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548
SICKLE CELL DISEASE: 
CLINICAL FEATURES AND MANAGEMENT
Yogen Saunthararajah and Elliott P. Vichinsky
C H A P T E R 40
Hemoglobinopathies are the most common genetic diseases in 
humans. In sickle cell disease (SCD), a mutated β-globin gene pro-
duces sickle hemoglobin (Hb S). This mutation has been positively 
selected during human evolution because one copy of the sickle gene 
and one normal β-globin gene (sickle cell trait) confers a survival 
advantage in malaria-endemic regions. With two copies of the sickle 
gene (Hb SS or sickle cell anemia) or the sickle mutation and another 
mutated β-globin gene, for example, sickle cell–β°-thalassemia (Hb 
S–β thal) or Hb SC disease (Hb SC), the less soluble Hb S can 
polymerize in deoxygenated regions of the circulation, resulting in 
red blood cell (RBC) rigidity, RBC adhesion to endothelium, and 
hemolysis. These events activate inflammation and coagulation path-
ways and cause vasoocclusion.1 These processes manifest clinically as 
chronic hemolytic anemia, recurrent painful episodes, and chronic 
organ damage from vasoocclusion. This chapter presents the diagno-
sis and natural history, describes overall clinical management, and as 
specific management by organ complications. Clinical interventions 
are founded on an understanding of underlying pathophysiologic 
processes. The exigency of living with a painful, life-threatening 
chronic disease in an ethnically diverse society adds complexity to the 
psychosocial aspects of this illness. A comprehensive management 
approach directed at preventing pain crises, chronic organ damage, 
and early mortality while effectively managing acute complications is 
recommended. For a full discussion of the fascinating history and 
molecular pathology of this disease, please see Chapter 42. Normal 
Hb synthesis, structure, and function are described in Chapter 33, 
and the thalassemias are considered in Chapter 41.
PREVALENCE
The distribution and frequency of the sickle cell gene in different 
areas of the world have been influenced by natural selection 
and transmission of the gene via trade routes and the slave trade.2 
Among African Americans,3 the prevalence of sickle cell trait is 8% 
to 10% among newborns,4 and in this population, the frequencies 
of the sickle cell (0.045), Hb C (0.015), and β-thalassemia (0.004) 
genes4 indicate that there are 4000 to 5000 pregnancies 
a year at risk for SCD. The burden of this disease in the United 
States is dwarfed by that in the rest of the world, as evidenced by a 
prevalence of the sickle cell gene as high as 25% to 30% in western 
Africa and an estimated annual birth of 120,000 babies with SCD 
in Africa.5
DIAGNOSIS
The diagnosis of a sickle cell syndrome is suggested by characteristic 
findings on the complete blood count (CBC) and peripheral 
smear, that prompt Hb electrophoresis. If a diagnosis of SCD is 
confirmed, evaluation of the various organ systems at risk is required. 
These evaluations are discussed in the section on clinical 
management.
Complete Blood Count and Peripheral Blood Smear
The chronic hemolytic anemia of SCD presents with mild to mod-
erately low hematocrit and Hb levels and a reticulocytosis of approxi-
mately 3% to 15%. Additional laboratory features of hemolysis are 
unconjugated hyperbilirubinemia, elevated lactate dehydrogenase 
(LDH), and low haptoglobin levels. The reticulocytosis accounts for 
high or high-normal mean corpuscular volume (MCV). If the age-
adjusted MCV is not elevated, the possibility of sickle cell–β-
thalassemia, coincident α-thalassemia, or iron deficiency must be 
considered.
In the peripheral smear (Fig. 40-1), there may be sickled forms, 
target cells, polychromasia indicative of reticulocytosis, and Howell-
Jolly bodies demonstrating hyposplenia. The RBCs are normochro-
mic unless there is coexistent thalassemia or iron deficiency. 
Sickled forms (irreversibly sickled cells [ISCs]) occur in the peripheral 
smear only in the SCDs and not in sickle cell trait. In Hb SS disease, 
ISCs predominate, and target cells may be few; in sickle cell–β-
thalassemia, ISCs, target cells, and hypochromic microcytic disco-
cytes are prominent; in Hb SC disease, target cells predominate, and 
ISCs are rare.
White blood cell (WBC) counts are higher than normal in Hb SS 
disease, particularly in patients under age 10 years. Mean WBC 
counts tend not to be elevated in Hb SC disease or sickle cell–β+-
thalassemia. Mean platelet counts are elevated in Hb SS disease, 
particularly in patients younger than age 18 years, but are usually 
normal in those with Hb SC disease and sickle cell–β+-thalassemia.
