kedar A, Koshy M, Steinberg M, Veith R, et al. (1997) ReothRx
(poloxamer 188) injection for the acute painful episode of sickle cell
disease: a pilot study. Blood 90:2041-2046.
Adamson, J., and Eschbach, J. (1990). Treatment of anemia of chronic renal
failure with recombinant human erythropoietin. Annual Review of Medicine 41,
349-360.
Alvarez J , Montero M, Garcia-Sancho J: High affinity inhibition of
Ca2+-dependent K+ channels by cytochrome P-450 inhibitors. J Biol Chem
1992,267:11789-11793.
Ammann, A. (1982). Current status of pneumococcal polysaccharide immunization
in patients with sickle cell disease or impaired splenic function. American
Journal of Pediatric Hematology Oncology 4, 301-6.
Ammann, A., Addiego, J., Wara, D., Lubin, B., Smith, W., and Mentzer, W.
(1977). Polyvalent pneumococcal-polysaccharide immunization of patients with
sickle-cell anemia and patients with splenectomy. New England Journal of
Medicine 297, 897-900.
Anand, A., and Glatt, A. (1994). Salmonella osteomyelitis and arthritis in
sickle cell disease. Semin Arthritis Rheum 24, 211-21.
Anastasi J. 1984. Hemoglobin S-mediated membrane oxidant injury: protection
from malaria and pathology in sickle cell disease. Med Hypotheses 14: 311-320.
Apperley, J. (1993). Bone marrow transplant for the haemoglobinopathies: past,
present and future. Baillieres Clin Haematol 6, 299-325.
Armstrong, F., Pegelow, C., Gonzalez, J., and Martinez, A. (1992). Impact of
children's sickle cell history on nurse and physician ratings of pain and
medication decisions. J Pediatr Psychol 17, 651-64.
Baldree LA, Ault BH, Chesney CM, Stapleton FB. (1990) Pediatr 86:238-243.
Balkaran, B., Char, G., Morris, J., Thomas, P., Serjeant, B., and Serjeant, G.
(1992). Stroke in a cohort of patients with homozygous sickle cell disease.
Journal of Pediatrics 120, 360-6.
Ballas, S. (1991). Sickle cell anemia with few painful crises is characterized
by decreased red cell deformability and increased number of dense cells. Am J
Hematol 36, 122-30.
Ballas, S., and Delengowski, A. (1993). Pain measurement in hospitalized
adults with sickle cell painful episodes. Ann Clin Lab Sci 23, 358-61.
Baruchel, S., Rees, J., Bernstein, M., and Goodyer, P. (1993). Relief of
sickle cell priapism by hydralazine. Report of a case. American Journal of
Pediatric Hematology-Oncology 15, 115-6.
Black WD, Hatch FE, Acchiardo S. Aminocaproic acid in prolonged hematuria of
patients with sicklemia. Arch Intern Med 1976; 136: 678-81.
Boletini, E., Svobodova, M., Divoky, V., Baysal, E., Curuk, M., Dimovski, A.,
Liang, R., Adekile, A., and Huisman, T. (1994). Sickle cell anemia, sickle
cell beta-thalassemia, and thalassemia major in Albania: characterization of
mutations. Hum Genet 93, 182-7.
Bonnerot, V., Sebag, G., de Montalembert, M., Wioland, M., Glorion, C., Girot,
R., and Lallemand, D. (1994). Gadolinium-DOTA enhanced MRI of painful osseous
crises in children with sickle cell anemia. Pediatr Radiol 24, 92-5.
Bouhassira, E., Lachman, H., Krishnamoorthy, R., Labie, D., and Nagel, R.
(1989). A gene conversion located 5' to the A gamma gene in linkage
disequilibrium with the Bantu haplotype in sickle cell anemia. Journal of
Clinical Investigation 83, 2070-2073.
Bridges KR, Garabino GD, Brugnara C, Cho MR, et al. (1996) A multiparameter
analysis of sickle erythrocytes in patients undergoing hydroxyurea therapy.
Blood 88:4701-4710.
Brugnara C, B Gee, C Armsby, S Kurth, M Sakamoto, N Rifai, SL Alper, O. Platt:
Therapy with oral clotrimazole induces inhibition of the Gardos channel and
reduction of erythrocyte dehydration in patients with sickle cell disease. J.
Clin. Invest. 1996; 97: 1227-1234.
Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. (1993>
Pneumococcal polysaccharide vaccine efficacy. An evaluation of current
recommendations. JAMA 270 1826-1831.
Carlson, J., Nash, G., Gabutti, V., al-Yaman, F., and Wahlgren, M. (1994).
Natural protection against severe Plasmodium falciparum malaria due to
impaired rosette formation. Blood 84, 3909-3814. Charache, S. (1991).
