40 :S ICKLE CELL ANEMIA AND OTHER SICKLING SYNDROMES
This abridged version of Chapter 40 from Wintrobe’s Clinical Hematology, 11 th edition,
is presented on Oncopedia with the permission of Lippincot, Williams and Wilkins. For
more information on this publication please visit http://www.lwwonline.com
Sickle Cell Anemia
Winfred C. Wang
This chapter discusses hemoglobin (Hb) variants that alter erythrocyte morphology and
rheology. The disorders resulting from sickle hemoglobin (Hb S) are enormously
important. Sickle cell anemia (Hb SS) is the most common inherited hematologic disease.
Each major hemoglobinopathy occurs in a heterozygous and homozygous form. In
the heterozygous state, red cells contain both normal adult Hb (Hb A) and the variant Hb.
Because heterozygotes rarely have clinical manifestations of disease, they are said to
have the trait for that abnormality, for example, sickle cell trait. In a homozygous
hemoglobinopathy, Hb A is totally lacking, and clinical manifestations are of variable
severity; these individuals have sickle cell anemia. Additionally, disease may result from
the combination of two variant hemoglobins or from a variant Hb and an interacting
thalassemia gene. These doubly heterozygous states are designated by both aberrant gene
products, such as Hb SC disease or Hb S/ß-thalassemia. The term sickle cell disease is
used genericly to refer to all of the sickling syndromes.
Hemoglobin S: Prevalence and Geographic Distribution
Hb S, from the sickle shape imparted to deoxygenated red cells, is responsible for
a spectrum of disorders that vary with respect to degree of anemia, frequency of crises,
extent of organ injury, and duration of survival. Some sickling syndromes lack significant
pathology but are easily confused with more clinically severe disorders on the basis of
laboratory evaluation; consequently, precision in diagnosis is essential to proper clinical
management and meaningful genetic counseling.
The highest prevalence of Hb S is in tropical Africa and among blacks in countries
that participated in the slave trade. It occurs with lower frequency in the Mediterranean
basin, Saudi Arabia, and parts of India. Results of studies of DNA polymorphisms linked
to the ßs gene suggest that it arose from three independent mutations in tropical Africa (1).
The most common ßs chromosome is found in Benin and central West Africa. A second
haplotype is prevalent in Senegal and the African West Coast, and a third haplotype is
seen in the Central African Republic (Bantu-speaking Africa). The same three haplotypes
are associated with the ßS gene in black Americans and Jamaicans (2). The Hb S gene in
the Eastern Province of Saudi Arabia and in Central India is associated with a different
DNA structure not encountered in Africa and probably represents a fourth independent
occurrence of the sickle cell mutation .In the United States , Latin America, and the
Caribbean , approximately 8% of blacks carry the sickle gene. In the United States, the
incidence of sickle cell anemia (Hb SS) at birth is 1 in 625. Allowing for increased
mortality, approximately 80,000 cases of sickle cell disease would be expected among
black Americans in the United States.
Without a selective advantage to Hb S trait, the sickle gene would have been
eliminated. The most widely accepted theory to account for the remarkable stability of
the sickle gene in Africa is that of balanced polymorphism (3,4). Sickle cell trait has its
highest prevalence in areas hyperendemic for malaria, suggesting that Hb S affords
selective protection against lethal forms of malaria. Selective removal of sickled cells
from the circulation probably reduces the degree of parasitemia and substantially limits
the infectious process.
Pathophysiology
The sickle mutation substitutes thymine for adenine in the sixth codon of the ß gene
(GAG→GTG), thereby encoding valine instead of glutamic acid in the sixth position of
the ß-chain. This minor change in structure is responsible for significant changes in
molecular stability and solubility.
Molecular Basis of Sickling
Deoxy Hb S polymers in the cell exist in a spectrum of forms from scattered individual
fibers to highly ordered fiber aggregates that fill and distort into the classic sickle shape
or other elongated forms. Polymer causes the reversible, oxygen-linked changes in the
rheologic properties of the sickle erythrocyte that characterize the disease. On
oxygenation, these polymers dissolve or “melt,” and the sickle erythrocyte loses most of
the pathologic properties caused by the presence of polymer.
Pathogenesis of Vasoocclusion
Possible risk factors for vasoocclusion include Hb S polymerization, sickle cell
deformability, blood viscosity, the fraction of dense cells, sickle cell–endothelial cell
adherence, endothelial cell activation, hemostatic activation, vascular tone, contributions
from white blood cells and platelets, local and regional environmental factors, and
psychosocial factors (5). A hypothetical interrelationship of the risk factors for
vasoocclusion is shown in Figure 40.4. The mechanisms of vasoocclusion may vary with
anatomic site and with different circumstances. For example, there is functional
heterogeneity of endothelial cells from large vessel and microvessel sources, and there
are organ-to-organ differences in microvascular architecture (6). During inflammation,
increased white blood cell interactions with endothelium could be a triggering event (2).
Under other circumstances, platelet activation might result in an elevation in
thrombospondin level or clinical dehydration might lead to an increased release of von
Willebrand factor, this promoting vasoocclusion.
Because of their higher Hb S concentration, the most dense cells are least
deformable and are at greatest risk for intracellular polymerization. Obstruction by these
cells develops at the arteriolar-capillary junctions in model systems (6). The role of dense
cells may be to create a logjam behind an obstruction rather than to initiate the vascular
plug. The proportion of dense cells increases immediately before an acute pain crisis and
falls during the first few days afterwards (8,9).
The abnormal interaction between sickle cells and vascular endothelium may be of
greater relevance for vasoocclusive events than are alterations in red cell morphology or
viscosity. Although endothelial adherence does not correlate with standard hematologic
measurements, it correlates significantly with the severity of pain crises (8). Likewise,
patients with clinically less severe sickling disorders, such as Hb SC disease, tend to have
less adherent red cells (9).
Sickled red cells may adversely affect local regulation of
vascular tone. An abnormal state of vasodilation and low vascular resistance in subjects
with sickle cell disease occurs during steady-state periods, but during crisis states, there is
a decrease in the levels of vasodilator substances like the prostacyclins and an increase in
vasoconstrictor substances including endothelin and prostaglandins. This shift in the
balance of vascular tone toward vasoconstriction results in slowing of vascular flow,
further obstruction, and more profound deoxygenation of sickled red cells (10). Low
arginine levels in sickle cell patients with vasoocclusive crisis and ACS provide a
rationale for arginine therapy in these conditions (11).
Alterations in the number and function of white blood cells may contribute to
vasoocclusive events (12,13). Alterations in chemotaxis and adhesion and increased
stickiness of neutrophil membranes also have been observed in crisis states (14,15).
Increased white blood cell counts in patients with sickle cell disease have been associated
with increased mortality and silent infarcts in the brain (16). The beneficial effect of
hydroxyurea in the Multi-Center Study of Hydroxyurea was associated with its effect in
reducing leukocyte counts (17). Data from the Cooperative Study of Sickle Cell Disease
(CSSCD) showed that increased baseline white blood cell counts in infants are a
predictive factor for severe manifestations of sickle cell disease in later childhood (18).
Furthermore, acute infection, possibly because of the attendant leukocytosis, is thought to
be a triggering mechanism for vasoocclusive pain events in many cases. In addition the
administration of granulocyte colony-stimulating factor (G-CSF) or granulocytemacrophage colony-stimulating factor (GM-CSF) has been linked to the initiation of
severe or even fatal sickle cell crisis (19-22). A multistep pathogenesis of vasoocclusion
based on white cell involvement has been proposed: (a) endothelial activation in
postcapillary venules; (b) recruitment of adherent leukocytes to the endothelium; (c)
interactions of sickle erythrocytes with adherent leukocytes; and (d) vascular clogging by
white blood cell/sickle red blood cell aggregates resulting in ischemia, further activation
of the endothelium, etc. (23).
Alterations in platelet numbers and function have suggested the involvement of
platelets in vasoocclusive events. Abnormalities include increased platelet counts,
increased platelet volume (24), decreased platelet survival (25), and decreased platelet
aggregation (26). The latter has been attributed to a refractory state resulting from in vivo
platelet activation. In support of this interpretation is the demonstration that plasma ßthromboglobulin, a measure of release activity from platelet α-granules, is elevated in the
steady state and increases further during vasoocclusive crises (27). The levels of the
contact factors (factor XII, prekallikrein, and high-molecular-weight kininogen) are low
and decrease further during crises (28). The coagulation inhibitors protein C and free
protein S are reduced in steady-state sickle cell disease (29,30); antithrombin III activity
levels have been variable, but increased thrombin–antithrombin III complexes and
plasma factor VII levels indicate increased tissue factor activity during the steady state
(31). Platelet activation is profoundly inhibited by NO and this inhibition is blocked by
plasma hemoglobin-mediated NO scavenging (32).Whether these alterations in
hemostasis and fibrinolysis are of pathogenic significance or are simply epiphenomena
remains to be determined.
Sickle Cell Anemia (Hemoglobin SS)
Clinical Features
Although disease attributed to Hb S has been observed in early infancy, affected
individuals are usually without symptoms until 6 months of age. The lack of clinical
expression during fetal and early postnatal life is explained by the production of Hb F
which limits clinically important sickling. Prospective studies of affected infants
followed from birth indicate a close temporal relationship between the decline in Hb F
and evolution of anemia (33). Mild hemolytic anemia is apparent by 10 to 12 weeks of
age (34) (Fig. 40.5). Splenomegaly is first noted after 6 months of age. The first
vasoocclusive episode is experienced, before 6 years of age by the majority (33), but not
until late childhood or adult life by a few. Dactylitis and ACS have the highest incidence
during the first year of life; dactylitis is a common presenting symptom. Loss of function
of the spleen has been documented as early as 5 months of age (35), and death from
overwhelming infection is an increased risk before 12 months of age (33).
The clinical features of sickle cell anemia result more from the vasoocclusive
consequences of sickle cells than from the anemia itself. The Cooperative Study of Sickle
Cell Disease (CSSCD) generated prospective information regarding the “natural history”
of sickle cell disease in a group of more than 3500 patients, some of whom were followed
for almost two decades.
Acute Events: Characteristics, Management, Prevention
Vasoocclusive Events
The term sickle cell crisis was introduced to describe a recurring attack of pain
involving the skeleton, chest, abdomen, or all three. Using the term in a broader sense,
vasoocclusive “crises” comprise a variety of syndromes that are typically recurrent and
potentially catastrophic. Clinical manifestations are sudden in onset and are directly
attributable to obstruction of the microcirculation by intravascular sickling. Modest
exacerbation of anemia and increased leukocytosis are common. Infections often precede
vasoocclusive episodes in children, suggesting that fever, dehydration, and acidosis may
be contributing factors. In adults, a triggering event is not often identified, but in a
Jamaican series, painful crises developed most often between 3:00 p.m. and midnight.
Perceived precipitating factors included skin cooling, emotional stress, physical exertion,
and pregnancy (36).
Hand-Foot Syndrome
The initial episode in young children often involves the small bones of the hands and feet
(the hand-foot syndrome). By 2 years of age, nearly 50% of Jamaican children and 25%
of American children with sickle cell anemia have experienced at least one episode of
dactylitis. Typically, the dorsa of the hands and feet are swollen, nonerythematous, and
painful. Fever and leukocytosis are common. Radiographic changes are limited initially
to soft-tissue swelling; cortical thinning and destruction of metacarpals, metatarsals, and
phalanges appear 2 to 3 weeks after the onset of symptoms. Dactylitis is sudden in onset
and may last 1 or 2 weeks. It may recur on one or more occasions until approximately 3
years of age.
Painful Crises
Typically, after the first few years of age, interruption of blood flow occurs in the larger
bones of the extremities, spine, rib cage, and periarticular structures, producing painful
crises of the bones and joints (37). The sinusoidal circulation of the bone marrow
provides an ideal vascular bed for the sickling phenomenon.
In the CSSCD, epidemiologic features of pain crises were analyzed in a large group
of patients with sickle cell disease (38). The average rate of pain was 0.8 episode/patientyear in Hb SS, 1.0 episode/patient-year in Hb Sß 0-thalassemia, and 0.4 episode/patientyear in Hb SC disease and Hb Sß +-thalassemia. However, the rate varied widely from
patient to patient: 39% of patients with sickle cell anemia had no episodes of pain, but
1% had more than six episodes/year. Five percent of Hb SS patients accounted for almost
one-third of all the episodes. The most frequent sites of bone involvement are the
humerus, tibia, and femur. Involvement of facial bones is less common but is well
documented. The swelling associated with infarction of the orbital bone may be sufficient
to produce proptosis and ophthalmoplegia (39). Swelling of the elbows or knees may
mimic rheumatic fever or septic arthritis (40). Laboratory findings are nonspecific. The
radiographic features of bone infarction and periostitis usually do not appear until after
the resolution of symptoms.. Although radionuclide bone and bone marrow scans
theoretically enable differentiation of bone infarcts from osteomyelitis, in practice they
are of limited value (37). Unlike osteomyelitis, bone infarcts are associated with no more
than a low-grade fever and little or no left shift in the leukocyte differential. As a cause of
bone pain, infarction is more than 50 times more common than osteomyelitis (37).