Solubility Tests and Hemoglobin Electrophoresis
Solubility test results (e.g., Sickledex) are positive in both SCD and 
sickle cell trait. All patients require definitive diagnosis with Hb 
electrophoresis (which separates Hb species according to amino acid 
composition) (Fig. 40-2) or high performance liquid chromatography 
(HPLC).6 Cellulose acetate electrophoresis at a pH of 8.4 is a standard 
method of separating Hb S from other variants. However, Hb S, G, 
and D have the same electrophoretic mobility with this method. 
Using citrate agar electrophoresis at pH 6.2, Hb S has a different 
mobility than Hb D and G, which comigrate with Hb A in this 
system.
Results from electrophoresis or thin-layer isoelectric focusing are 
similar in Hb SS disease and sickle cell–β°-thalassemia: nearly all of 
the Hb consists of Hb S. Although differences in the fetal Hb (Hb 
F) (see Variant Sickle Cell Syndromes) and Hb A2 levels may be useful 
in distinguishing these syndromes, the presence of microcytosis or of 
one parent without sickle cell trait is a more useful indicator of sickle 
cell–β°-thalassemia. The diagnosis of Hb SC disease is straightfor-
ward; nearly equal amounts of Hb S and Hb C are detected. Sickle 
cell–β+-thalassemia and sickle cell trait both have substantial amounts 
of Hb A and Hb S. This superficial electrophoretic similarity does 
not provide an obstacle to diagnosis: whereas sickle cell trait is associ-
ated with neither anemia nor microcytosis and has an Hb A fraction 
more than 50%,7 sickle cell–β+-thalassemia is associated with anemia, 
microcytosis, and an Hb A fraction that ranges from 5% to 30%.
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 549
and spotted onto filter paper for stable transport and subsequent 
HPLC. (Solubility testing is unreliable because of the large amount 
of Hb F present.)
As Hb S increases and Hb F declines in the first months of life 
(Fig. 40-3), the clinical manifestations of SCD, including anemia, 
emerge.13 ISCs can be seen on the peripheral blood smear (Fig. 40-4) 
of children with sickle cell anemia at 3 months of age, and by 4 
months of age, moderately severe hemolytic anemia is evident.
A requirement for tests used in newborn screening is the capability 
to distinguish among Hb F, S, A, and C. The Hb distribution pattern 
is described in descending order according to the quantities detected. 
Therefore, a newborn with sickle cell anemia who has predominantly 
Hb F with a small amount of Hb S and no Hb A is described as 
having an FS pattern. An FS pattern is obtained also in newborns 
who have sickle cell–β°-thalassemia, sickle cell–hereditary persistence 
of Hb F (HPFH), and sickle cell–Hb D or sickle cell–Hb G (i.e., Hb 
D and E have the same electrophoretic mobility as Hb S). A newborn 
with sickle cell trait will have Hb F, Hb A, and Hb S (FAS pattern). 
The Hb F level is usually slightly to moderately elevated; the 
degree varies among patients. The amount of Hb F present is a func-
tion of the number of reticulocytes that contain Hb F, the extent of 
selective survival of Hb F–containing reticulocytes that become 
mature Hb F–containingerythrocytes (F cells), and the amount of 
Hb F per F cell.8 The Arab–Indian and Senegal haplotypes are associ-
ated with higher levels of Hb F than the others.9
Newborn Screening
The use of prophylactic penicillin10 and the provision of comprehen-
sive medical care during the first 5 years of life have reduced the 
mortality rate from approximately 25% to less than 3%, thereby 
underlining the importance of early identification of infants with 
SCD. Based on its economy and superiority of detection, universal 
screening of all newborns is preferred over ethnically targeted 
approaches.11,12 Blood samples for testing are obtained by heel stick 
Figure 40-1 SICKLE CELL DISEASE AND HEMOGLOBIN SC PERIPHERAL BLOOD SMEARS. The peripheral smear in sickle cell disease (A) shows 
sickle cells that are mostly irreversibly sickled and sometimes referred to as “cigar forms.” Higher power detail (B) shows a sickle cell (upper left), red blood cell 
containing a Howell-Jolly body (middle right), and polychromatophilic cell (lower center). These indicate sickle cell anemia and splenic dysfunction but marrow 
response with reticulocytosis, respectively. A peripheral smear of a patient with Hgb SC (C) shows no sickled cell, but there are target forms (D) and occasional 
cells (E) with hemoglobin condensed at each pole of the cell. 