Hydroxyurea as treatment for sickle cell anemia. Hematol Oncol Clin North Am
5, 571-83.
Charache, S., Scott, J., and Charache, P. (1979). "Acute chest syndrome" in
adults with sickle cell anemia. Microbiology, treatment, and prevention.
Archives of Internal Medicine 139, 67-9.
Charache, S., Terrin, M., Moore, R., Dover, G., Barton, F., Eckert, S.,
McMahon, R., and Bonds, D. (1995). Effect of hydroxyurea on the frequency of
painful crises in sickle cell anemia. Investigators of the Multicenter Study
of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 332, 1317-22.
Clark, M., Mohandas, N., and Shohet, S. (1980). Deformability of oxygenated
irreversibly sickled cells. J Clin Invest 65, 189-196.
Clarkson, J. (1992). The ocular manifestations of sickle-cell disease: a
prevalence and natural history study. Transactions of the American
Opthalmologic Society 90, 481-504.
Cohen, A., Martin, M., Silber, J., Kim, H., Ohene-Frempong, K., and Schwartz,
E. (1992). A modified transfusion program for prevention of stroke in sickle
cell disease. Blood 79, 1657-61.
Cohen, A., and Schwartz, E. (1979). Iron chelation therapy in sickle cell
anemia. American Journal of Hematology 7, 69-76.
Condon, P., and Serjeant, G. (1980). Photocoagulation in proliferative sickle
retinopathy: results of a 5-year study. British Journal of Opthalmology 64,
832-40.
Davies, S. (1993). Bone marrow transplant for sickle cell disease--the
dilemma. Blood Reviews 7, 4-9.
Davies, S., and Brozovic, M. (1989). The presentation, management and
prophylaxis of sickle cell disease. Blood Reviews 3, 29-44.
DeBaun, M., Glauser, T., Siegel, M., Borders, J., and Lee, B. (1995).
Noninvasive central nervous system imaging in sickle cell anemia. A
preliminary study comparing transcranial Doppler with magnetic resonance
angiography. J Pediatr Hematol Oncol 17, 29-33.
Diamond, W., Brown Jr, F., Bitterman, P., Klein, H., Davey, R., and Winslow,
R. (1980). Delayed hemolytic transfusion reaction presenting as sickle-cell
crisis. Ann Intern Med 93, 231-4.
Dover, G., Brusilow, S., and Charache, S. (1994). Induction of fetal
hemoglobin production in subjects with sickle cell anemia by oral sodium
phenylbutyrate. Blood 84, 339-43.
Earley CJ, Kittner SJ, Feeser BR, Gardner J, Epstein A, Wozniak MA, Wityk R,
Stern BJ, Price TR, Macko RF, Johnson C, Sloan MA, Buchholz D. (1998) Stroke
in children and sickle-cell disease: Baltimore-Washington Cooperative Young
Stroke Study. Neurology 51:169-176.
Eaton, W., Hofrichter, J., and Ross, P. (1976). Delay Time of Gelation: A
Possible Determinant of Clinical Severity in Sickle Cell Disease. Blood 47,
621-627.
Eaton, W. A., and Hofrichter, J. (1990). Sickle cell hemoglobin
polymerization. [Review]. Advances in Protein Chemistry 40, 63-279.
Embury, S., Dozy, A., Miller, J., Davis, J. J., Kleman, K., Preisler, H.,
Vichinsky, E., Lande, W., Lubin, B., Kan, Y., and Mentzer, W. (1982).
Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of
anemia. N Engl J Med 306, 270-274.
Emond, A., Holman, R., Hayes, R., and Serjeant, G. (1980). Priapism and
impotence in homozygous sickle cell disease. Arch Intern Med 140, 1434-7.
Emre, U., Miller, S., Gutierez, M., Steiner, P., Rao, S., and Rao, M. (1995).
Effect of transfusion in acute chest syndrome of sickle cell disease. J
Pediatr 127, 901-4.
Epps Jr, C., Bryant 3d, D., Coles, M., and Castro, O. (1991). Osteomyelitis in
patients who have sickle-cell disease. Diagnosis and management. J Bone Joint
Surg 73, 1281-94.
Falk, R., Mattern, W., Lamanna, R., Gitelman, H., Parker, N., Cross, R., and
Rastall, J. (1983). Iron removal during continuous ambulatory peritoneal
dialysis using deferoxamine. Kidney Int 24, 110-2.
Falk, R., Scheinman, J., Phillips, G., Orringer, E., Johnson, A., and
Jennette, J. (1992). Prevalence and pathologic features of sickle cell
nephropathy and response to inhibition of angiotensin-converting enzyme. The
New England Journal of Medicine 326, 910-5.
Fernbach, D., and Burdine Jr, J. (1970). Sepsis and functional asplenia. New
England Journal of Medicine 282, 691.