Abdominal pain crises are attributed to small infarcts of the mesentery and
abdominal viscera and are characterized by severe abdominal pain and signs of peritoneal
irritation. Persistence of bowel sounds differentiates pain crises from acute intraabdominal disorders requiring surgical intervention. Diagnosis is facilitated by prior
experience with the patient, because the pattern of pain tends to repeat itself from crisis to
crisis. Atypical clinical or laboratory features should suggest one of several complications
to which patients with sickle cell anemia are especially susceptible such as ACS, urinary
tract infection, or cholecystitis.
On average, painful crises persist for 4 or 5 days, although protracted episodes may
last for weeks. Data from the CSSCD indicate that an increased frequency of painful
events is associated with a high hematocrit and a low fetal Hb level (38). No additional
influence on pain rate results from concurrent α-thalassemia among patients with sickle
cell anemia who are older than 20 years of age. Adults with high rates of pain episodes
tend to die earlier than those with low rates (38). Of potential therapeutic significance, it
was noted in the CSSCD that even when the Hb F level is low, a small increase is
associated with an ameliorating effect on the pain rate and may ultimately improve
survival.
No specific form of therapy has proven effective for vasoocclusive crises. Lowmolecular-weight dextran, phenothiazines, fibrinogenolytic agents, bicarbonate and other
alkalis, and urea solutions, when evaluated in controlled clinical studies, were found to be
without apparent effect on vasoocclusive crises.. The duration and severity of pain crises
are variable, and the natural course is one of spontaneous improvement. Consequently,
uncontrolled reports of effective therapies must be viewed with skepticism, especially if
the proposed treatment entails an element of risk.
Currently, therapy consists of fluids and analgesics. The volume of fluids
administered should be sufficient to abolish any deficit, correct hypertonicity, and fully
compensate for ongoing losses imposed by fever, hyposthenuria, vomiting, or diarrhea.
Because urinary sodium losses are increased during crises, maintenance sodium
requirements also are exaggerated (41). Precipitants of the crisis should be sought and
eliminated. Infection, a common precipitating cause in children, may require antibiotic
therapy. Acidosis is corrected readily with intravenous administration of sodium
bicarbonate. Oxygen therapy in the absence of documented hypoxemia is without benefit
and triggers an increase in the number of ISCs when discontinued (42). Pain control
requires the liberal use of analgesics. Recently, benefit from adjunctive therapy with a
short course of high-dose corticosteroid (methylprednisolone) (43) or a long-acting
nonsteroidal antiinflammatory drug (e.g., ketorolac) (44) has been reported. The use of
patient-controlled analgesia, which enables patients to inject themselves with limited
boluses of intravenous morphine, has been beneficial for some and provides an element
of self-control in pain management. Self-hypnosis has been used successfully for pain
control in selected subjects (45). Blood transfusions do not modify the course of an
established crisis and are not without risk. Because fever and back pain are common
features of pain crises, transfusion reactions may escape early recognition (46).
Central Nervous System Events
Stroke is a catastrophic complication of sickle cell anemia that affects 6 to 17% of
children and young adults (47,48). Data from the CSSCD, in which approximately 4000
patients were followed for an average of 5 years, indicated that infarctive stroke was most
frequent in children and older adults with Hb SS, whereas hemorrhagic stroke had the
highest incidence in patients 20 to 29 years of age (48). The mortality rate was 26% after
hemorrhagic stroke and 0% after infarctive stroke. Transient ischemic attack (TIA),
anemia, a history of recent or recurrent acute chest syndrome, and hypertension were
independent risk factors for ischemic stroke; anemia and leukocytosis were independent
risk factors for hemorrhagic stroke (48). The risk of stroke appears to be increased in
patients with Hb F levels less than 8% (49) and in patients with siblings who have had
strokes. Data from the CSSCD also revealed that silent infarcts on MRI were a strong
independent risk factor for stroke (50,51). In addition, nocturnal hypoxemia was found to
be a risk factor for acute neurological events (stroke, TIA, or seizures) (52). The best
predictor of stroke risk at this time, however, is TCD velocity (53).
The distal internal carotid and proximal middle and anterior cerebral arteries are
stenotic or occluded in sickle cell patients who have experienced a stroke (54). In
response to chronic anemia and hypoxemia, cerebral blood flow is markedly increased
(55) and TCD velocities in the major cerebral arteries are abnormally elevated in patients
at high risk for stroke (53). The commonest sites of ischemic stroke are the areas
supplied by the anterior and middle cerebral arteries.
The role of nitric oxide and hemolytic anemia in the pathogenesis of stroke has been
explored recently following intense investigation of nitric oxide metabolism in the
etiology of pulmonary hypertension. Chronic intravascular hemolysis is associated with
endothelial dysfunction characterized by reduced nitric oxide bioavailability and
prooxidant and proinflammatory stress, resulting in a proliferative vasculopathy. The
arteriopathy of pulmonary hypertension closely resembles that of stroke in SCD,
suggesting that reduced nitric oxide bioactivity associated with high-grade hemolysis is a
common mechanism. Patients with obliterative central nervous system (CNS)
vasculopathy were found to have pulmonary hypertension and a high rate of hemolysis
(56).
In the past 10 years, increasing evidence for genetic modifiers of stroke has
accumulated. In an epidemiology study, 42 sibships with sickle cell anemia in which one
child had a stroke revealed a greater than expected number of families in which two or
more children had a stroke (57). Another study found that children with sickle cell
anemia were far more likely to have an elevated flow velocity on TCD if they had a
sibling with an abnormal TCD (58).
Clinically, strokes are characterized by the abrupt onset of hemiparesis, aphasia,
seizures, sensory deficits, and altered consciousness. The patient may recover fully, but
residual neurologic deficits are common. Although findings may be negative early in
infarction, MRI permits noninvasive visualization of focal damage. Normal cerebral
vessels on magnetic resonance angiography and no evidence of brain infarction on MRI
are rarely encountered after lclinical signs of a cerebrovascular accident.. Patients with
moyamoya are more than twice as likely to incur subsequent stroke or transient ischemic
attack despite treatment with chronic transfusions (59).
Strokes tend to be repetitive because of the progressive nature of cerebral vascular
disease. Unless patients begin a long-term transfusion program, they are at risk for
recurrent cerebral infarctions with progressive neurologic deterioration. Chronic
transfusion therapy to maintain the level of Hb S below 30% slows or arrests the
progression of arterial abnormalities and reduces the risk of recurrent strokes (within 36
months) from approximately 70-90% to 10-20%. Interruption or termination of treatment,
even after 8 years of chronic transfusion, is associated with a stroke recurrence rate
similar to that of untransfused patients, suggesting that transfusion therapy for secondary
stroke prophylaxis should be continued indefinitely. However, reduction of the intensity
of chronic transfusion to allow pretransfusion Hb S levels to reach 50% appears safe after
the first few years of prophylaxis (60). Many chronically transfused children have
transfusions discontinued when they reach adulthood. In one series of nine adult patients
who stopped transfusion after a median of 6 years, none suffered recurrent stroke (61). In
an initial report, long-term treatment with hydroxyurea appeared to prevent stroke
recurrence in five children who were treated with relatively high doses (30–40
mg/kg/day) for an average of 80 months (62). In a larger prospective trial, 35 children
with sickle cell anemia and stroke had transfusions discontinued and hydroxyurea started
(63). Initially, transfusion was stopped before hydroxyurea therapy was started, but later
transfusion was overlapped until full dose hydroxyurea therapy was tolerated. Overall,
stroke reoccurred at a rate of 5.7 events per 100 patient-years, but children receiving
overlapping therapy had only 3.6 events per 100 patient-years. Along with hydroxyurea
treatment, patients had monthly phlebotomy, which resulted in a marked decrease in
median serum ferritin levels. Since this trial suggested that hydroxyurea plus phlebotomy
may be as effective as chronic transfusion plus iron chelation in the long-term
management of sickle cell stroke patients, a national multicenter trial was launched in
2006.
In a series of studies led by Dr Robert Adams, an abnormal transcranial Doppler
(TCD) ultrasound examination (defined by a time-averaged mean maximum velocity >
200 cm/s in the distal internal carotid or proximal middle cerebral artery) was found to be
predictive of a 40% stroke risk in HbSS patients (53). In the Stroke Prevention in Sickle
Cell Anemia (STOP) Trial, 130 patients with abnormal TCD velocities were randomized
to receive chronic transfusion or observation (65). A 92% reduction in the risk of stroke
occurred in the patients receiving chronic transfusion, which led to a “clinical alert”
recommending consideration of TCD screening and chronic transfusion for primary
prevention of stroke in patients with abnormal velocities. The appropriate length of time
for transfusion for primary stroke prevention in patients with abnormal TCD velocities
was addressed by the STOP II Trial (66). Patients enrolled in STOP II had had an initial
abnormal TCD velocity and transfusion for at least 30 months, during which time the
TCD velocity became normal (<170 cm/s). Patients were randomly assigned to continue
or stop transfusion and the primary endpoint was stroke or a reversion to an abnormal
TCD exam. Among the 41 children enrolled in the discontinuation of transfusion group,
abnormal TCD results developed in 14 and stroke in two others within a mean of 4.5
months (range 2.1–10.1 months) of the last transfusion. None of these endpoint events
occurred in the 38 children who continued to receive transfusions. In the two children
who had overt strokes, the events occurred before a TCD could be performed and
transfusion resumed. Overall, among 209 total patients who underwent randomization in
STOP and STOP II, 20 strokes occurred. Unfortunately, despite the results of the STOP
Trial, performance of TCD screening has been variable.
The use of hydroxyurea for primary stroke prevention deserves consideration. In a
French study, 6 of 10 patients with abnormal TCD whose velocities normalized on
transfusion were switched to hydroxyurea (67). In a Belgian study, patients with
abnormal TCD were treated with hydroxyurea and observed for a total of 96 patient-years
(68). Only one neurologic event, a seizure, was observed.
Acute Chest Syndrome
Pulmonary events characterized by fever, tachypnea, chest pain, increased leukocytosis,
and pulmonary infiltrates are a frequent cause of morbidity and mortality in patients with
sickle cell anemia. Because it may be impossible to determine the relative importance of
vascular occlusion and infection in the process in any given patient, the term acute chest
syndrome has been applied. Infection tends to predominate in children and infarction in
adults, but the two processes are often interrelated and concurrent (69). Data from the
CSSCD indicate that patients with Hb SS have an incidence of ACS of approximately
13/100 patient-years; the rate is highest in children 2 to 4 years of age (25/100 patientyears) and decreases gradually with increasing age to that seen in adults (9/100 patientyears) (70). A higher ACS rate is associated with a higher rate of mortality from all
causes. The risk of ACS is associated with a lower fetal Hb level and a higher steadystate hematocrit and leukocyte count.
Before the availability of pneumococcal vaccines and use of penicillin prophylaxis,
pulmonary events in children typically were the result of bacterial infection.
Streptococcus pneumoniae was the most common causative organism. Infiltrates often
affected multiple lobes, and resolution was slower than in the general population.
Identified infectious agents have included Mycoplasma pneumoniae, Chlamydia,
parvovirus B19, and respiratory viruses. The National Acute Chest Syndrome Study
Group reported causes and outcomes based on analysis of 671 episodes of ACS (71).
Nearly one-half the patients were initially admitted for another reason, primarily pain.
The mean length of hospitalization was 10.5 days; 13% required mechanical ventilation,
and 3% died. Patients who were 20 years of age or older had a more severe course. A
specific cause of ACS was identified in 38% of all episodes and 70% of episodes with
complete data. The most common specific causes were pulmonary fat embolism,
chlamydia, mycoplasma, miscellaneous viruses, and bacterial infections due to
coagulase-positive Staphylococcus aureus and S. pneumoniae. Treatment with
transfusion and bronchodilators improved oxygenation, although older patients often
progressed to respiratory failure.