A B C E
D
Figure 40-2 COMPARATIVE ANALYSES OF SEVERAL MUTANT HEMOGLOBINS USING ALKALINE ELECTROPHORESIS, ACID 
ELECTROPHORESIS, AND THIN-LAYER ISOELECTRIC FOCUSING. On the right are shown the components of the standard (top) and the 
phenotypes of the other six samples. Their analyses are shown by alkaline hemoglobin electrophoresis in the left panel, acid electrophoresis in the center 
panel, and thin-layer isoelectric focusing in the right panel. Locations of the various hemoglobin bands are shown below the left and center panels. (Courtesy 
M.H. Steinberg.)
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Part V Red Blood Cells550
methods for detecting the sickle gene include restriction analysis (Fig. 
40-5), allele-specific hybridization, reverse dot blotting, and allele-
specific fluorescence PCR. PCR-based diagnosis for Hb SC disease 
is possible using specific molecular methods for detecting the Hb C 
gene, and the diagnosis of sickle cell–β-thalassemia can be made using 
reverse dot-blot methodology to screen the many African American 
β-thalassemia mutations, as well as the Hb S and Hb C mutations, 
in a single hybridization reaction.
CLINICAL PRESENTATION AND MANAGEMENT
The cardinal clinical manifestations of SCD are chronic hemolytic 
anemia; recurrent painful episodes; and chronic organ damage, par-
ticularly of the spleen, bones, brain, kidneys, lungs, skin, and heart. 
The pattern of disease manifestation varies among the major geno-
types of Hb SS, Hb SC, and Hb S–β-thalassemia but also within the 
same genotype. Some of this variability results from additional inher-
ited genotypes, for example, α-thalassemia or HPFH (discussed at 
the end of this chapter).
Typically, patients are anemic but lead a relatively normal life 
punctuated by painful episodes. However, it is important to realize 
that chronic organ damage and decreased survival occur even in 
patients who do not have recurrent pain. This section begins with a 
brief overview of natural history and survival followed by a discussion 
of basic management that has as its aim improving this natural history 
(disease modification) and then a discussion of management of 
organ-specific complications.
Natural History and Life Expectancy
The manifestations of disease begin after the first few months of life 
as Hb F levels decline and Hb S levels increase. Certain complications 
predominate in particular age groups. Between the ages of 1 and 3 
years, affected individuals have splenomegaly and splenic sequestra-
tion (Fig. 40-6), pneumonia, and meningitis from Streptococcus pneu-
moniae and other encapsulated organisms (because of functional 
hyposplenism), and hand–foot syndrome; in early childhood, they 
have stroke, acute chest syndrome, and osteonecrosis; in midchild-
hood, they have pain crises, osteonecrosis, and acute chest syndrome; 
between ages 12 and 20 years, they have strokes, priapism, and pain 
The quantity of Hb A is greater than that of Hb S. If the quantity 
of Hb S exceeds that of Hb A, the presumptive diagnosis is sickle 
cell–β+-thalassemia (FSA pattern). It may not be possible to distin-
guish FAS and FSA patterns in newborns, so DNA-based testing or 
repeat Hb testing at age 3 to 6 months is recommended.
Prenatal Diagnosis
One large survey found that parents at risk for having a child with 
SCD were interested in prenatal diagnosis and would consider ter-
mination of pregnancy for an affected fetus.14 Community acceptance 
of reproductive genetic services depends on the effectiveness of educa-
tion and counseling. One major ethical issue pertains to our diagnos-
tic skills’ having outstripped our ability to predict the severity of 
diagnosable conditions.
Fetal DNA samples are obtained by chorionic villus sampling at 
8 to 10 weeks’ gestation. Polymerase chain reaction (PCR)–based 
Figure 40-3 FETAL HEMOGLOBIN (HB F) DECLINE IN CHILDREN 
WITH HEMOGLOBINS AA AND SS. (Data from O’Brien, Mclatosh S, Aspnes 
AT, et al: Prospective study of sickle cell anemia in infancy. J Pediatr 89:205, 1976.)