Flanagan, G., Packham, D., and Kincaid-Smith, P. (1993). Sickle cell disease
and the kidney. American Journal of Kidney Diseases 21, 325-7.
Fowler Jr, J., Koshy, M., Strub, M., and Chinn, S. (1991). Priapism associated
with the sickle cell hemoglobinopathies: prevalence, natural history and
sequelae. J Urol 145, 65-8.
Friedman, E., Webber, A., Osborn, H., and Schwartz, S. (1986). Oral analgesia
for treatment of painful crisis in sickle cell anemia. Ann Emerg Med 15,
787-91.
Gaston, M., Verter, J., Woods, G., Pegelow, C., Kelleher, J., Presbury, G.,
Zarkowsky, H., Vinchinsky, E., Iyer, R., Lobel, J., Diamond, S., Holbrook, C.,
Gill, F., Ritchey, K., Falletta, J., and Group, t. P. P. S. (1986).
Prophylaxis with oral penicillin in children with sickle cell anemia. A
randomized trial. New England Journal of Medicine 314, 1593-9.
Gelfand, M., Daya, S., Rucknagel, D., Kalinyak, K., and Paltiel, H. (1993).
Simultaneous occurrence of rib infarction and pulmonary infiltrates in sickle
cell disease patients with acute chest syndrome. Journal of Nuclear Medicine
34, 614-8.
Gendrel, D., Kombila, M., Nardou, M., Gendrel, C., Djouba, F., and
Richard-Lenoble, D. (1991). Protection against Plasmodium falciparum infection
in children with hemoglobin S. Pediatr Infect Dis J 10, 620-1.
Gerry, J., Bulkley, B., and Hutchins, G. (1978). Clinicopathologic analysis of
cardiac dysfunction in 52 patients with sickle cell anemia. Am J Cardiol 42,
211-6.
Gil, K., Phillips Jr, G., Edens, J., Martin, N., and Abrams, M. (1994).
Observation of pain behaviors during episodes of sickle cell disease pain.
Clin J Pain 10, 128-32.
Gil, K., Williams, D., Thompson, R., and Kinney, T. (1991). Sickle cell
disease in children and adolescents: the relation of child and parent pain
coping strategies to adjustment. J. Ped. Psych. 16, 643-663.
Gill, F., Sleeper, L., Weiner, S., Brown, A., Bellevue, R., Grover, R.,
Pegelow, C., and Vichinsky, E. (1995). Clinical events in the first decade in
a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell
Disease. Blood 86, 776-83.
Gillams AR, McMahon L, Weinberg G, Carter AP (1998) MRA of the intracranial
circulation in asymptomatic patients with sickle cell disease. Pediatr Radiol
28:283-287.
Gladwin MT, Schechter AN, Shelhamer JH, Pannell LK, Conway DA, Hrinczenko BW,
Nichols JS, Pease-Fye ME, Noguchi CT, Rodgers GP, Ognibene FP. (1999) Inhaled
nitric oxide augments nitric oxide transport on sickle cell hemoglobin without
affecting oxygen affinity. J Clin Invest 104:937-945
Goldberg, M., Brugnara, C., Dover, G., Schapira, L., Charache ,S., and Bunn,
H. (1990. Treatment of sickle cell anemia with hydroxyurea and erythropoietin.
N Eng J Med 323, 366-372.
Goldberg, M., Brugnara, C., Dover, G., Schapira, L., Lacroix, L., and Bunn, H.
(1992). Hydroxyurea and erythropoietin therapy in sickle cell anemia.
Seminarys in Oncology 19, 74-81.
Gonzalez-Carrillo, M., Rudge, C., Parsons, V., Bewick, M., and White, J.
(1982). Renal transplantation in sickle cell disease. Clin Nephrol 18, 209-10.
Gow AJ, Stamler JS. (1998) Reactions between nitric oxide and haemoglobin
under physiological conditions. Nature 391:169-73.
Griffin, T., McIntire, D., and Buchanan, G. (1994). High-dose intravenous
methylprednisolone therapy for pain in children and adolescents with sickle
cell disease. N Engl J Med 330, 733-737.
Gupta AK, Kirchner KA, Nicholson R, Adams JG 3d, Schechter AN, Noguchi CT,
Steinberg MH. (1991) Effects of alpha-thalassemia and sickle polymerization
tendency on the urine-concentrating defect of individuals with sickle cell
trait J Clin Invest 88: 1963-1968.
Haynes Jr, J., and Allison, R. (1986). Pulmonary edema. Complication in the
management of sickle cell pain crisis. Am J Med 80, 833-40.
Haynes Jr, J., and Kirkpatrick, M. (1993). The acute chest syndrome of sickle
cell disease. American Journal of Medical Science 305, 326-30.