Recently, the relationship of asthma/reactive airway disease to ACS has been
examined. In children with Hb SS, asthma is associated with an increased incidence of
sickle cell-related morbidity, including ACS and pain episodes (72). Sickle cell patients
with asthma were four times more likely to develop ACS during a hospital admission for
pain and had a substantially longer duration of hospitalization. Less information is
availible for adult patients, but a high prevelance of airway hyperresponsiveness to
methacholine challenge was noted in those with a history of reactive airway disease (73).
Hematologically, ACS is characterized by a sudden drop in Hb concentration and an
increase in the number of platelets and leukocytes. Rib infarcts are a primary cause of
ACS when bone pain is followed by soft-tissue reaction, pleuritis, splinting,
hypoventilation, atelectasis, and the typical radiologic picture. Incentive spirometry with
the use of maximal inspirations every 2 hours has been shown to prevent ACS in patients
with sickle cell disease who were hospitalized with chest or back pain (74). Lung crises
may result from embolization of fat from infarcted bone marrow (pulmonary fat emboli)
or deep vein thrombi. Occlusion of major pulmonary vessels is a recognized cause of
sudden death. Pulmonary fat emboli are found more commonly than previously
appreciated when a diagnosis is sought by fat staining of pulmonary macrophages
obtained by bronchoalveolar lavage. Fat emboli are associated with bone pain, chest pain,
neurologic symptoms, acute decreases in Hb level and platelet count, and prolonged
hospitalization. Secretory phospholipase A2, an inflammatory mediator that liberates free
fatty acids and lysophospholipids and may be responsible for acute lung injury, is
markedly elevated in sickle cell patients 24-48 hours before the diagnosis of ACS in
patients presenting with a pain event (75) and in most patients at the time of diagnosis of
ACS.
Because the relative importance of infection and infarction is difficult to ascertain,
broad-spectrum parenteral antibiotics, such as a 3rd and 4th generation cephalosporin,
should be provided for children with fever, chest pain, and pulmonary infiltrates. A
macrolide antibiotic is indicated to cover Mycoplasma and Chlamydia. Correction of
hypoxemia is important. If the arterial PO2 is less than 75 mm Hg or the O2 saturation by
pulse oximetry is significantly below baseline, simple or partial exchange transfusion
should be considered. Recently, intravenous dexamethasone was shown to result in a
shorter hospital stay and reduced need for blood transfusion and oxygen when compared
to placebo in children with ACS (76). However, there was a high risk of recurrent
symptoms and hospital readmission after dexamethasone was discontinued so further
studies are underway. Nitric oxide inhalation has been utilized in the regulation of
hypoxic pulmonary vasoconstriction (77), but definitive trials have not been reported.
Priapism
Priapism, an unwanted, painful erection of the penis, has been recently reviewed
(78). The incidence of priapism in patients with sickle cell disease is reported to be
between 5% and 45% ; age of onset peaks at 5 to 13 years and again at 21 to 29 years of
age. Most episodes begin during sleep and may be associated with dehydration and
hypoventilation, which result in metabolic acidosis followed by increases in sickling and
stagnation of blood within the penile sinusoids or the corpora cavernosa. In data from the
CSSCD, subjects with priapism had significantly lower levels of hemoglobin and higher
levels of bilirubin, reticulocytes, WBC, and platelets, suggesting an association of
priapism with increased hemolysis, perhaps related to a diminished availability of
circulating NO, which plays an important role in erectile function (79). Although usually
self-limited and of relatively short duration, priapism is often recurrent and may become
chronic. “Stuttering” priapism refers to multiple episodes, each less than 4 hours in
duration, which may occur several times a week and may herald a prolonged event.
Usually, these do not require medical intervention. Typically, priapism results from
engorgement of the paired cavernosal bodies with sparing of the glans and corpus
spongiosum and is maintained by the partial obstruction of venous drainage. However,
tricorporal priapism may occur, especially in postpubertal patients, and is associated with
a poor prognosis (80). Although it occurs with approximately equal frequency in
prepubertal and postpubertal males, priapism is more difficult to manage in the latter
group (81). The repetitive trapping of cells in the corpora cavernosa, with or without
surgical intervention, may lead to fibrosis of the septa and impotence.
Of particular concern is an increased rate of impotence reported in sickle cell
patients whose attacks lasted more than 24 hours (82). As with other complications
resulting from the sludging of sickled erythrocytes, aggressive hydration and adequate
analgesia are important and should be initiated within the first few hours of symptoms. If
no response is seen in 12 to 24 hours, partial exchange transfusion to lower the Hb S level
to less than 30% may be performed. If no resolution occurs within another 12 to 24 hours,
corporal aspiration and irrigation with saline may be indicated through such means as a
Winter procedure (83), in which a fistula between the glans penis and the corpora
cavernosa is created using a biopsy needle. If this is unsuccessful, creation of a cavernosa
spongiosum shunt (84) or a venous bypass may be considered. The Dallas program
reported rapid complete detumescence in 35/37 consecutive episodes of prolonged
priapism in pediatric patients treated with aspiration and irrigation with a dilute
epinephrine solution (85).
Prevention of recurrent priapism has been accomplished in some patients with
chronic transfusion, particularly through exchange transfusion. α-adrenergic agonists
increase contraction of the smooth muscle of the trabecular arteries of the cavernosa and
facilitate venous outflow from the corpora promoting detumescence. Agents including
etilefrine pseudoephedrine and phenylephrine may be administered either orally or by
intracavernous injection. Other approaches have been the administration of
diethylstilbestrol, the gonadotropin-releasing hormone analog leuprolide acetate, lowdose anti-androgens and oral phosphodiesterase S inhibitor.
Hematologic Crises
Hematologic crises, characterized by sudden exaggeration of anemia, are
pathogenetically and temporally unrelated to vasoocclusive crises. If unrecognized or
untreated, the decrease in Hb concentration may be so precipitous and severe as to cause
heart failure and death within hours.
Aplastic Crises
These events are the most common of the hematologic complications. The pathogenesis
and course of aplastic crises in sickle cell anemia are similar to those of other chronic
hemolytic states. Several characteristics suggest an infectious basis: Crises are often
preceded by or associated with febrile illnesses; several family members with congenital
hemolytic anemia may have concurrent aplasia (86); recurrence of crisis within the same
individual is not observed; and most aplastic episodes occur during childhood.
Epidemiologic studies clearly implicate human parvovirus B19 as the cause for almost all
aplastic crises. Aplasia is the result of direct cytotoxicity of the parvovirus to erythroid
precursors, especially colony-forming units, erythroid (CFU-E) (87). However, not all
parvovirus infection result in problems; serologic evidence of prevous infection was
found in 71% of subjects with sickle cell anemia who reached adulthood, but only 27%
had a previous clinically recognized aplastic crisis (88).
Susceptible hospital workers exposed to patients with aplastic crises are at high risk
of contracting nosocomial erythema infectiosum. Because infection during the
midtrimester of pregnancy may result in hydrops fetalis and stillbirth, isolation
precautions are a necessity if an aplastic crisis is suspected (89).
Early during an aplastic crisis, reticulocytes and bone marrow normoblasts disappear
or are greatly reduced in number. Because red cell survival in Hb SS is no more than 10
to 20 days, cessation of erythropoiesis is followed by a rapid decrease in Hb
concentration. The process is self-limited. Within 10 days, red cell production resumes
spontaneously, and large numbers of reticulocytes and nucleated erythrocytes appear in
the peripheral blood and the Hb concentration returns to its precrisis level. Often, the
patient is first seen early in the recovery phase, when differentiation from a hemolytic
crisis may be difficult. Although leukocytes and platelets are usually normal, all marrow
elements may be affected. Treatment consists of supportive care with red cell transfusion
when necessary.
Splenic Sequestration
This event is characterized by sudden trapping of blood in the spleen. A splenic
sequestration crisis is defined by a decrease in the steady-state Hb concentration of at
least 2 g/dl, evidence of compensatory erythropoiesis, and an acutely enlarging spleen
(90). This complication occurs in infants and young children whose spleens are
chronically enlarged before autoinfarction and fibrosis. Although splenic sequestration
can occur in infants as young as 3 months of age, it is observed most commonly during
the second 6 months of life and less frequently after 2 years of age.
Children experiencing splenic sequestration may have an earlier onset of
splenomegaly and a lower level of Hb F at 6 months of age (91). Crises are often
associated with respiratory tract infections or with parvovirus B19 usually in conjunction
with an aplastic crisis. The already enlarged spleen rapidly increases in size at the
expense of blood volume; hypovolemic shock and death may occur within hours. The
sole pertinent postmortem finding is engorgement of splenic sinusoids with sickled cells.
Individuals who survive have a tendency for recurrent episodes until 5 or 6 years of age,
by which time sufficient fibrosis of the spleen has occurred to limit its expansion. The
long-term management of patients with splenic sequestration has not been well defined.
Chronic transfusion is of limited benefit in preventing reoccurrence of splenic
sequestration (92). In a large series of Jamaican Hb SS patients with recurrent splenic
sequestration or chronic hypersplenism, splenectomy did not increase the risk of death or
bacteremic illness (93). Although encountered much less frequently, sudden trapping of
blood in the liver (hepatic sequestration crisis) also occurs.
Hemolytic Crises (Hyperhemolytic Crises)
Such crises result from a sudden acceleration of the hemolytic process. They have been
described in association with hereditary spherocytosis and mycoplasma infection.
Although approximately 10% of black male patients with sickle cell anemia have the
unstable A variant of glucose-6-phosphate dehydrogenase, they have no more severe
anemia and no greater frequency of acute hemolytic episodes than those with normal
levels of G-6PD, even when challenged with oxidant drugs and infections, due to.the
young mean age of sickle red blood cells.
Megaloblastic Crises
These crises result from the sudden arrest of erythropoiesis by folate depletion (94).
Chronic erythroid hyperplasia imposes a drain on folate reserves, and biochemical
evidence of mild folate deficiency often occurs in sickle cell anemia. Megaloblastic crises
occur when food consumption is interrupted by illness or alcoholism or when the folate
requirement is augmented by rapid growth or pregnancy. The inverse relationship
between plasma homocysteine concentration and folate status has led to a series of
reports describing homocysteine levels and the possible need for folate supplementation.
Currently, folic acid deficiency, as a cause of exaggerated anemia in sickle cell disease,
appears to be extremely rare in the United States. Nevertheless, it is common practice to
prescribe prophylactic folic acid (1 mg/day) to patients with sickle cell disease.
Infections
Overwhelming infection may be the presenting manifestation of sickle cell anemia in
early childhood. Acute infection has been the commonest cause of hospitalization and
death, during the first 3 years of life. S. pneumoniae is the usual infecting organism; the
blood and spinal fluid are the major sites of infection (95). Previously, the incidence of
invasive infection with S. pneumoniae was approximately 7/100 patient-years in children
with sickle cell anemia younger than 5 years of age; this rate was 30 to 100 times greater
than that in a healthy population of this age. More than 70% of meningitis in children
with sickle cell anemia resulted from S. pneumonia. The mortality rate of pneumococcal
sepsis was as high as 35%, but the widespread improvement in parental education and
aggressive management of the febrile child greatly improved the likelihood of surviving a
septic event (96). Additionally, penicillin prophylaxis and pneumococcal vaccines have
dramatically lowered the risk of invasive pneumococcal infection.
A major threat to continued success in prevention and management of S.
pneumoniae invasive infection is the emergence of antibiotic-resistant pneumococcal
organisms over the past two decades. One report cited 16 cases of intermediate or high
resistance to penicillin among S. pneumoniae causing sepsis in children with sickle cell
anemia in the United States (97); many of the organisms were also resistant to extendedspectrum cephalosporins and other antibiotics.
Above 5 years of age, gram-negative bacteria replace S. pneumoniae as the major
infectious agents (95). In contrast to infections in young children, those in older children
and adults generally have an identifiable source or focus (e.g., Escherichia coli associated
with urinary tract infection). Osteomyelitis, sometimes involving multiple sites, occurs
with increased frequency at all ages. The increased risk of osteomyelitis may stem from
tissue ischemia and infarction associated with pain crises; these provide a potential nidus
for infection in the long bones. Although more than 80% of hematogenous osteomyelitis
in the general population is caused by staphylococcus, most cases of osteomyelitis
occurring in individuals with sickle cell anemia are caused by Salmonella (98). A positive
blood culture for Salmonella in a patient with sickle cell anemia strongly suggests the
diagnosis of osteomyelitis. Staphylococcal bone infection, clinically indistinguishable
from Salmonella infection, also occurs with increased frequency in sickle cell disease.