H
b 
F
 (
%
)
100
80
60
40
20
0
0 10 20 30 40 50 60
Age (wk)
Normal
Sickle cell disease
Figure 40-4 The peculiar elongated shapes of the erythrocytes is what Her-
rick’s intern Ernest E. Irons noted, and together with a report from the 
German literature of sichel formen blood cells, inspired the name by which 
this condition is now known. 
Figure 40-5 POLYMERASE CHAIN REACTION (PCR)–BASED 
RESTRICTION ANALYSIS FOR THE SICKLE CELL GENE. The geno-
types of the DNA samples tested are shown below. The size in base pairs for 
the undigested PCR product and the products resulting from Oxa Nl are 
shown at the left in base pairs. The fragments from normal β-globin DNA 
(AA) shows complete Oxa Nl cleavage, from sickle cell trait DNA (AS) shows 
partial cleavage, and from sickle cell anemia (SS) shows no cleavage. 
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 551
Figure 40-6 THE SPLEEN IN SICKLE CELL DISEASE. Histologic section (A) of the splenic red pulp shows engorgement of the splenic cords with sickled 
cells. In infants, excessive pooling in cords can lead to a splenic sequestration crisis. Later in life, the spleen undergoes autoinfarction. The gross pathology 
(B) shows a tiny 4.5-cm spleen with rough external surface caused by scarring from repeated infarcts. Histologic section reveals classic Gamna-Gandy bodies 
(C and D) also caused by repeated infarction. These are composed of hemosiderin-laden macrophages, calcium deposits, and foreign body giant cells. 
A B C D
Figure 40-7 Life expectancy in patients with sickle cell disease for patients with Hb SS disease (A), Hb SC disease (B), and with different levels of fetal 
hemoglobin (Hb F) (C). (From Platt OS, Brambilla DJ, Rosse WF, et al: Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 
330:1639, 1994.)
1.0
0.9
0.8
0.7
0.6
0.4
0.3
0.2
0.1
0.0
0 10 20 30 40 50 60 70
Age (yr)
P
ro
ba
bi
lit
y 
of
 s
ur
vi
va
l
0.5 Females with SS
Males with SS
Black males
Black females 1.0
0.9
0.8
0.7
0.6
0.4
0.3
0.2
0.1
0.0
0 10 20 30 40 50 60 70
Age (yr)
P
ro
ba
bi
lit
y 
of
 s
ur
vi
va
l
0.5
Females
with SC
Males with SC
1.0
0.9
0.8
0.7
0.6
0.4
0.3
0.2
0.1
0.0
0 1020 30 40 50 60 70
Age (yr)
P
ro
ba
bi
lit
y 
of
 s
ur
vi
va
l
0.5
Hb F <8.6%
Hb F >8.6%
A B C
crises; between ages 20 and 30 years, they have renal insufficiency, 
pulmonary hypertension, disabling osteonecrosis, retinopathy, leg 
ulcers, and pain crises; and at age older than 30 years, they have renal 
failure, congestive heart failure, and pain crises.
Life expectancy is decreased, although in the past 30 years, this 
has dramatically improved for patients in the West. In 1973, Diggs15 
reported that the mean survival was 14.3 years; in 1994, Platt et al16 
reported that life expectancy was 42 years for men and 48 years for 
women with sickle cell anemia (Fig. 40-7). This improvement in 
survival is most likely the result of improved general medical care, 
including prophylactic penicillin therapy and vaccination against S. 
pneumoniae.9 These survival profiles are likely to be relevant even 
today, although a cohort of patients followed since 1975 show 
improvement in the probability of survival to age 20 years compared 
with patients born before 1975 (89% versus 79%).17 The poor sur-
vival and litany of chronic organ damage in survivors emphasize the 
need for disease-modifying interventions to prevent vasculopathy.17 
There are indications that disease-modifying agents such as hydroxy-
urea (HU) can improve survival.18,19
Predictors of Disease Severity
The ability to predict clinical course would allow more rational tailor-
ing of therapy to individual patients (e.g., selection of patients for 
high-risk but effective options such as stem cell transplant). Higher 
Hb F levels and the coinheritance of an α-thalassemia trait have been 
identified as favorable disease modifiers in multiple studies (Table 
40-1).20-22 The level of chronic anemia (which is influenced by the 
presence of an α-thalassemia trait and by Hb F levels) is of 
Table 40-1 Effect of α-Thalassemia on the Level of Anemia in Sickle 
Cell Anemia
Reference αα/αα* −α/αα −α/−α
Embury et al241 7.8† (n = 25)‡ 9.7 (n = 18) 9.2 (n = 4)
Higgs et al242 7.8 (n = 88) 8.1 (n = 44) 8.8 (n = 44)
Steinberg et al243 8.0 (n = 73) 9.0 (n = 39) 9.5 (n = 13)
Felice et al, age 
5 years244
8.6 (n = 88) 8.4 (n = 52) 8.3 (n = 50)
Felice et al, age 
11 years244
7.9 (n = 40) 8.5 (n = 34) 9.6 (n = 2)
*The different α-globin genotypes indicate the presence of four (αα/αα), three 
(−α/αα), or two (−α/−α) α-globin genes.