Head CA, Brugnara C, Martinez-Ruiz R, Kacmarek, et al. (1997) Low
concentrations of nitric oxide increase oxygen affinity of sickle erythrocytes
in vitro and in vivo. J Clin Invest 100:1193-1198.
Hernigou, P., Bachir, D., and Galacteros, F. (1993). Avascular necrosis of the
femoral head in sickle-cell disease. Treatment of collapse by the injection of
acrylic cement. J Bone Joint Surg Br 75, 875-80.
Holbrook, C. (1990). Patient-controlled analgesia pain management for children
with sickle cell disease. J Assoc Acad Minor Phys 1, 93-6.
Humbert, J., Winsor, E., Githens, J., and Schmitz, J. (1990). Neutrophil
dysfunctions in sickle cell disease. Biomed Pharmacother 44, 153-8.
Ingram, V.M. (1956) A specific chemical difference between globins of normal
and sickle-cell anúmia húmoglobins. Nature 178, 792-794.
Issitt, P. (1994). Race-related red cell alloantibody problems. Br J Biomed
Sci 51, 158-67.
Johnson, K., Stastny, J., and Rucknagel, D. (1994). Fat embolism syndrome
associated with asthma and sickle cell-beta(+)-thalassemia. Am J Hematol 46,
354-7.
Kalinyak, K., Morris, C., Ball, W., Ris, M., Harris, R., and Rucknagel, D.
(1995). Bone marrow transplantation in a young child with sickle cell anemia.
Am J Hematol 48, 256-61.
Kar, B., Satapathy, R., Kulozik, A., Kulozik, M., Sirr, S., Serjeant, B., and
Serjeant, G. (1986). Sickle cell disease in Orissa State, India. Lancet 2,
1198-201.
Kario, K., Matsuo, T., Kodama, K., Nakao, K., and Asada, R. (1992). Reduced
erythropoietin secretion in senile anemia. Am J Hematol 41, 252-7.
Kaul, D., Fabry, M., and Nagel, R. (1989). Microvascular sites and
characteristics of sickle cell adhesion to vascular endothelium in shear flow
conditions: pathophysiological implications. Proc Natl Acad Sci U S A 86,
3356-60.
Kaul, D. K., Fabry, M. E., Windisch, P., Baez, S., and Nagel, R. L. (1983).
Erythrocytes in sickle cell anemia are heterogeneous in their rheological and
hemodynamic characteristics. Journal of Clinical Investigation 72, 22-31.
Keidan, A., Marwah, S., Vaughan, G., Franklin, I., and Stuart, J. (1987).
Painful sickle cell crises precipitated by stopping prophylactic exchange
transfusions. J Clin Pathol 40, 505-7.
Kimmel, A., Magargal, L., and Tasman, W. (1986). Proliferative sickle
retinopathy and neovascularization of the disc: regression following treatment
with peripheral retinal scatter laser photocoagulation. Ophthalmic Surgery 17,
20-2.
Kinney, T., Ware, R., Schultz, W., and Filston, H. (1990). Long-term
management
Kinney TR, Sleeper LA, Wang WC, Zimmerman RA, Pegelow CH, Ohene-Frempong K,
Wethers DL, Bello JA, Vichinsky EP, Moser FG, Gallagher DM, DeBaun MR, Platt
OS, Miller ST. (1999) Silent cerebral infarcts in sickle cell anemia: a risk
factor analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics
103:640-645.
of splenic sequestration in children with sickle cell disease. J Pediatr 117,
194-9.
Kirkpatrick, M., Haynes Jr, J., and Bass Jr, J. (1991). Results of
bronchoscopically obtained lower airway cultures from adult sickle cell
disease patients with the acute chest syndrome. American Journal of Medicine
90, 206-10.
Kodish, E., Lantos, J., Stocking, C., Singer, P., Siegler, M., and Johnson, F.
(1991). Bone marrow transplantation for sickle cell disease. A study of
parent's decisions. N Engl J Med 325, 1349-1353.
Kontessis P, Mayopoulou-Symvoulidis D, Symvoulidis A, Kontopoulou-Griva I.
(1992) Renal involvement in sickle cell-beta thalassemia. Nephron 61: 10-15.
Koren, A., Wald, I., Halevi, R., and Ben Ami, M. (1990). Acute chest syndrome
in children with sickle cell anemia. Pediatric Hematology Oncology 7, 99-107.
Koshy, M., Burd, L., Dorn, L., and Huff, G. (1987). Frequency of pain crisis
during pregnancy. Prog Clin Biol Res 240, 305-11.
Koshy, M., Entsuah, R., A, K., Kraus, A., Johnson, R., Bellvue, R.,
Flournoy-Gill, Z., and Levy, P. (1989). Leg ulcers in patients with sickle
cell disease. Blood 74, 1403-8.