Bloodstream infections in hospitalized adults with sickle cell disease have been
increasingly recognized. In one series (99), 28% were caused by staphylococcus aureus,
the majority of which were methicillin-resistant. Gram-negative organisms, anaerobes,
and yeast were also found and over 80% of the infections were considered catheterrelated.
Human parvovirus B19 has been noted to produce sequelae other than aplastic crises
in patients with sickle cell disease. In a series from Jamaica, seven patients developed
glomerulonephritis with proteinuria and symptoms of nephrotic syndrome within 7 days
after an aplastic crisis (100). Renal failure appears to be a common consequence of this
complication. Parvovirus may also result in severe pulmonary problems and in
cerebrovascular complications, including hemiplegia, encephalitis, and seizures.
The pathophysiologic basis for increased susceptibility to aggressive infection
relates in large part to the loss of spleen function (101). During the first few years of life,
recurrent perivascular hemorrhage and infarction reduce the spleen to a small
siderofibrotic vestige. Despite the frequent occurrence of splenomegaly in the first few
years, spleen function often is impaired by 6 to 12 months of age. Howell-Jolly bodies
and “pits” (depressions in the red blood cell membrane) are seen in peripheral blood
erythrocytes (102), and radiolabeled sulfur colloid is not cleared by the spleen (103).
Spleen function is temporarily restored by transfusion therapy in early life, suggesting
that functional asplenia is a consequence of altered perfusion imposed by intrasplenic
sickling. Spleen function is necessary for effective host response to S. pneumoniae in the
absence of preformed antibodies; in the presence of antibody, organisms are trapped
effectively at extrasplenic sites. Because the acquisition of pneumococcal antibodies
occurs with advancing age, young children without spleen function fare less well than
older children and adults.. Other mechanisms may contribute to the vulnerability of
children with sickle cell disease to infectious crises. Serum IgM levels are decreased. The
alternative pathway for complement activation may be defective
Prevention of Infection
Penicillin prophylaxis has been a major advance in the management of sickle cell disease.
Two controlled trials, one in Jamaica and the other in the United States, led to acceptance
of penicillin prophylaxis as standard therapy (104,105). In the latter trial, twice-daily oral
penicillin V resulted in an 84% reduction in the incidence of pneumococcal bacteremia in
infants younger than 36 months of age. Current recommendations are to initiate penicillin
prophylaxis by 3 months of age and to continue it at least until 5 years of age in children
with Hb SS or Hb Sß0-thalassemia. A multiinstitutional controlled trial found no further
advantage of penicillin in the prevention of invasive pneumococcal infection in children
older than 5 years of age (106). The use of prophylaxis in young children with Hb SC
+
disease or sickle ß -thalassemia is controversial, but many centers maintain all children
with sickle cell disease on penicillin until 5 years of age.
Unfortunately, the pneumococcal serotypes that are most prevalent in the
community and most highly virulent (types 6A, 14, 19, and 23F) are least immunogenic
(107,108). Although the immunologic response of children 2 years of age and older to
polysaccharide-conjugated pneumococcal vaccine is comparable to that of the general
population (109), antibody titers fall more rapidly than in adults. Children with sickle cell
disease should receive a primary immunization with the 23-valent polysaccharide vaccine
at 2 years of age and a booster immunization 3 to 5 years later; the vaccine is ineffective
in children younger than 2 years of age. Administration of booster doses of this vaccine
to older children and adults with sickle cell disease is controversial. In contrast, the
seven-valent protein-conjugated pneumococcal vaccine (Prevnar), is immunogenic in the
first few months of life and is routinely administered to infants in the U.S. This vaccine
(which includes serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) administered at 2, 4, and 6
months of age produces adequate antibody concentrations in the same range as those
achieved among infants without sickle cell disease (110). In addition, significant rises are
seen in antibody concentration to all seven protein-conjugated pneumococcal vaccine
serotypes after the administration of polysaccharide-conjugated pneumococcal vaccine at
24 months of age. Recently, the protein-conjugated vaccine has been reported to lower
the incidence of invasive pneumococcal disease by more than 90% in children with sickle
cell disease below 2 years of age (111).
The conjugated H. influenzae type B vaccine induces protective antibody levels
in infants with sickle cell anemia and has virtually eliminated invasive H. influenzae
infection in this population. The influenza virus vaccine, hepatitis B vaccine, and
meningococcal vaccine offer further protection.
Management of Fever
Any fever greater than 38.5°C in a child with sickle cell anemia is a medical emergency
because of the potential risk of overwhelming pneumococcal sepsis, especially in
children between 6 months and 3 years of age. Previously, routine hospitalization of
febrile patients with sickle cell anemia was standard management to deliver intravenous
antibiotic coverage until blood cultures were negative. More recently, the majority of
febrile patients have been managed in the emergency and outpatient setting if they do not
have high-risk characteristics (e.g., toxic appearance, very high fever, serious localized
infection, exceptionally high or low white blood cell count, a history of invasive infection,
or inadequate capacity for close follow-up) (112).
Chronic Organ Damage
Growth and Development
The sickling syndromes affect growth and development. Growth curves for the height,
weight, and sexual development of children with sickle cell anemia have been
constructed to permit the identification of individuals whose growth delay is greater than
what can be accounted for by the hemoglobinopathy (113). Although normal at birth, the
heights and weights of children with sickle cell anemia are significantly delayed by 2
years of age. The growth curves maintain a relatively normal configuration but deviate
progressively from the normal curves. Increases in velocity of adolescent height and
weight growth occur later, and the magnitude of the growth spurt is substantially less
than in healthy children. Puberty also is delayed. Menarche occurs 2 to 3 years later than
in the general population (median age, 14.0 to 15.5 years) By adulthood, both men and
women with sickle cell disease appear to acquire normal or near-normal heights, but their
mean weights are still lower than those of controls. Investigations in small numbers of
subjects show that growth hormone, thyroid hormone, adrenocorticotropic hormone and
cortisol levels, and pituitary responses to growth hormone–releasing factor are normal
(114).
Low weight appears to be the most critical variable influencing differences in
physical maturation among the sickling syndromes. Caloric intake is decreased during
admission for acute illness, contributing to an overall energy deficit. Other studies have
suggested increased requirements for zinc, folate, riboflavin, vitamin B 6, ascorbate, and
the fat-soluble vitamins A and E, but consistent correlations between deficiencies and
growth retardation have not been established.
Bones and Joints
In addition to the acute episodes of skeletal pain described previously, chronic and
progressive destruction of the bones and joints may take place in the absence of clearly
defined episodes of pain. The most prominent changes evolve slowly from the
cumulative effect of recurrent, small episodes of ischemia or infarction within the
spongiosa of bone. Radiographs of the long bones of adults show a mottled, strandlike
increase in density randomly distributed within the medullary region. Because the bone is
weakened during the early stages of repair, weight-bearing may collapse the femoral head,
producing the clinical and radiologic features of osteonecrosis, which affects patients
with all the genotypes of sickle cell disease but occurs most often in those with Hb SS
and ß-thalassemia (4.5 cases/100 patient-years). The overall prevalence of osteonecrosis
of the hip in persons with sickle cell disease is approximately 10%, but it occurs in 50%
in those over age 35 years (115). The prevalence of osteonecrosis of the humoral head is
approximately one-half as much. Typically, the pain from osteonecrosis of the hip begins
insidiously, is brought on by walking or quick movements, and is localized to the groin or
buttock. After several months, radiographs may show areas of increased density mixed
with areas of increased lucency, followed by the appearance of a “crescent sign,”
segmental collapse, molding of the femoral head, loss of joint space, involvement of the
acetabulum, and complete degeneration of the joint. When osteonecrosis occurs in the
femoral capital epiphysis before closure, healing with minimal destruction may occur.
However, long-term follow-up shows that in the majority of cases, the hip is painful and
permanently damaged. Because weight-bearing is not required of the shoulder joint, the
prognosis of osteonecrosis of the humeral head is substantially better. Only
approximately 20% of patients have pain or limited range of movement at the time of
diagnosis,
Avoidance of weight-bearing in the early phases of bone necrosis may
permit sufficient repair to preserve reasonable joint function. More often the deformity is
progressively crippling. Total hip replacement is usually recommended for the painful hip
in stages III or IV or for restoration of joint movement, if this is desired. However, the
prognosis for hip replacement has been suboptimal with a 30% chance that arthroplasty
will require revision within 4 to 5 years Recently, in a prospective randomized trial,
physical therapy alone appeared to be as effective as hip core decompression followed by
physical therapy improving hip function and postponing the need for additional surgical
intervention at a mean of three years after treatment (116).
Recurrent infarcts of the main vertebral arteries lead to ischemic damage of the
central portion of the vertebral body growth plates. Because the outer portion of the
plates is supplied by numerous apophyseal arteries, vertebral growth is irregular,
producing a “fish-mouth” deformity in which symmetric cuplike depressions are confined
to the central three-fifths of the vertebral plates. Other skeletal changes result from
expansion of medullary cavities owing to long-standing erythroid hyperplasia.
Radiographs of the skull show a thickening of the diplöe and thinning of the outer table
of the calvaria in the frontal and parietal regions. Gnathopathy (prominent maxillary
overbite) may result from overgrowth of maxillary bone and frequently leads to
significant malocclusion.
Joints may be affected by avascular necrosis of adjacent bone. The joint effusion,
pain, fever, and leukocytosis accompanying such infarcts make differentiation from
septic arthritis difficult. Numerous neutrophils and sickled erythrocytes are found in the
joint fluid. Less commonly, joint disease is related to infection, gout, or synovial
hemosiderosis.
Central Nervous System
Children with a history of overt stroke have significant cognitive impairment, reduced
language function, and problems in adjustment. Several reports have identified deficits in
global and specific neuropsychological functioning in school-aged children with sickle
cell disease when compared with their siblings or healthy children (117). Diminished
performance has been noted in the areas of visual-motor integration, attention and
concentration, arithmetic, memory, and reading. Routine MRI of the central nervous
system performed prospectively in children between the ages of 6 and 14 years as part of
the CSSCD disclosed a 17% prevalence of “silent infarcts” (areas of increased signal
intensity primarily in deep white matter or watershed areas of the cerebral cortex) in
children with Hb SS and no history of stroke. In general, increased stroke risk may be
related to both environmental factors (e.g., hypoxia and inflammation) and genetic factors
(e.g., mutations resulting in thrombogenesis).
Interventions for improving neurocognitive performance in patients with sickle cell
disease are lacking. An association of oral hydroxyurea therapy with improved cognitive
functioning on tests of verbal comprehension, fluid reasoning, and general cognitive
ability has been seen in a small group of children with sickle cell disease and may be an
effect of improved blood and oxygen supply to the brain or reduced fatigue and illness
related to HU treatment (118).
Cardiovascular System
Cardiac enlargement, particularly an increase in left ventricular dimensions and mass,
results from an increase in cardiac output imposed by chronic anemia and has its onset in
early childhood (119). The typical physical examination reveals cardiomegaly, a
hyperdynamic precordium, and a grade II-III systolic ejection murmur with wide
radiation. Adult sickle cell patients may have right ventricular enlargement and
dysfunction (decreased right ventricular ejection fraction) even in the absence of overt
pulmonary hypertension. In one study, PHT was found in 58% of adult patients (120).
In general, there is an absence of atherosclerotic heart disease, although one study
reported myocardial infarction and fibrosis in 17% (121). Adults with sickle cell disease
may present with clinical signs of acute myocardial infarction in the absence of
atherosclerosis or coronary occlusion, but this is uncommon. In children, rare cases of
myocardial infarction and transient ventricular dysfunction have been reported
(122) Congestive heart failure generally does not occur in the absence of extracardiac
complications of sickle cell disease. However, physical performance is severely
compromised; adults are usually unable to exceed 50% of expected work capacity, and
children and adolescents have 60 to 70% work capacities (123-124). This is the result of a
high cardiac output at rest and an inability to increase output adequately under stress as
demonstrated by abnormalities of systolic (ejection) and diastolic (filling) function.
Pulmonary System
Chronic pulmonary disease is characterized by a decrease in the radiolucency of the lungs
and by moderate to severe impairment of pulmonary function. Typically, the vital
capacity and total lung capacity are reduced and gas mixing and exchange are
compromised. Less often, obstructive lung disease is noted. Blood is shunted through
poorly aerated or collapsed segments of the lung, creating a disparity between ventilation
and perfusion. The resulting reduction in the functional pulmonary vascular tree is
responsible for a decrease in arterial oxygen tension (70 to 90 mm Hg) and desaturation
of arterial blood. Monitoring of arterial oxygen saturation through transcutaneous pulse
oximetry has led to more careful assessment of oxygenation in sickle cell patients
hospitalized for ACS and painful crises.. Among patients with Hb SS, a decrease in
steady-state oxygen saturation correlates with a decrease in hemoglobin, an increase in
reticulocytes, older age, and male gender (125), but correlations with previous episodes
of ACS and pain have generally not been found. Children with acute pulmonary illness
often have an oxygen saturation level that is below their baseline state and less than 96%.