†The mean hemoglobin level (g/dL) for each group is shown.
‡The number of subjects in each group is denoted by n.
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Part V Red Blood Cells552
Baseline Evaluations
Baseline blood, urine, and other evaluations are directed at quantify-
ing the chronic hemolytic anemia and organ-specific complications 
(Table 40-2). They also provide baseline parameters that can be fol-
lowed to assess response to therapeutic interventions.
In pediatric patients, at least annual assessment of cerebral blood 
flow in the internal carotid artery and the middle or anterior cerebral 
artery using transcranial Doppler ultrasonography (TCD) is recom-
mended. This evaluation is a validated predictor of stroke risk. 
Primary prevention with chronic transfusion is effective in such 
patients.29 In adults, magnetic resonance imaging (MRI) or magnetic 
resonance angiography (MRA) of the brain can be used instead of 
TCD30 to assess thrombotic or hemorrhagic stroke risk, especially in 
those with a history of stroke or seizure. The recognition of cardio-
pulmonary complications as a cause of early mortality in SCD war-
rants evaluation for this condition with either echocardiogram or 
brain natriuretic peptide (BNP) levels. Retinal evaluation is begun at 
school age and continued on an annual basis. More frequent retinal 
evaluations are necessary if retinopathy is noted.
Basic Management and Disease Modification
Sufficient evidence suggests that a number of treatments should be 
considered in all patients. These treatments have been demonstrated 
to decrease symptoms and complications, increase survival, or both 
(Table 40-3) (disease modification). There are other treatments for 
which there are sufficient scientific grounds or clinical data to suggest 
a potential impact on disease natural history. However, there is pres-
ently insufficient clinical data to make firm recommendations (see 
considerable predictive value. Patients with more severe anemia are 
more likely to develop infarctive and hemorrhagic stroke,23 to have 
glomerular dysfunction,24,25 and perhaps to give birth to low-
birthweight babies.26,27 Conversely, they have fewer episodes of acute 
chest syndrome28 and (after age 20 years) a lower mortality rate.28 
Progressive anemia from renal endocrine deficiency or a decrease in 
bone marrow function from vasoocclusion is associated with early 
death.18,19
A number of other genetic polymorphisms may be relevant to 
disease severity, for example, with regards to the risk of stroke. 
However, most of these markers are not widely used to guide decision 
making.21
Principles of Management
The twin pillars of therapy are disease modification (prevention of 
crises, complications, chronic organ damage, and early mortality) and 
compassionate, prompt, effective, and safe relief of acute crises, 
including pain episodes. Therefore, outpatient clinic management is 
mostly directed at initiating measures to prevent pain crises, prevent 
organ complications, and improve survival. This effort should include 
identification of existing organ complications and initiation of mea-
sures to prevent further deterioration. Outpatient management can 
thus be divided into baseline evaluations, basic treatment or disease 
modification, and additional treatment dictated by the organ com-
plications that are identified. The suggested treatments are based on 
current understanding of SCD pathophysiology. As shown in Fig. 
40-8, some treatments address only one aspect of pathophysiology, 
but others may have a broader impact. Inpatient management is 
directed at effective and safe relief of acute crises.
Figure 40-8 WHERE THERAPEUTICS INTERVENE IN THE PATHOPHYSIOLOGICAL CASCADE. Hb, 
Hemoglobin; RBC, red blood cell. 
Deoxygenation
Hb S concentration
Acidosis
RBC rigidity RBC adhesion
Endothelial damage Anemia
Coagulation
pathway activation
Inflammatory
pathway activation
Vasoocclusion
Splenic, cerebral, pulmonary, renal,
muscle, bone, retinal, skin complications
Renal, cardiac,
skin complications
Pulmonary
hypertension
Hemolysis
Hb polymerization
O2
Aspirin?