Landesman, S., Rao, S., and Ahonkhai, V. (1982). Infections in children with
sickle cell anemia. Special reference to pneumococcal and salmonella
infections. American Journal of Pediatric Hematology and Oncology 4, 407-18.
Lanzkowsky, P., Shende, A., Karayalcin, G., Kim, Y., and Aballi, A. (1978).
Partial exchange transfusion in sickle cell anemia. Use in children with
serious complications. Am J Dis Child 132, 1206-8.
Lucarelli, G., Galimberti, M., Polchi, P., Angelucci, E., Baronciani, D.,
Giardini, C., Andreani, M., Agostinelli, F., Albertini, F., and Clift, R.
(1993). Marrow transplantation in patients with thalassemia responsive to iron
chelation therapy. N Engl J Med 329, 840-844.
Mallouh, A., and Qudah, A. (1993). Acute splenic sequestration together with
aplastic crisis caused by human parvovirus B19 in patients with sickle cell
disease. Journal of Pediatrics 122, 593-5.
Mankad, V., Williams, J., Harpen, M., Manci, E., Longenecker, G., RB, M.,
Shah, A., Yang, Y., and Brogdon, B. (1990). Magnetic resonance imaging of bone
marrow in sickle cell disease: clinical, hematologic, and pathologic
correlations. Blood 75, 274-83.
Mantadakis E, Cavender JD, Rogers ZR, Ewalt DH, Buchanan GR. 1999. Prevalence
of priapism in children and adolescents with sickle cell anemia. J Pediatr
Hematol Oncol 21: 518-522.
McPherson, E., Perlin, E., Finke, H., Castro, O., and Pittman, J. (1990).
Patient-controlled analgesia in patients with sickle cell vaso-occlusive
crisis. Am J Med Sci 299, 10-2.
Miller, B., Olivieri, N., Salameh, M., Ahmed, M., Antognetti, G., Huisman, T.,
Nathan, D., and Orkin, S. (1987). Molecular analysis of the high-hemoglobin-F
phenotype in Saudi Arabian sickle cell anemia. N Engl J Med 316, 244-50.
Miller, S., Hammerschlag, M., Chirgwin, K., Rao, S., Roblin, P., Gelling, M.,
Stilerman, T., Schachter, J., and Cassell, G. (1991). Role of Chlamydia
pneumoniae in acute chest syndrome of sickle cell disease. Journal of
Pediatrics 118, 30-3.
Miller ST, Sleeper, LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, Wethers DL,
Smith J, Kinney TR. (2000) Prediction of adverse outcomes in children with
sickle cell disease. N Engl J Med 342: 83-99.
Mok, Q., Underhill, G., Wonke, B., Aldouri, M., Kelsey, M., and Jefferies, D.
(1989). Intradermal hepatitis B vaccine in thalassaemia and sickle cell
disease. Arch Dis Child 64, 535-40.
Moran, M. (1995). Osteonecrosis of the hip in sickle cell hemoglobinopathy. Am
J Orthop 24, 18-24.
Moriarty, B., Acheson, R., Condon, P., and Serjeant, G. (1988). Patterns of
visual loss in untreated sickle cell retinopathy. Eye 2, 330-5.
Mykulak, D., and Glassberg, K. (1990). Impotence following childhood priapism.
J Urol 144, 134-5.
Nagel, R., and Fleming, A. (1992). Genetic epidemiology of the ßS gene.
Baillieres Clin Haematol 5, 331-365.
Nagel, R., Vichinsky, E., Shah, M., Johnson, R., Spadacino, E., Fabry, M.,
Mangahas, L., Abel, R., and Stamatoyannopoulos, G. (1993). F reticulocyte
response in sickle cell anemia treated with recombinant human erythropoietin:
a double-blind study. Blood 81, 9-14.
Ohene-Frempong, K. (1991). Stroke in sickle cell disease: demographic,
clinical and therapeutic considerations. Seminars in Hematology 28, 213-219.
Olatunji PO, Davies SC. (2000) The predictive value of white cell count in
assessing clinical severity of sickle cell anaemia in Afro-Caribbeans
patients. Afr J Med Med Sci 29: 27-30.
Olopoenia, L., Frederick, W., Greaves, W., Adams, R., Addo, F., and Castro, O.
(1990). Pneumococcal sepsis and meningitis in adults with sickle cell disease.
Southern Medical Journal 83, 1002-4.
Orjih, A., Chevli, R., and Fitch, C. (1985). Toxic heme in sickle cells: an
explanation for death of malaria parasites. Am J Trop Med Hyg 34, 223-7.
Overturf, G., Powars, D., and Baraff, L. (1977). Bacterial meningitis and
septicemia in sickle cell disease. American Journal of Diseases of Childhood
131, 784-7.