Oxygen saturation measured by pulse oximetry has been compared with arterial
cooximeter blood gas measurements. Pulse oximetry may underestimate true arterial
saturation, but pulse oximetry values correlate positively with Hb and fetal Hb levels in
patients with Hb SS.
In the past decade pulmonary hypertension (PHT) has been increasingly recognized
in adults with sickle cell disease and is now considered a major cause of morbidity and
mortality (126). PHT may represent one element of generalized vasculopathy seen in
some patients with sickle cell disease (associated with systemic hypertension, renal
failure, priapism, and cerebrovascular events), but it is not associated with markers of
inflammation, fetal hemoglobin level, or platelet count. There is growing evidence that
altered arginine metabolism is involved, in particular, the intravascular release of
arginase activity from ongoing hemolysis (127). In fact, hemolytic rate has been
associated with multiorgan failure, priapism, leg ulcers, and stroke in addition to PHT
and mortality. Treatment of risk factors such as hypoxemia, severe anemia, or left
ventricular systolic and diastolic dysfunction is indicated. In addition, erythropoietin has
been recommended for those with associated PHT and renal insufficiency.
Hepatobiliary and Gastrointestinal Systems
Liver enlargement is present by 1 year of age and persists throughout life. Sickle cell
disease may be associated with disturbance in hepatic function. In adult life, diffuse
nodular cirrhosis may occur. Acute enlargement of the liver, such as may occur with
sequestration of sickle cells, subcapsular infarction, or hepatic vein thrombosis, is
associated with tenderness or right upper quadrant pain. Intrahepatic infarcts may be
complicated by abscess formation. In addition, hepatic function as assessed by lidocaine
metabolism is impaired in patients with sickle cell disease, suggesting caution when
using hepatically metabolized medication in these patients (128).
Hyperbilirubinemia frequently occurs during the course of sickle cell anemia. These
episodes may result from intercurrent infectious hepatitis, intrahepatic sickling (hepatic
crisis, “sickle hepatopathy”), or choledocholithiasis. Coexistent glucose-6-phosphate
dehydrogenase deficiency may be a contributing factor.
The clinical picture of acute viral hepatitis is similar to that seen in non–sickle cell
patients except for the remarkable elevation of serum bilirubin concentration (which may
reach 100 mg/dl) (129). Hepatitis A virus may be a frequent cause of acute icteric
hepatitis in endemic areas and may result in fulminant hepatic failure and death. Most
sickle cell patients respond normally to hepatitis B vaccine, although surface antibody
titers after immunization should be measured to identify those who do not convert and
require booster injections.
In a recent report, sickle hepatopathy was defined by a total seum bilirubin
concentration > 13 mg/dl and not explained by severe acute hemolysis, viral hepatitis,
extrahepatic obstruction, or hepatic sequestration (130). In children, manifestations of
sickle hepatopathy are relatively mild and transient. These include right upper quadrant
pain, hepatomegaly, fever and leukocytosis, mild elevation of serum transaminase levels,
and moderate to marked elevation of serum bilirubin and alkaline phosphatase levels.
Although the course in children is benign and symptoms usually resolve in 1 to 3 weeks,
progression to fulminant hepatic failure, generalized bleeding, and death are much more
frequent in adults and are occasionally seen in adolescents. Prompt exchange transfusion
and, occasionally, chronic transfusion have been the only effective therapies in these
patients (131).
Because of a sustained increase in heme catabolism, the frequency of pigmentary
gallstones in sickle cell disease is high. These stones, which may be either radiolucent or
radiopaque, have been documented in children younger than 5 years of age (132). The
incidence of gallstones increases with age, from 12% in the 2- to 4-year-old age group to
42% in the 15- to 18-year-old age group and 60% in adults (133). When ultrasonography
is used routinely, the finding of gallbladder sludge with or without concurrent stones is
common; even if not present initially, patients with sludge eventually develop
stones.
Although patients are not always able to distinguish the pain of
choledocholithiasis from that of abdominal vasoocclusive crises, elective
cholecystectomy may be followed by a dramatic decrease in the frequency of abdominal
crises. Laparoscopic cholecystectomy has replaced open cholecystectomy in most centers
because it results in shorter hospitalization and decreased postoperative pain and other
complications. Nevertheless, cholecystectomy generally is not warranted in persons with
asymptomatic gallstones.
Kidneys
A variety of defects in renal function have been described (134), and a number of
histologic alterations have been noted (135).
Hyposthenuria (136,137) and a limited
capacity for hydrogen ion excretion are present after 6 or 12 months of age.
Hyposthenuria may be corrected temporarily by red cell transfusions until up to 15 years,
but not thereafter (136). Disruption of the countercurrent multiplication system owing to
sludging of sickle cells in the more hypertonic portions of the renal medulla has been
proposed as the mechanism responsible for the concentrating defect (136). Presumably
because of the large fluid consumption necessitated by the renal concentrating defect,
most patients experience enuresis. Enuretic sickle cell patients have nocturnal urine
osmolality equivalent to that of nonenuretic patients but may respond to desmopressin.
Hematuria is common and may be both brisk and prolonged. Bleeding may originate
in one kidney or both, or it may take place in an alternating fashion. The most common
lesion is an ulcer in the renal pelvis at the site of a papillary infarct (138). The possibility
that painless hematuria may be the result of poststreptococcal glomerulonephritis, renal
medullary carcinoma, or other disorders unrelated to the hemoglobinopathy should not be
overlooked. Idiopathic hematuria rarely requires more than symptomatic treatment. The
risk of clotting within the collecting system is best minimized with a high fluid intake.
Although there is no controlled study of its use, ε
-aminocaproic acid is said to shorten the
duration of hematuria in both sickle cell anemia and sickle trait patients. Its use, however,
is attended by a risk of ureteral obstruction resulting from blood clots.
The nephrotic syndrome is an infrequent but well-documented complication of
sickle cell anemia that occurs in adolescents and adults. The syndrome may be associated
with hypertension, hematuria, and progressive renal insufficiency culminating in renal
failure. Pathologic lesions include glomerular enlargement and focal segmental
glomerulosclerosis (139). In more advanced disease, a lesion that resembles
membranoproliferative glomerulopathy has been described (140); immune complex
nephropathy has also been reported. Microalbuminuria occurs in 46% of children
between the ages of 10 to 18 years and is directly related to age and degree of anemia
(140). Chronic red cell transfusion begun at an early age may be protective against
microalbuminemia. Approximately one-fourth of adult sickle cell patients have at least
1+ proteinuria, and 7% have serum creatinine concentrations above the normal range.
Administration of enalapril, an angiotensin-converting enzyme inhibitor, reduces
proteinuria, suggesting that glomerular capillary hypertension may be a pathogenetic
factor in sickle cell nephropathy. The combination of enalapril and hydroxyurea was
beneficial in a small number of children with nephropathy (141). The overall incidence of
hypertension in patients with Hb SS is 2 to 6%, compared with a published incidence of
28% for the black population in the United States (142). Intermittent hypertension
occurring during sickle cell crises and associated with transient elevation of plasma renin
activity has been attributed to the reversible sludging of red cells in the small vessels of
the kidney.
Renal failure, which occurs in approximately 4% of patients with sickle cell anemia
at a median age of onset of 23 years (143), is a significant cause of mortality in adults.
The preazotemic manifestations of hypertension, proteinuria, and increasingly severe
anemia predict end-stage renal failure with an average survival (despite dialysis) of 4
years after diagnosis (143). Management of renal failure is the same as that for renal
insufficiency from other causes. Both hemodialysis and peritoneal dialysis, when used in
conjunction with a transfusion program, are efficacious in transiently correcting uremic
complications. The role of renal transplantation has not been well established because of
limited numbers of patients and posttransplant problems of increased pain crises, graft
thrombosis, and recurrence of sickle nephropathy (144). Pharmacologic doses of
exogenous erythropoietin have been effective in correcting anemia, but higher
hematocrits have been associated with increased pain crises.
Eyes
A variety of ocular lesions result from occlusion of the small vessels of the eye by sickled
erythrocytes. Sludging of blood in conjunctival vessels is responsible for the so-called
conjunctival sign, which consists of dark red, comma-shaped or corkscrew-shaped
vascular fragments that appear to be isolated from other vessels. The anomalous
segments are seen most often in that part of the temporal bulbar conjunctiva covered by
the lower lid.
Vasoocclusive disease of the retina is responsible for both nonproliferative and
proliferative (neovascular) changes (145,146). The former consist of “salmon patches,”
produced by small intraretinal hemorrhages; iridescent spots, representing collections of
iron-loaded retinal macrophages; and schisis cavities, left after resorption of blood.
Hemorrhages that break into the potential space between the sensory retina and pigment
epithelium stimulate pigment production and migration, giving rise to black, disc-shaped
scars known as black sunbursts. Proliferative changes begin with the formation of
arteriovenous anastomoses, followed by the development of vascular fronds resembling
sea fans. With time, repeated vitreous hemorrhages cause vitreous degeneration and
vitreoretinal traction, which in turn produces retinal holes, tears, and detachment. These
changes may culminate in loss of vision, less often in association with Hb SS than with
Hb SC disease (147). No correlation has been found between retinopathy and age, sex,
systemic complications, and various hematologic parameters except Hb F level, which is
higher in less affected patients.
Proliferative retinal disease may be arrested by laser photocoagulation or
cryocoagulation , in order to seal off the feeder vessels of neovascular patches and
coagulate vascular leaks. Because of a high rate of long-term complications, feeder vessel
treatment has been abandoned in favor of scatter photocoagulation, except in recalcitrant
cases with repetitive bleeding. Vitreous hemorrhages can be removed by pars plana
vitrectomy followed by photocoagulation. Retinal detachment is treated by scleral
buckling surgery; potential complications include persistent intraocular hemorrhage,
hyphema with secondary glaucoma, infarctions of the macula and optic nerve from
elevated intraocular pressure, and the potential for intraoperative sickling crises.
An additional ocular complication of sickle cell disease is hyphema. Bleeding into
the anterior chamber leads to trapping of sickled red cells, mechanical obstruction of the
outflow apparatus, compromised circulation of the aqueous humor, and increased
intraocular pressure, which may result in sudden blindness (148). This complication,
which also can occur with sickle cell trait red cells, may be effectively managed by
lowering intraocular pressure through anterior chamber paracentesis.
Mild edema of the eyelids is frequently seen in association with vasoocclusive pain
crises, but more significant sickle “orbitopathy” has been described in approximately 20
patients (149). A vasoocclusive process in the marrow space around the orbit may result
in frontal headache, fever, eyelid edema, and orbital compression. Subperiosteal
hematomas are common and appear to result from bone marrow infarction. Although
supportive care is usually adequate, the presence of optic nerve dysfunction or unusually
large hematomas may require surgical evacuation to prevent loss of vision.
Leg Ulcers
Breakdown of the skin over the malleoli and distal portions of the legs is a recurring
problem during adult life (Fig. 40.11) (150). Stasis of blood in the small vessels
supplying these areas may interfere with the healing of minor traumatic abrasions. Leg
ulcers were observed in 2.5% of sickle cell patients over 10 years of age in North
America (151), but they affect as many as 75% of adults with sickle cell anemia who live
in tropical areas (152). A number of other risk factors have been identified. Ulcers are
common in patients with Hb SS but quite rare in those with Hb SC disease or Hb S ß+thalassemia. They are more common in men than in women and in those older than 20
years of age. There is a positive correlation with a low steady-state Hb concentration and
with a low level of Hb F.
The ulcers typically form a shallow depression with a smooth and slightly elevated
margin; often, they have a surrounding area of edema. There may be exudation, crusting,
and granulation at the base. Secondary infection of the ulcer with undermining of the
edges and progressive extension are common. Single or multiple bacterial organisms may
be cultured from the lesions and may contribute to their refractoriness. Healing leaves a
thinned, depigmented epithelium often surrounded by areas of hyperpigmentation and
hyperkeratosis. This fragile epithelium is likely to break down with minimal trauma or
edema, leading to recurrence rates greater than 70%.