Vaccination, penicillin, vitamin supplementation, 
analgesia, wound care, laser for retinopathy
Erythropoietin? Antioxidants?
Iron chelation?
 Hb F:
Hydroxyurea, decitabine?,
HDAC inhibitor?
Replace Hb S with Hb A:
Exchange transfusion,
Stem cell transplant
Nitric oxide
Avoid 
dehydration
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 553
Fig. 40-8 and Table 40-3). Although treatments such as vaccination 
and penicillin prophylaxis do not directly affect the sickling process 
or vasculopathy, they have had an impact on survival and therefore 
are included under the umbrella of disease-modifying therapies.
Therapeutic options are further discussed in the sections describ-
ing organ-specific complications.
Vaccination and Penicillin Prophylaxis
Children should be immunized against S. pneumoniae, Haemophilus 
influenzae, hepatitis B, and influenza.31 Vaccination and penicillin 
prophylaxis can reduce the risk of serious pneumococcal infections.9,32 
Vaccination schedules recommend inoculation with heptavalent 
pneumococcal conjugated vaccine (PCV7)at 2 months followed by 
two more doses 6 to 8 weeks apart (primary series) and a booster at 
12 months. This is followed by Pneumovax at age 2 and 5 years. In 
adults, the Pneumovax should be readministered every 5 years (http://
www.cdc.gov/vaccines/pubs/vis/default.htm).
For children younger than age 5 years, prophylactic penicillin 
recommendations are 125 mg penicillin V orally twice daily until age 
2 to 3 years and 250 mg thereafter.31 Penicillin prophylaxis begins at 
2 months. Randomized, double-blind, placebo-controlled studies of 
prophylactic penicillin beginning in infancy, including the prophy-
lactic penicillin or placebo study (PROPS), have found that this 
therapy reduced the incidence of S. pneumoniae bacteremia by 84% 
in children younger than 3 years.9,32 A randomized, double-blind, 
placebo-controlled study, the PROPS II study concluded that it is 
safe to stop prophylactic penicillin therapy at age 5 years in children 
who have not had prior severe pneumococcal infection or splenec-
tomy and are receiving regular follow-up care.33 However, the power 
of the study was restricted by the limited number of S. pneumoniae 
systemic infection events. In an analysis of a patient population 
receiving penicillin prophylaxis and the Pneumovax, the rate of severe 
S. pneumoniae infections was 2.4 per 100 patient-years. This was 
favorable compared with the historical pre-penicillin prophylaxis rate 
of 3.2 to 6.9 per 100 patient-years.34 These measures reduce risk but 
do not remove it. The risk of recurrent S. pneumoniae sepsis and death 
in patients who have had previous sepsis is much increased; all 
patients having a history of pneumococcal sepsis should remain on 
penicillin prophylaxis indefinitely and are not candidates for outpa-
tient management of febrile episodes.35 Parents must be aggressively 
counseled to seek medical attention for all febrile events.
Hydroxyurea and Fetal Hemoglobin Reactivation
The level of Hb F in erythrocytes plays a critical role in determining 
patient outcomes. Individuals who have SCD and another condition 
called HPFH have 70% Hb S in their RBCs but are neither anemic 
nor symptomatic.36 The uniform distribution of Hb F among their 
RBCs interferes with Hb S polymerization, increases its solubility, 
and prevents RBC sickling.37,38 Even at lower levels of Hb F seen in 
patients without HPFH, crisis rate and mortality are inversely pro-
portional to Hb F level.19-22 These findings prompted the idea that 
pharmacologic reactivation of Hb F production might be of benefit 
to patients.
Hydroxyurea is an inhibitor of ribonucleotide reductase and a 
cytotoxic agent that can elevate Hb F levels via an unknown pathway. 