Pegelow, C. (1992). Survey of pain management therapy provided for children
with sickle cell disease. Clin Pediatr (Phila) 31, 211-4.
Pegelow, C., Adams, R., McKie, V., Abboud, M., Berman, B., Miller, S.,
Olivieri, N., Vichinsky, E., Wang, W., and Brambilla, D. (1995). Risk of
recurrent stroke in patients with sickle cell disease treated with erythrocyte
transfusions. J Pediatr 126, 896-9.
Perlin, E., Finke, H., Castro, O., Rana, S., Pittman, J., Burt, R., Ruff, C.,
and McHugh, D. (1994). Enhancement of pain control with ketorolac tromethamine
in patients with sickle cell vaso-occlusive crisis. Am J Hematol 46, 43-7.
Perrine, R., Pembrey, M., John, P., Perrine, S., and Shoup, F. (1978). Natural
history of sickle cell anemia in Saudi Arabs. A study of 270 subjects. Ann
Intern Med 88, 1-6.
Perrine, S., Dover, G., Daftari, P., Walsh, C., Jin, Y., Mays, A., and Faller,
D. (1994). Isobutyramide, an orally bioavailable butyrate analogue, stimulates
fetal globin gene expression in vitro and in vivo. Br J Haematol 88, 555-61.
Perrine, S., Ginder, G., Faller, D., Dover, G., Ikuta, T., Witkowska, E., Cai,
S.-P., Vichinsky, E., and Olivieri, N. (1993). A short-term trial of butyrate
to stimulate fetal-globin-gene expression in the beta-globin disorders. New
England Journal of Medicine 328, 81-86.
Perrine, S., Miller, B., Faller, D., Cohen, R., Vichinsky, E., Hurst, D.,
Lubin, B., and Papayannopoulou, T. (1989). Sodium butyrate enhances fetal
globin gene expression in erythroid progenitors of patients with Hb SS and
beta thalassemia. Blood 74, 454-9.
Platt, O., Brambilla, D., Rosse, W., Milner, P., Castro, O., Steinberg, M.,
and Klug, P. (1994). Mortality in sickle cell disease. Life expectancy and
risk factors for early death. N Engl J Med 330, 1639-44.
Platt, O., Orkin, S., Dover, G., Beardsley, G., Miller, B., and Nathan, D.
(1984). Hydroxyurea enhances fetal hemoglobin production in sickle cell
anemia. J Clin Invest 74, 652-656.
Platt, O., Thorington, B., Brambilla, D., Milner, P., Rosse, W., Vichinsky,
E., and Kinney, T. (1991). Pain in sickle cell disease. Rates and risk
factors. N Engl J Med 325, 11-16.
Poncz, M., Kane, E., and Gill, F. (1985). Acute chest syndrome in sickle cell
disease: etiology and clinical correlates. Journal of Pediatrics 107, 861-6.
Powars, D., Elliott-Mills, D., Chan, L., Niland, J., Hiti, A., Opas, L., and
Johnson, C. (1991). Chronic renal failure in sickle cell disease: risk
factors, clinical course, and mortality. Ann Intern Med 115, 614-20.
Powars, D., and Hiti, A. (1993). Sickle cell anemia. Beta s gene cluster
haplotypes as genetic markers for severe disease expression. Am J Dis Child
147, 1197-1202.
Powars, D., Sandhu, M., Niland-Weiss, J., Johnson, C., Bruce, S., and Manning,
P. (1986). Pregnancy in sickle cell disease. Obstet Gynecol 67, 217-28.
Powars DR, Conti PS, Wong WY, Groncy P, Hyman C, Smith E, Ewing N, Keenan RN,
Zee CS, Harold Y, Hiti AL, Teng EL, Chan LS. (1999) Cerebral vasculopathy in
sickle cell anemia: diagnostic contribution of positron emission tomography.
Blood 93:71-79.
Prasad, A., Abbasi, A., and Ortega, J. (1977). Zinc deficiency in man: studies
in sickle cell disease. Prog Clin Biol Res 14, 211-239.
Pulido, J., Flynn Jr, H., Clarkson, J., and Blankenship, G. (1988). Pars plana
vitrectomy in the management of complications of proliferative sickle
retinopathy. Arch Ophthalmol 106, 1553-7.
Ramasamy, S., Balakrishnan, K., and Pitchappan, R. (1994). Prevalence of
sickle cells in Irula, Kurumba, Paniya & Mullukurumba tribes of Nilgiris
(Tamil Nadu, India). Indian J Med Res 100, 242-5.
Rao, V., Mitchell, D., Rifkin, M., Steiner, R., Burk Jr, D., Levy, D., and
Ballas, S. (1989). Marrow infarction in sickle cell anemia: correlation with
marrow type and distribution by MRI. Magnetic Resonance Imaging 7, 39-44. <
Robieux, I., Kellner, J., Coppes, M., Shaw, D., Brown, E., Good, C.,
O'Brodovich, H., Manson, D., Olivieri, N., Zipursky, A., and al, e. (1992).