Healing of leg and ankle ulcerations is facilitated by bed rest, elevation of the
affected extremities, wet-to-dry dressings, and eradication of documented wound
infections with systemically administered antibiotics. When acute inflammation has
subsided, occlusive zinc oxide–impregnated gel boots (Unna boots) are applied, and
partial ambulation is permitted. In refractory or progressive cases, the healing process
may be enhanced if the level of Hb S is maintained below 40% with transfusions. Splitthickness skin grafting may be necessary. A number of alternative approaches have also
been described in recent years. Zinc deficiency has been invoked to explain slow tissue
healing, and oral zinc therapy may hasten healing in some patients. Erythropoietin and
hydroxyurea may improve healing by increasing fetal or total (or both) Hb
levels. Nevertheless, the lack of consistently effective approaches to management along
with the significant psychosocial effects of the condition have led to current treatment
being called “Medieval Medicine” (153).
Pregnancy
Pregnancy poses potentially serious problems for the woman with sickle cell anemia, as
well as for the fetus and neonate (154). In the absence of medical supervision, the
mortality for mother and infant has been as high as 20% and 50%, respectively (155).
With optimal care, mortality and morbidity are reduced substantially, even in difficult
settings in Africa (156). The jeopardy imposed by pregnancy is explained in part by
marginal health status before conception and in part by the sinusoidal circulation of the
placenta, whereby a high degree of oxygen extraction provides an excellent milieu for
sickling, stasis, and infarction. Although life-threatening complications generally are not
encountered until the third trimester, an increased incidence of pyelonephritis, hematuria,
and thrombophlebitis is noted throughout pregnancy. Anemia is more severe and may be
compounded by folate deficiency. During late pregnancy and the postpartum period,
major infarctions may involve the lungs, kidneys, or brain. Toxemia, heart failure, and
postpartum puerperal endometritis occur with greater frequency in women with sickle
cell anemia than in the general population.
The risk to the fetus is serious; fetal wastage results from a combination of abortion
and stillbirth. There is no increased incidence of congenital malformations. Opiates are
not associated with teratogenicity, congenital malformations, or toxic effects other than
transient suppression of movement and variablility in fetal heart tones. Hydroxyurea,
even when used throughout pregnancy, has not been associated with birth defects in a
small number of pregnancies (157). Nevertheless, is is a teratogen in animals and should
be stopped once pregnancy is recognized.
Infants born to women with sickle cell anemia are at greater risk of preterm birth,
low birth weight, being small for gestational age, and neonatal jaundice, but since 1980,
the neonatal mortality rate has ranged from 0-10% (154). The efficacy and safety of
various methods of contraception have not been investigated systematically in women
with sickle cell disease. Despite a theoretical possibility of enhancing thrombotic risk,
low-estrogen-dose birth control pills are sometimes recommended. Recent studies found
no adverse effects from the progestational contraceptive implant and a possible
improvement in fetal Hb level (158). An association of pain crises and menstrual periods
seen in 37% of women suggests the use of a continuous combined contraceptive pill
regimen or Depo-Provera to induce amenorrhea in severe cases (159). Recently, a review
of the progesterone-only contraceptive use suggested that they are safe and result in less
frequent and severe painful crises (160).
Prognosis
Prognostic expectations for persons with sickle cell anemia have undergone dramatic
change as a result of early diagnosis, patient education, and therapeutic intervention. In a
1976 report of a screening program which used cord blood samples, 31% of children
diagnosed at birth died before 15 years of age at a mean age of 2 years (161). The
disproportionate number of reported deaths occurring in early childhood was the result of
overwhelming bacterial infections and splenic sequestration crises.
Newborn screening for sickle cell disease and greater awareness of the unique needs
of affected infants and children have resulted in an improved prognosis. The simple
adoption of a standardized protocol for the management of febrile illnesses reduced the
mortality in children with sickle cell anemia 0 to 5 years of age from 3.2/100 patientyears to 1.4/100 patient-years (96). In 1989, the CSSCD documented an 85% survival
rate at 20 years of age (162). In that study, peak incidence of death (mostly resulting from
infections) occurred between 1 and 3 years of age. Cerebrovascular accidents and
traumatic events exceeded infections as a cause of death in the second decade of life.
Determinants of Severity
Extensive data from the CSSCD highlighting frequency/incidence and risk factors for
various complications of sickle cell disease have been published (163). Because of the
large number of patients involved and the efforts to avoid patient selection bias, these
data represent an ambitious attempt to describe the natural history of sickle cell disease.
A large, carefully followed cohort of sickle cell patients from Jamaica described in
numerous publications and a textbook provides another major source of data for
prognostic analysis.
Sickle cell anemia is remarkably variable in its clinical expression, even among
affected members of the same family. At least four important modulators of hematologic
and clinical severity have been identified: Hb F level, the presence of α-thalassemia, the
ß-globin gene cluster haplotype, and gender.
Because Hb F is excluded from the Hb S polymer, individuals with relatively greater
amounts of Hb F should have less severe disease than those with less Hb F. The level of
Hb F in patients with sickle cell anemia is determined by the number of red cells
containing Hb F (F cells), the Hb F concentration within F cells, and the survival of F
cells (164).
In the eastern province of Saudi Arabia and in Kuwait, Iran, India, and the West
Indies , mild disease is associated with Hb F levels of 15 to 30%. Levels of Hb F
influence the age at which symptoms develop and partially determine the risk of acute
splenic sequestration , stroke, ACS, leg ulcers, pain crises, loss of spleen function, and
mortality. An improvement in measures of clinical severity related to increased Hb F has
been difficult to establish. One study concluded that Hb F levels substantially lower than
20% conferred minimal benefit on disease severity, indicating a threshold effect.
However, evidence from the CSSCD indicates that even when the fetal Hb level is low,
small increments in the level may have an ameliorating effect on the pain rate and may
ultimately improve survival.
Co-inheritance of sickle cell anemia and α-thalassemia is not an unusual event.
Nearly 30% of black Americans have a single αgene deletion, and in approximately 2%,
deletion of two of the four α-globin genes has been found. Hematologic studies provide
support for the clinical relevance of α-thalassemia. Subjects with sickle cell anemia and
α-thalassemia have a higher Hb concentration, lower MCV and MCHC, fewer ISCs, a
lower reticulocyte count, lower serum bilirubin concentration, and relatively more Hb A2
than subjects without concurrent α-thalassemia. There is relatively little effect of αthalassemia on Hb F levels,
Data from the CSSCD demonstrated that coexistent α-thalassemia is associated with
a diminished mortality risk in patients older than 20 years of age Osteonecrosis and
perhaps sickle retinopathy occur more often in sickle cell subjects with coexistent α-
thalassemia (165,166). Sickle cell trait is also influenced by ß-thalassemia. Subjects with
lower fractional content of Hb S associated with α-thalassemia have less severely
impaired urinary-concentrating ability (167).
Genetic factors that modulate the phenotype of sickle cell disease are now known to
be associated with restriction fragment length polymorphic sites within the ß-globin–like
gene cluster (168). These ß-globin gene haplotypes are characteristic of different
populations; most patients with sickle cell anemia in the United States have the Benin
haplotype, with fewer having the Bantu (Central African Republic) and Senegal types.
The Senegal haplotype is associated with higher levels of Hb F (169) and with fewer
hospitalizations and painful episodes. By contrast, the Bantu haplotype has been
associated with the highest incidence of organ damage, particularly renal failure.
Laboratory Features
Red Blood Cells
In sickle cell anemia, a moderately severe normocytic, normochromic anemia manifests
by 3 months of age and persists throughout life. The average Hb concentration is 8.0 g/dl,
with a range from approximately 6.0 to 10.0 g/dl. Mean Hb levels vary with gender and
with age. In adults with Hb SS, the mean MCV is approximately 90 fl, and the mean
MCHC is approximately 34.0 g/dl. The MCV and MCHC are substantially lower (mean,
72 fl and 32.5 g/dl, respectively) in patients with concurrent α-thalassemia minor (-α/-α
genotype) and in children with incidental iron deficiency Blood smears contain variable
numbers of sickled forms, target cells, cigar-shaped cells, and ovalocytes (Fig. 40.12).
The morphologic features of accelerated erythropoiesis, which include
polychromatophilia, basophilic stippling, and normoblastosis, are prominent. The mean
reticulocyte count is approximately 10%, with a range of 4 to 24%. Howell-Jolly bodies
reflect functional asplenia.
The white blood cell count is consistently elevated owing to an increase in the
number of mature granulocytes. The mean leukocyte count under steady-state conditions
is 12 to 15 x 109 /L, with a range of 6 to 20 x 109/L . This increase is explained to a large
extent by a shift of granulocytes from the marginated to the circulating compartments.
Both total and segmented leukocyte numbers increase during vasoocclusive crises and
infections, but only with bacterial infections does a consistent increase occur in
nonsegmented neutrophils, often to levels above 1 x 109/L .
Platelets and Coagulation
9
The platelet count is increased (mean, approximately 440 x 10 /L), reflecting reduced or
absent splenic sequestration. Totals of both platelets and megathrombocytes decrease
during vasoocclusive crises. Platelet aggregation is decreased, the likely result of in vivo
platelet activation. The contact factors are decreased, whereas factor VIII activity,
fibrinogen concentration, and fibrinolytic activity are increased. Some of these alterations
likely reflect vascular endothelial damage inflicted by the sickling process and not
primary perturbations responsible for crises.
Other Laboratory Tests
The sedimentation rate is consistently low, even in the presence of anemia,
hyperfibrinogenemia, and active inflammation, because of the failure of sickle cells to
undergo rouleaux formation.
Diagnosis
The diagnosis of sickle cell anemia rests on the electrophoretic or chromatographic
separation of hemoglobins in hemolysates prepared from peripheral blood. The
predominant hemoglobin is S; Hb F is present in varying concentrations; and Hb A2 is
normal. There is no Hb A. Electrophoresis using cellulose acetate and an alkaline buffer
is rapid, inexpensive, and effective in the separation of normal hemoglobins from
common variants. Whole blood, blood specimens dried on filter paper, or Hb solutions
may be used (170). However, several relatively rare Hb variants have an electrophoretic
mobility identical to that of Hb S on cellulose acetate. Because most of these variants do
not copolymerize with Hb S on deoxygenation, the doubly heterozygous states are
seldom associated with the clinical and hematologic features of sickling. The interaction
of Hb S with ß0-thalassemia also gives an electrophoretic pattern that is indistinguishable
from that of homozygous sickle cell anemia. In general, the appropriate diagnosis can be
made by taking into consideration associated hematologic data. .
A variety of simple tests permit detection of Hb S. The sickling phenomenon can be
induced by sealing a drop of blood under a coverslip to exclude oxygen or by adding
agents that induce chemical deoxygenation, such as 2% sodium metabisulfite or sodium
dithionite. The decreased solubility of deoxy Hb S forms the basis for tests in which
blood is added to a buffered solution of a reducing agent such as sodium dithionite. Hb S
is insoluble and precipitates in solution, rendering it turbid, whereas solutions containing
hemoglobins other than Hb S remain clear. Hyperglobulinemia and other sickling
hemoglobins may cause false-positive results; false-negatives may result from the
addition of an inadequate number of red cells. Neither the sickle cell preparation nor
solubility tests differentiate sickle cell anemia from sickle cell trait or detect Hb variants
that interact with Hb S. Thus, they should never be used as a primary screening test.
Their principal value has been as an adjunct to electrophoretic identification of Hb S.
Quantitation of Hb A2 is performed by minicolumn chromatography or HPLC.
Quantitation of Hb F can be carried out by alkali denaturation, HPLC, or
radioimmunodiffusion. The distribution of Hb F in red cells may be analyzed by its
resistance to acid elution or, more precisely, by Hb F–specific antibodies that measure the
number of “F cells” .
Although the diagnosis of Hb SC disease is straightforward, that of Hb Sß-thalassemia
may sometimes be problematic. In Hb Sß+-thalassemia, there is a preponderance of Hb S,
with Hb A comprising 5 to 30% of the total. This must be distinguished from sickle cell
trait in which Hb A exceeds Hb S and from the presence of Hb A resulting from red
blood cell transfusions within the previous 3 to 4 months. Hb Sß0-thalassemia produces
an electrophoretic pattern that is visually indistinguishable from that of sickle cell anemia,
but a diagnosis can often be made by the presence of an elevated Hb A2 level and a
decreased MCV. However, because sickle cell anemia with coincident ß-thalassemia also
has a phenotype with reduced MCV and elevated Hb A2, family or DNA-based studies
may be necessary to make this distinction.