A double-blind, placebo-controlled, intention-to-treat multicenter 
study of HU as treatment of pain crisis in SCD found that HU 
produced definite hematologic changes. HU was started at 0.15 mg/
kg/day and escalated to 0.30 mg/kg/day as tolerated and to maintain 
an absolute neutrophil count no lower than 2000 × 109 L−1. There 
were significant increases in the levels of Hb, Hb F, F cells, F reticu-
locytes, packed cell volume (PCV), and MCV and declines in the 
mean level of leukocytes, polymorphonuclear leukocytes, reticulo-
cytes, and dense sickle cells (Table 40-4).39 The significant clinical 
changes were decreased rate of acute painful episodes, longer interval 
to first and second acute painful episode, fewer episodes of acute chest 
Table 40-2 Baseline Evaluations to Consider
Tests
Blood tests CBC with differential
Reticulocyte count
Hemoglobin electrophoresis
LDH
Renal function tests
Liver function tests
Mineral panel
Serum iron, ferritin, TIBC
Hepatitis B sAg
Hepatitis C antibody
RBC alloantibody screen
RBC typing
D-dimer*
C-reactive protein*
Brain natriuretic peptide
Urine and kidney tests Urinalysis
Renal ultrasonography†
Radiology MRI or MRA brain (adults)‡ or transcranial 
Doppler ultrasonography starting at age 2 
years (children)
Chest radiography§
Hip or shoulder radiograph or MRI (or both)‡
Bone density in teenagers and adults
Cardiology and pulmonary Echocardiogram
Neurocognitive Neurocognitive testing§
LDH, lactate dehydrogenase; MRA, magnetic resonance angiography; MRI, 
magnetic resonance imaging; RBC, red blood cell; sAg, surface antigen; TIBC, 
total iron-binding capacity.
*Consider following as surrogate markers after initiation of disease-modifying 
intervention.
†If hematuria with red blood cells in urine.
‡As clinically indicated.
§If the patient has poor school performance, an abnormal memory, or abnormal 
MRI findings.
Table 40-3 Disease-Modifying Treatments to Consider*
Robust clinical data Penicillin prophylaxis
Streptococcus pneumoniae vaccination
Hydroxyurea
Chronic exchange transfusion
Iron chelation for chronic iron overload†
Limited clinical data Folate supplementation‡
Haemophilus influenzae vaccination
Influenza vaccination
Erythropoietin
Phlebotomy
Experimental Hb F reactivation with decitabine, histone 
deacetylase inhibitors, or imids
Erythropoietin for chronic relative 
reticulocytopenia
Nutritional supplements and antioxidants (e.g., 
glutamine, zinc, multivitamins)
N-acetylcysteine
Hb F, Fetal hemoglobin.
*See text for specific indications and limitations.
†Best data from thalassemia patient experience.
‡Risks minimal (however, can mask vitamin B12 deficiency). Therefore, it is 
generally done.
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http://www.cdc.gov/vaccines/pubs/vis/default.htm
http://www.cdc.gov/vaccines/pubs/vis/default.htm
Part V Red Blood Cells554
neutrophil count <2 × 109 L−1) is not produced. Lower doses may be 
required in patients with renal insufficiency and/or relative reticulo-
cytopenia. The dose is increased to a stable maximum HbF response 
or neutropenia, but most patients receive between 1000 and 2000 mg/
day. Response is defined by clinical symptoms, by a persistent and 
significant (>0.5 g/dL) increase in total Hb or Hb F, and a decrease 
in LDH. These improvements in symptomatology and hematologic 
indices may require at least 3 to 4 months of therapy but can be seen 
as soon as week 6.
In studies of HU as a therapy for children with SCD, the drug was 
well tolerated and produced favorable hematologic changes similar to 
those seen in the adult population.42 In approximately 10% of the 
children treated, the increase in Hb F was less than 2%. Baseline Hb 
F levels, baseline total Hb levels, and compliance were associated with 
the final Hb F level.43 Other studies in children have documented a 
decrease in the number of days of hospitalization and suggest a 
decreased incidence of vasoocclusive crises.44 The favorable changes in 
hematologic indices suggest that HU therapy might be an alternative 
to blood transfusions for the prevention of recurrent stroke in children 
with SCD.45,46 HU therapy appears to lower transcranial Doppler 
velocities in children with SCD.47 Studies in the United States and in 
Belgium support the potential role of HU in the prevention of cere-
brovascular accidents.46,48,49 HU was found to improve, but not correct, 
the abnormal cerebral oxygen saturation associated with SCD.50
A persistent concern pertaining to the use of HU in SCD is its 
putative leukemogenic effect. This concern derives from reports on 
HU treatment of myeloproliferative diseases, conditions associated 
with an inherent propensity for leukemic conversion. Although the 
use of HU combined with 32P or alkylating agents is associated with 
increased leukemic conversion in patients with myeloproliferative 
disease,51 reports claiming a leukemogenic effect for HU alone in 
polycythemia vera either lacked control subjects52 or were not designed 
to assess this issue.53 In children with the nonmalignant underlying 
condition of erythrocytosis secondary to inoperable cyanotic congeni-
talheart disease, no leukemic conversion was observed.54
Vitamin or Nutritional Supplementation
Chronic hemolysis results in increased utilization of folic acid stores. 