Analgesia in children with sickle cell crisis: comparison of intermittent
opioids vs. continuous intravenous infusion of morphine and placebo-controlled
study of oxygen inhalation. Pediatric Hematology Oncology 9, 317-26.
Rodgers, G., Dover, D., Uyesaka, N., Noguchi, C., Schechter, A., and Neinhuis,
A. (1993). Augmentation by erythropoietin of the fetal-hemoglobin response to
hydroxyurea in sickle cell disease. New England Journal of Medicine 328,
73-80.
Rodgers, G., Dover, G., Noguchi, C., Schechter, A., and Nienhuis, A. (1990).
Hematologic responses of patients with sickle cell disease to reatment with
hydroxyurea. N Engl J Med 322, 1037-45.
Roshkow, J., and Sanders, L. (1990). Acute splenic sequestration crisis in two
adults with sickle cell disease: US, CT, and MR imaging findings. Radiology
177, 723-5.
Rosse, W., Gallagher, D., Kinney, T., Castro, O., Dosik, H., Moohr, J., Wang,
W., and PS, L. (1990). Transfusion and alloimmunization in sickle cell
disease. The Cooperative Study of Sickle Cell Disease. Blood 76, 1431-7.
Roth Jr, EF, Friedman M, Ueda Y, Tellez I, Trager W Nagel RL. 1978. Sickling
rates of human AS red cells infected in vitro with Plasmodium falciparum
malaria. Science 202: 650-652.
Rubin, L., Voulalas, D., and Carmody, L. (1989). Immunization of children with
sickle cell disease with Haemophilus influenzae type b polysaccharide vaccine.
Pediatrics 84, 509-13.
Saarinen, U., Chorba, T., Tattersall, P., Young, N., Anderson, L., Palmer, E.,
and Coccia, P. (1986). Human parvovirus B19-induced epidemic acute red cell
aplasia in patients with hereditary hemolytic anemia. Blood 67, 1411-7.
Sanders, D., Severance, H., and Pollack, C. J. (1992). Sickle cell
vaso-occlusive pain crisis in adults: alternative strategies for management in
the emergency department. Southern Medical Journal 85, 808-11.
Schiliro, G., Spena, M., Giambelluca, E., and Maggio, A. (1990). Sickle
hemoglobinopathies in Sicily. American Journal of Hematology 33, 81-5.
Schwartz, J. (1982). Pneumococcal vaccine: clinical efficacy and
effectiveness. Annals of Internal Medicine 96, 208-20.
Sears D. (1978) The morbidity of sickle cell trait: a review of the
literature. Am J Med 64:1021-1036.
Sears, D., and Udden, M. (1985). Splenic infarction, splenic sequestration,
and functional hyposplenism in hemoglobin S-C disease. American Journal of
Hematology 18, 261-8.
Seeler, R. (1973). Intensive transfusion therapy for priapism in boys with
sickle cell anemia. J Urol 110, 360-3.
Seoud, M., Cantwell, C., Nobles, G., and Levy, D. (1994). Outcome of
pregnancies complicated by sickle cell and sickle-C hemoglobinopathies. Am J
Perinatol 11, 187-91.
Serjeant, G., de Ceulaer, K., and Maude, G. (1985). Stilboestrol and
stuttering priapism in homozygous sickle-cell disease. Lancet 2, 1274-6.
Shapiro, M., and Hayes, J. (1984). Fat embolism in sickle cell disease. Report
of a case with brief review of the literature. Archives of Internal Medicine
144, 181-2.
Sher, G., Ginder, G., Little, J., Yang, S., Dover, G., and Olivieri, N.
(1995). Extended therapy with intravenous arginine butyrate in patients with
beta-hemoglobinopathies. N Engl J Med 332, 1606-10.
Solanki, D., Kletter, G., and Castro, O. (1986). Acute splenic sequestration
crises in adults with sickle cell disease. American Journal of Medicine 80,
985-90.
Sprinkle, R., Cole, T., Smith, S., and Buchanan, G. (1986). Acute chest
syndrome in children with sickle cell disease. A retrospective analysis of 100
hospitalized cases. American Journal of Pediatric Hematology Oncology 8,
105-10.
Stamatoyannopoulos, G., Wood, W., Papayannopoulou, T., and Nute, P. (1975). A
new form of hereditary persistence of fetal hemoglobin in blacks and its
association with sickle cell trait. Blood 46, 683-92.
Stamatoyannopoulos, J., and Nienhuis, A. (1992). Therapeutic approaches to
hemoglobin switching in treatment of hemoglobinopathies. Annu Rev Med 43,
497-521.