Neonatal Diagnosis
The impetus for universal screening came from the demonstration that early diagnosis
and comprehensive care could reduce morbidity and mortality in infants with sickle cell
anemia, particularly through the prevention of pneumococcal sepsis with penicillin
prophylaxis. A National Institutes of Health Consensus Conference concluded that every
child should be screened early for sickle cell disease (171), leading to statewide newborn
screening programs in almost all 50 states (172). Universal rather than targeted screening
is necessary to insure that all with disease are identified. .
In 1990, more than 3.4 million newborns were tested, and approximately 2800 with
clinically significant Hb variants were detected (172). Most programs use dried blood
spots on filter paper because Hb testing can easily be integrated into existing metabolic
programs with established methods of sample collection, specimen processing, data
management, and quality control. Isoelectric focusing and HPLC have replaced cellulose
acetate electrophoresis in most screening programs (173).
The primary goal of newborn screening for sickle syndromes is reduction of morbidity
and mortality by identifying affected infants at birth, initiating prophylactic penicillin
early, and providing ongoing care by knowledgeable health professionals. The number of
early deaths avoided has been estimated at 0.6 to 1.2/100 births (174). All cases of
suspected disease still must be confirmed with a separate sample from the infant because
clerical errors may be encountered. A common problem is the need to establish a
mechanism for educating and counseling parents of carriers detected by testing at birth
(171). Prenatal education for expectant mothers, which includes information about
newborn sickle cell screening, significantly increases the follow-up rate for infants with
sickle cell trait and contributes to a greater retention of information.
Treatment
Several recent review articles reflect the rapid pace of development of feasible and
effective treatment options for patients with sickle cell disease (175,176). In addition to
prophylactic measures aimed at preventing specific complications of sickle cell disease,
three treatment options have been increasingly used for overall management: chronic
blood transfusion, hydroxyurea, and stem cell transplantation. Gene therapy remains a
future goal.
Preventive Measures
Until a safe and widely applicable mechanism for the prevention of intravascular sickling
is found, a high priority must be placed on the prevention of complications. Because
vasoocclusive crises are precipitated by infection, fever, dehydration, acidosis,
hypoxemia, and cold exposure, measures to prevent or remedy these conditions assume
importance. Optimal hydration is essential, especially during febrile illnesses. In
estimating fluid requirements, the hyposthenuria of sickle cell anemia, as well as
increased insensible losses, must be considered. Because the liberal use of salicylates
imposes an acid load, acetaminophen is the preferred antipyretic. Sudden transition to
high altitude and exposure to situations likely to cause chilling should be avoided.
The high risk of overwhelming pneumococcal disease in children mandates the use of
penicillin prophylaxis and pneumococcal vaccination. Preventive measures and early
medical intervention for febrile illnesses substantially reduce mortality.
Blood Transfusion
One of the most effective therapeutic measures presently available is the transfusion of
normal red cells. However, because of the complications of transfusion therapy, it is
reserved for selected complications, such as severe anemia, progressive or recurrent
organ damage, surgery, and certain severe acute vasoocclusive events. Transfusion
therapy facilitates improved blood and tissue oxygenation, reduces the propensity for
vasoocclusion by diluting host cells, and temporarily suppresses the production of red
cells containing Hb S. With chronic transfusion support, splenic involution and fibrosis
are reversed in some patients (177). Replacement of patient cells with donor cells is
readily accomplished by a limited exchange transfusion, in which patient blood is
removed before or during packed cell transfusion. Repeated partial exchange transfusion,
which can be performed through erythrocytapheresis, greatly reduces the net gain of iron .
However, the long-term central venous access, which is often required, may be associated
with an unusually high rate of catheter infection, thrombosis, and premature removal of
the central line. Repeated simple transfusions are probably equally effective in
terminating the consequences of in vivo sickling. Packed red cell transfusions at 3- to 4week intervals generally are sufficient to maintain the relative number of donor cells in
the circulation above 70%, but Hb S is more easily suppressed in some patients than
others. Furthermore, chronic transfusion may result in recurrent splenomegaly and the
additional problem of hypersplenism.
Although effective in circumventing the numerous complications of sickle cell anemia
(178), chronic transfusion therapy is limited by logistic and toxicologic considerations.
The requisite commitment of personnel and blood resources is considerable, and the risks
of alloimmunization and hemosiderosis are cumulative and potentially life-limiting.
Among individuals with sickle cell anemia, 18 to 36% become alloimmunized,
considerably more than with other forms of anemia (179). The greater risk of
alloimmunization in sickle cell anemia is primarily a result of racial differences between
the blood donor and recipient populations. Hemolytic transfusion reactions are associated
with as many as 3% of transfusions. Most occur several days after the transfusion and are
accompanied by a falling hematocrit, hemoglobinuria, increased jaundice, and, frequently,
a pain episode. In some cases, a delayed hemolytic transfusion reaction may lead to a fall
in Hb level to a level lower than before transfusion, with a life-threatening or fatal
outcome resulting from attempts to provide further transfusions.
Iron overload has been an inevitable result if chronic transfusion is not performed by
partial exchange methodology, such as erythrocytapheresis. The severity of iron overload
commonly has been monitored with serum ferritin concentration, and there is a strong
intrapatient correlation between ferritin levels and volumes transfused (180). However,
there is wide interpatient variability, indicating a need to assess iron stores directly by
liver biopsy to determine the necessity for iron chelation (180). Innovations in
noninvasive methods to measure iron levels by magnetic resonance techniques such as
T2* MRI have expanded and improved the clinical management of iron overload in
target organs such as the liver and heart (181).
Although chelation with desferrioxamine (Desferal) has reduced organ damage and
significantly prolonged life expectancy in transfused thalassemia patients, its use has
several serious limitations. The administration of desferrioxamine as a life-long, daily,
subcutaneous or intravenous infusion is cumbersome and has caused logistical hardships
that promote inconsistent adherence to treatment.
Deferiprone (L1), an oral chelator that was licensed in Europe and Asia over the past
decade, is a small molecule with a short half-life believed to have better access to
intracellular iron. It is administered 3 times a day and its side-effects are well recognized:
agranulocytosis occurring in 0.6/100 patients per year, and, more commonly, transient
neutropenia, arthropathy, zinc deficiency, increased transaminase levels and
gastrointestinal symptoms (182). Encouraging preliminary reports suggestive of effective
penetration into cardiac cells prompted a large retrospective study, which showed a
significantly lower rate of cardiac death and cardiac events in patients treated by
deferiprone (75 mg/kg/day) compared to those treated by standard subcutaneous
desferrioxamine (183).
The tridentate chelator, deferasirox (ICL670; Exjade), can be given as a single daily
oral dose due to its long halflife. Deferasirox was recently approved in the US for
transfusion-induced iron overload. In a large phase III comparison study with
desferrioxamine, the dose of deferasirox was determined by the baseline liver iron
concentration (LIC), with the highest LIC assigned the maximum deferasirox dose.
Maintenance of LIC and neutral iron balance was achieved in those who received 20
mg/kg/day of deferasirox, whereas reduction in iron load was achieved at a higher dose
of 30 mg/kg/day. Common side-effects of deferasirox included rash (in 11%) and
transient gastrointestinal symptoms (in 10–15%).
Oral chelators such as deferasirox and deferiprone have the potential to improve therapy
for iron overload by improving compliance and therefore clinical response.
Anemia
Anemia with Hb levels as low as 5 g/dl generally is well tolerated and requires no therapy.
During hematologic crises, however, the Hb concentration may fall precipitously,
requiring rapid correction. An aplastic crisis caused by parvovirus infection often requires
a single packed red cell transfusion before erythropoiesis eventually returns. A severe
splenic sequestration crisis may require an immediate transfusion to restore blood volume
and oxygen-carrying capacity. If the patient does not have an elective splenectomy,
chronic transfusion therapy to maintain splenic function has been used as an alternative.
However, recurrences of sequestration have occurred despite transfusion.
Progressive Organ Damage
The risks and expense of a long-term transfusion program are justified if progressive or
recurrent vasoocclusive events threaten major organ function. Chronic transfusion
therapy minimizes the risk of recurrent or progressive neurologic deterioration in children
who have had a stroke (184). Progressive retinopathy, sickle cell renal disease, and
cardiac decompensation may also be arrested with repeated transfusions. Short-term
transfusion therapy may be of benefit for a variety of complications, including ACS pain
events, priapism, protracted hematuria, and chronic skin ulcerations (178).
Surgery
Anesthesia, surgery, and postsurgical convalescence expose patients to hypoventilation,
hypotension, cooling, dehydration, acidosis, and immobilization. Recommendations for
the preparation of patients for surgery vary; simple transfusions before elective
procedures and partial exchange transfusions before emergency surgery have been used.
In a recent national survey of practice in the United Kingdom, it was found that most
patients undergoing cholecystectomy and adenoidectomy do so without preoperative
blood transfusion, whereas almost all patients undergoing hip arthroplasty are prepared
by exchange transfusion (185). There was no difference in the rate of postoperative
complications in patients who received a transfusion and those who did not.
Pregnancy
Women with sickle cell anemia also have a decrease in Hb concentration during
pregnancy as a consequence of hemodilution. Generally, no therapy is indicated.
However, the final weeks of pregnancy are often complicated by vasoocclusive events
that may have devastating consequences for both mother and fetus. In an attempt to
prevent progressive placental infarction and premature delivery, the use of transfusion
therapy during the third trimester has been proposed. In the only randomized study of its
effectiveness, prophylactic transfusion therapy did not have a favorable impact on
maternal morbidity (other than a reduction in the number of pain crises) or fetal wastage
(186).
New Approaches to Therapy
Activation of Hemoglobin F Synthesis
Reinstitution of Hb F synthesis is a long-standing treatment approach that appears
increasingly attainable. This therapeutic strategy is based on the observation that clinical
expression of the sickle gene is prevented by Hb F synthesis in the perinatal period, as
well as throughout life in individuals with HPFH.
Hydroxyurea increases Hb F production in patients with severe sickle cell anemia
(187). Hydroxyurea preferentially arrests the development of the more mature erythroid
precursors, perhaps resulting in the recruitment of earlier erythroid progenitors with a
greater capacity for Hb F synthesis. Alternatively, hydroxyurea may have a direct effect
on “reprogramming” globin synthesis by early erythroid progenitors, a suggestion that is
supported by the fact that the increase in F-reticulocyte numbers that follows
hydroxyurea administration occurs sooner (within 2 to 3 days) than would be expected if
the effect represented recovery from bone marrow suppression (188). Patients taking
hydroxyurea develop macrocytosis and show a rapid correction toward normal of red cell
density distribution and improved whole blood viscosity.
In 1995, a double-blind
multiinstitutional trial of hydroxyurea versus placebo in approximately 300 adults with
moderate to severe sickle cell disease was concluded with convincing evidence of clinical
benefit from the drug (189). Patients treated with hydroxyurea had approximately 50%
lower rates of pain crises, ACS, hospitalization, and transfusion. There was wide
variability in drug tolerance and clinical response, but the primary toxicity and doselimiting factor was mild neutropenia. Long-term follow-up of these hydroxyurea-treated
patients indicated that they have reduced mortality. Because of the favorable outcome in
the majority of treated patients, hydroxyurea has become widely used in the treatment of
adult patients who experience frequent vasoocclusive crises.. Studies in pediatric patients
are more limited, but a multicenter phase I-II trial indicated that school-aged children
treated with hydroxyurea had increases in fetal Hb, Hb concentration, and MCV similar
to those of adults and suggested that clinical benefit and toxicity may also be similar
(190). Long-term hydroxyurea therapy at a maximum tolerated dose (MTD) (average
dose 25 mg/kg/d) was well tolerated by pediatric patients and had sustained hematologic
efficacy with apparent long-term safety (191). Recent studies in children 6 to 24 months
of age (at onset of treatment) have not indicated unusual toxicity from hydroxyurea and
follow-up indicated that after 4 years, hydroxyurea was associated with increased Hb
concentration, percentage of Hb F, and MCV, and decreased reticulocytes, WBC, and
platelets. In general, infants with SCD tolerated prolonged hydroxyurea therapy with
sustained hematologic benefits, fewer ACS events, improved growth, and possibly
preserved organ function (192). The capacity of this treatment for prevention or reversal
of organ dysfunction remains to be established, but a return of splenic function was noted
in several other patients treated with hydroxyurea. A modified dose based on HU
pharmacokinetics in patients with renal dysfunction has been recommended (193).
Hydroxyurea can be utilized as an oral solution (100 mg/mL) (194). Although caution
about the long-term carcinogenic and teratogenic potential of hydroxyurea needs to be
exercised, to date there is no evidence that the drug leads to an increased cancer risk or to
congenital anomalies in offspring of women who inadvertently became pregnant while
taking hydroxyurea
A recent report suggests that erythropoietin therapy may allow
more aggressive HU dosing in high-risk sickle cell patients and in the setting of mild
renal insuffiencey, common to the aging sickle cell population (195). Furthermore,
erythropoietin appears to be safe when used in conjunction with hydroxyurea.
Bone Marrow (Stem Cell) Transplantation
Bone marrow transplantation has the potential to normalize Hb synthesis in patients with
sickle cell anemia; the current status of the field has been recently reviewed (196). The
majority of donors have been HLA-identical relatives, and pretransplant conditioning
regimens have generally consisted of busulfan and cyclophosphamide with or without
antithymocyte globulin. In the U.S. multiinstitutional study (197), 50 children younger
than 16 years of age received HLA-identical marrow allografts because of a history of
stroke, recurrent ACS, or recurrent pain crises. Kaplan-Meier probabilities of survival
and event-free survival at a median follow-up of 58 months were 94% and 84%,
respectively. Lung function was stable in almost all patients. Among those with prior
CNS vasculopathy who had engraftment, stabilization of cerebrovascular disease was
documented by MRI and MRA. The availability and the relative success of bone marrow
transplantation worldwide have raised a number of social and ethical questions about its
use. For example, how severe must sickle cell disease be to justify a transplant-associated
mortality rate of 5 to 10%? In the United States, only 6% of patients with sickle cell
anemia met the criteria for transplantation specified in the study protocol; furthermore, a
survey of children with sickle cell anemia in the San Francisco area estimated that only
18% would have sibling donors (198).
Sickle Cell Trait
Sickle cell trait, the heterozygous state for the Hb S gene, is present in approximately 8%
of black Americans and in as many as 30% of some African populations. The red cells of
such individuals contain both Hb A and Hb S, but there is always more Hb A than Hb S.
Clinical Features
Sickle cell trait rarely is associated with clinical or hematologic manifestations of
significance. Individuals have no anemia, and red cell morphology is normal.
Complications of the trait are well documented but relatively rare: hematuria, urinary
tract infection, and splenic infarction. The former generally is transient and probably is
related to poor perfusion of the renal papillae. Frank renal papillary necrosis has been
described. Urine-concentrating ability also is impaired, although renal acidification is
normal. There are numerous reports of splenic infarction in individuals with sickle cell
trait who are exposed to altitudes of 10,000 feet or more in unpressurized aircraft, but this
has not been reported in commercial flights, in which cabin pressure is equivalent to
approximately 8000 feet. Most individuals with sickle cell trait, however, tolerate
simulated high altitude.
Screening Programs
There are two reasons to screen groups for the presence of sickle cell trait: (a) to inform
affected persons of health risks and (b) to provide information that might affect an
individual’s reproductive decisions. Most hemoglobinopathy screening is now done to
identify sickle cell disease in neonates. Therefore, identification of sickle cell trait occurs
at a time when counseling of the affected individual is impossible. Counseling of family
members of newborns with sickle cell trait may be of value but is only performed
sporadically in most states.
The technique chosen for screening should be genetically diagnostic and should clearly
differentiate between sickle cell trait and those disorders of Hb having implications for
health. Conventional Hb electrophoresis and thin-layer isoelectric focusing on acrylamide
gel and high performance liquid chromatography have been adapted satisfactorily to mass
screening. Because solubility tests do not detect ß-thalassemia trait, Hb C, and other Hb
variants that interact with Hb S to cause disease, they should not be used for screening.
Other Sickling Syndromes
Several of the doubly heterozygous states for Hb S and a second disorder of Hb synthesis
are characterized by clinical and hematologic aberrations that to some extent mimic the
features of sickle cell anemia. The clinically significant disorders resulting from double
heterozygosity for Hb S and a second Hb variant are considered forms of sickle cell
disease.
Hemoglobin SC Disease
The sickling disorder known as hemoglobin SC disease results from the inheritance of an
Hb S gene from one parent and an Hb C gene from the other parent.. The disorder occurs
with an approximate frequency of 1 in 1100 births among black Americans.
Clinical Features
The clinical manifestations of Hb SC disease are similar to, but on average less severe
than, those of sickle cell anemia (199). Growth and sexual development are delayed
compared to normal children, but less so than in children with sickle cell anemia.
Symptoms in the first year are rare, and one-fourth of affected individuals remain
asymptomatic throughout the first decade of life (199). The most common symptom is
episodic abdominal or skeletal pain, qualitatively similar to that caused by vasoocclusive
events in sickle cell anemia. The average number of painful episodes/year for Hb SC
patients is approximately one-half that for persons with sickle cell anemia (0.4 vs. 0.8
episodes/year). Moderate enlargement of the spleen is present in approximately twothirds of children and often persists into adult life. Spleen perfusion is intact, however,
and as a result, symptomatic splenic infarction and acute splenic sequestration may occur
in adults as well as in children. Loss of spleen function is more gradual and occurs at a
later age than occurs in sickle cell anemia. The frequency of infections of patients with
Hb SC disease is increased, but fatal pneumococcal septicemia, although well
documented, is less of a risk than is noted in sickle cell anemia. In contrast to the
infectious complications of sickle cell anemia, those of Hb SC disease are
characteristically associated with a primary focus, tend not to recur, and respond
promptly to therapy. S. pneumoniae is the most common bacterial isolate, and the
respiratory tract is the most common focus. The incidence of bacteremia drops abruptly
after 2 years of age. Because bacteremia rarely progresses to septicemia and a fatal
outcome in young children with Hb SC disease, prophylactic penicillin is thought to be
unnecessary by some investigators. However, fatal pneumococcal septicemia has been
reported in a series of seven children, six of whom were older than 3 years of age (200).
Central nervous system deficits, asymptomatic hematuria, ankle ulceration, priapism, and
other complications of sickling occur with Hb SC disease but are infrequent events.
Because of the frequency with which they occur, certain complications of Hb SC
disease deserve special comment. Proliferative retinopathy is more common and more
severe than in sickle cell anemia. Progressive loss of vision may have its onset early in
the second decade, and patients should be encouraged to have an annual ophthalmologic
examination after reaching adolescence. Aseptic necrosis of the femoral head has been
reported to have a greater frequency in Hb SC disease than in Hb SS, but the age-adjusted
prevalence is lower. ACS, attributed to fat emboli after bone marrow infarction, occurs
most commonly during the final months of pregnancy in women with Hb
SC.
Moderately severe complications of in vivo sickling occur in Hb SC-Harlem
disease and in the Hb SC/α-thalassemia syndrome.
Laboratory Features
Anemia is mild or nonexistent; 75% of children 2 to 15 years of age have a hematocrit
between 28 and 38, and 75% of adults have a hematocrit between 28 and 42 (with males
having higher levels than females). Blood films contain as many as 50% target cells.
Although sickled cells are relatively rare, cells containing Hb “crystals” are noted
regularly. These hyperchromic, shrunken cells are distorted into pyramidal or elongated
contours by condensed aggregates of Hb (Fig. 40.12). The white blood cell count and
leukocyte differential are normal.
Treatment
Unlike the extensive investigations of the use of hydroxyurea in adults and children with
Hb SS, data in patients with Hb SC disease are lacking. One study involving six adult Hb
SC disease patients noted that hydroxyurea resulted in an increase in hematocrit and
MCV, improved cell hydration, and no significant difference in Hb F level (201). In a
study of six severely affected children with Hb SC disease, MCV and Hb F increased,
and patients improved clinically, but Hb concentration did not change after hydroxyurea
treatment (202). A randomized trial is needed to determine if hydroxyurea or other drugs
that may affect red cell density are of benefit.
Hemoglobin S–ß -Thalassemia
0
The doubly heterozygous condition of Hb S and ß-thalassemia is designated as Sß thalassemia if there is no ß-globin synthesis from the affected allele and Sß+-thalassemia
if ß-globin synthesis is present but reduced. The clinical manifestations are quite variable,
and patients may be nearly asymptomatic or have problems similar to those occurring in
0
the worst cases of sickle cell anemia. In general, Hb Sß -thalassemia resembles Hb SS in
severity, and Hb Sß+-thalassemia is somewhat milder than Hb SC disease.
Hemoglobin S/Hereditary Persistence of Fetal Hemoglobin (HPFH)
In HPFH, Hb F levels are elevated relative to the patient’s age. Deletional mutations
typically involve large segments of DNA and result in a pancellular distribution of Hb F.
Approximately 1:1000 African-Americans carry the deletion HPFH gene. Nondeletion
mutations result in more variable levels of Hb F (4 to 30%) and heterocellular or
pancellular distribution. The doubly heterozygous condition for Hb S and HPFH results
in a heterogeneous disorder that is generally extremely mild and associated with a
pancellular distribution of Hb F, normal blood counts, microcytosis, target cells, and 20
to 30% Hb F. Overall, there is approximately 1 case of Hb S/HPFH for every 100 cases
of Hb SS, but it is important to identify this condition because of its extremely good
prognosis.
Hemoglobin SE Disease
Hb E is characterized by the substitution of lysine for glutamic acid at position 26 of the
ß-chain and results in a mild ß-thalassemia phenotype. Because of the increase in the
Asian population in the United States, the doubly heterozygous condition of Hb SE is
now occasionally seen. Patients with Hb SE may have mild anemia and microcytosis
along with approximately 30% Hb E, but blood smears look relatively normal (except for
target cells), and patients are usually asymptomatic (203).
Hemoglobin SD Disease
Of the 16 variants fulfilling the electrophoretic and solubility criteria for Hb D or Hb G,
at least nine have been recognized in association with Hb S. With one exception, the
doubly heterozygous states for Hb S and Hb D or Hb G are clinically silent. Hb D-Punjab
(Hb D-Los Angeles) interacts with Hb S to produce mild hemolytic anemia and
symptoms that mimic those of mild sickle cell anemia. The Hb SD-Punjab syndrome was
first detected in a Caucasian man whose case had been previously reported as an instance
of sickle cell anemia in the white race. Subsequently, Hb SD-Punjab disease was
recognized in a number of subjects, most of African origin. In each of these subjects, the
clinical and hematologic features were those of mild sickle cell anemia.
Hemoglobin SO-Arab Disease
Hb O-Arab interacts strongly with Hb S in vitro. As would be predicted, the doubly
heterozygous state is clinically and hematologically indistinguishable from sickle cell
anemia (204). Functional asplenia occurs at an early age and is followed by progressive
splenic infarction. The disorder is differentiated readily from Hb SC disease, with which
it is confused on electrophoretic grounds, by the greater prominence of symptoms, the
severity of the anemia, and the presence of numerous ISCs on blood smears.
Hemoglobin C Disorders
In Hb C, lysine replaces glutamic acid in the sixth position of the β-chain. The
heterozygous state is noted in 2 to 3% of blacks, and homozygous Hb C disease affects
approximately 1 in 5000.
Hemoglobin C Disease
Hemoglobin C disease (Hb CC) is a mild disorder that characteristically is detected
through newborn hemoglobinopathy screening programs or during the investigation of an
unrelated medical problem. Growth and development are appropriate, and pregnancy and
surgery are well tolerated. Mild intermittent abdominal discomfort, arthralgia, and
headaches are noted in some reports, but their relationship to the hemoglobinopathy, if
any, is unclear. The spleen is enlarged in many affected individuals, and spontaneous
rupture of the organ has been reported. Spleen function is unaffected, however, and
unusual infectious problems are not observed. As with other hemolytic disorders,
cholelithiasis occurs with increased frequency.
Anemia is mild to moderate in severity. Erythrocyte morphology is strikingly abnormal,
with microcytosis, target cells (≥90%), occasional spherocytes, and cells distorted by
what appear to be crystals of hemoglobin. Target cells appear more plump and smaller in
diameter than those seen in individuals with liver disease, although their resistance to
osmotic lysis is similar to that of other target cells. Red blood cell survival is shortened
with evidence of splenic sequestration. Considering the relative indolence of the
hemolytic process, it is surprising that anemia is not fully compensated by a greater
erythropoietic effort. This apparent inconsistency is explained by an increase in the
oxygen saturation of hemoglobin of Hb CC erythrocytes, which have an intracellular pH
lower than that of normal cells. The right-shifted oxygen dissociation curve of whole
blood permits normal tissue oxygenation in spite of a smaller-than-normal red blood cell
mass. Shortened red cell survival probably is related to the decreased solubility of deoxyHb C. Diagnosis rests on the electrophoretic or chromatographic analysis of hemoglobin.
The major fraction is Hb C, Hb A is absent, and Hb F is slightly increased. Therapy is
neither available nor needed.
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