Steinberg, M., and Embury, S. (1986). Alpha-thalassemia in blacks: genetic and
clinical aspects and interactions with the sickle hemoglobin gene. Blood 68,
985-90.
Szwed, J., Yum, M., and Hogan, R. (1980). A beneficial effect of splenectomy
in sickle cell anemia and chronic renal failure. Am J Med Sci 279, 169-72.
Tobias, J. (1993). Indications and application of epidural anesthesia in a
pediatric population outside the perioperative period. Clin Pediatr (Phila)
32, 81-5.
Tuck, S., James, C., Brewster, E., Pearson, T., and Studd, J. (1987).
Prophylactic blood transfusion in maternal sickle cell syndromes. Br J Obstet
Gynaecol 94, 121-5.
Van Hoff, J., Ritchey, A., and Shaywitz, B. (1985). Intracranial hemorrhage in
children with sickle cell disease. Am J Dis Child 139, 1120-3.
Vichinsky, E., Earles, A., Johnson, R., Hoag, M., Williams, A., and Lubin, B.
(1990). Alloimmunization in sickle cell anemia and transfusion of racially
unmatched blood. N Engl J Med 322, 1617-21.
Vichinsky, E., and Lubin, B. (1980). Sickle cell anemia and related
hemoglobinopathies. Pediatr Clin North Am 27, 429-447.
Vichinsky, E., Williams, R., Das, M., Earles, A., Lewis, N., Adler, A., and
McQuitty, J. (1994). Pulmonary fat embolism: a distinct cause of severe acute
chest syndrome in sickle cell anemia. Blood.
Walters, M., Patience, M., Leisenring, W., Eckman, J., Scott, J., Mentzer, W.,
Davies, S., Ohene-Frempong, K., Bernaudin, F., Matthews, D., Storb, R., and
Sullivan, K. (1996). Bone marrow transplantation for sickle cell disease. N
Engl J Med 335, 369-376.
Walters MC, Patience M, Leisering W, Rogers ZR, et. al. (1997) Collaborative
multicenter investigation of marrow transplantation for sickle cell disease:
current results and future directions. Biol Blood Marrow Transplant 3:310-315.
Wang, W., Ahmed, N., and Hanna, M. (1986). Non-transferrin-bound iron in
long-term transfusion in children with congenital anemias. J Pediatr 108,
552-557.
Wang, W., Kovnar, E., Tonkin, I., Mulhern, R., Langston, J., Day, S., Schell,
M., and Wilimas, J. (1991). High risk of recurrent stroke after discontinuance
of five to twelve years of transfusion therapy in patients with sickle cell
disease. J Pediatr 118, 377-82.
Wang, Z., Bogdan, A., Zimmerman, R., Gusnard, D., Leigh, J., and
Ohene-Frempong, K. (1992). Investigation of stroke in sickle cell disease by
1H nuclear magnetic resonance spectroscopy. Neuroradiology 35, 57-65.
Wethers, D. (1982). Problems and complications in the adolescent with sickle
cell disease. Am J Pediatr Hematol Oncol 4, 47-53.
Wethers, D., Ramirez, G., Koshy, M., Steinberg, M., Phillips Jr., G., Siegel,
R., Eckman, J., and Prchal, J. (1994). Accelerated healing of chronic
sickle-cell leg ulcers treated with RGD peptide matrix. RGD Study Group. Blood
84, 1775-9.
White DA, DeBaun M. (1998) Cognitive and behavioral function in children with
sickle cell disease: a review and discussion of methodological issues. J
Pediatr Hematol Oncol 20:458-462.
Willcox M, Bjorkman A, Brohult J, Pehrson PO, Rombo L, Bengtsson E. 1983. A
case-control study in northern Liberia of Plasmodium falciparum malaria in
haemoglobin S and beta-thalassaemia traits. Ann Trop Med Parasitol 77:239-246.
Wong, W., Powars, D., Chan, L., Hiti, A., Johnson, C., and Overturf, G.
(1992). Polysaccharide encapsulated bacterial infection in sickle cell anemia:
a thirty year epidemiologic experience. American Journal of Hematology 39,
176-82.
Wright, S., Norris, R., and Mitchell, T. (1992). Ketorolac for sickle cell
vaso-occlusive crisis pain in the emergency department: lack of a
narcotic-sparing effect. Ann Emerg Med 21, 925-8.
Yang, Y., Donnell, C., Farrer, J., and Mankad, V. (1990). Corporectomy for
intractable sickle-associated priapism. Am J Med Sci 300, 231-3.
Yaster, M., Tobin, J., Billett, C., Casella, J., and Dover, G. (1994).
Epidural analgesia in the management of severe vaso-occlusive sickle cell
crisis. Pediatrics 93, 310-5.