Megaloblastic crises from folic acid deficiency have been reported.55,56 
Pediatric patients with SCD had higher homocysteine levels than 
age-matched control African American patients.57 Folic acid, 1 mg/
day orally, is administered as a standard of care.58 Vitamin B12 defi-
ciency can also be seen in patients with SCD. Folate replacement can 
mask and possibly exacerbate vitamin B12 deficiency.59
A growing body of research indicates that sickle cell patients have 
widespread mineral and vitamin deficiencies, including zinc, vitamin 
C, vitamin E, acetylcysteine, calcium, vitamin D, vitamin A, and 
others.60 Fifty percent of children with SCD have evidence of osteo-
porosis or osteopenia that is associated with inadequate calcium and 
vitamin D intake.61-63 Recently, zinc supplementation in a prospective 
trial documented significant improvement in linear growth and 
weight gain in children with SCD.64
Despite increased intestinal absorption of iron in SCD, the com-
bination of nutritional deficiency and urinary iron losses results in 
iron deficiency in 20% of children with SCD.65 The diagnosis of iron 
deficiency may be obscured by the elevated serum iron levels associ-
ated with chronic hemolysis, necessitating the detection of a low 
serum ferritin level or an elevated serum transferrin level for the 
diagnosis.
Transfusion Therapy
The two main approaches to transfusion in SCD are simple transfu-
sion and exchange transfusion. These transfusions can be adminis-
tered in an episodic fashion or in a chronic fashion. Therefore, 
transfusion therapy in SCD is of the following types: episodic simple, 
episodic partial exchange, or chronic partial exchange. In both simple 
syndrome, and diminished number of subjects and units transfused 
(Table 40-5).40 In follow-up analysis, higher pre- or posttreatment Hb 
F levels were associated with a reduction in mortality rate (although 
no significant changes were observed in the incidence of stroke, 
hepatic sequestration, or death in the initial study).18 No short-term 
toxicity caused by HU was observed. One child born to a patient 
taking HU and two born to partners of patients taking HU were 
normal at birth. Although the follow-up analyses suggest the impor-
tance of Hb F to better outcomes, it is possible that some HU-induced 
changes in sickle cell erythrocytes, such as increased water content 
and decreased Hb S concentration,41 may be independent of Hb F.
In the original study, only patients with two or more pain crises 
per year requiring hospitalization were eligible. However, other at-risk 
patients should be considered for HU therapy. These include patients 
with evidence of chronic organ damage, patients with severe anemia 
(unless the reticulocyte count is <250,000 µL−1, in which case con-
sider erythropoietin [EPO] deficiency from renal damage or bone 
marrow suppression that may require alternative treatment), and 
patients with indications for chronic transfusion but who have allo-
antibodies. After obtaining the baseline evaluations per Table 40-2, 
HU is usually started at 500 to 1000 mg/day with monitoring of the 
CBC every 4 to 8 weeks to ensure that neutropenia (absolute 
Table 40-5 Clinical Effects of Hydroxyurea Therapy
Variable Hydroxyurea Placebo P
Acute pain crisis rate 2.5/yr 4.5/yr <.001
Hospitalization rate for acute pain crisis 1.0/yr 2.4/yr <.001
Interval to first pain crisis 3.0 mo 1.5 mo <.001
Interval to second pain crisis 8.8 mo 4.6 mo <.001
Acute chest syndrome 25 51 <.001
Subjects transfused 48 73 .001
Blood units transfused 336 586 .004
Adapted from data in Charache S, Barton FB, Moore RD, et al: Hydroxyurea 
and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. 
The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine 
(Baltimore) 75:300, 1996.
Table 40-4 Hematologic Effects of Hydroxyurea Therapy
Variable Hydroxyurea Placebo P
Leukocytes (103 cells/µL) 9.9 12.2 .0001
PMNs (103 cells/µL) 4.9 6.4 .0001
Reticulocytes (103 cells/µL) 231 300 .0001
Hemoglobin (g/dL) 9.1 8.5 .0009
PCV (%) 27.0 25.1 .0007
MCV (fl) 103 93 .0001
Hb F (%) 8.6 4.7 .0001
F cells (%) 48 35 .0001
(103 cells/µL) 17 15 .0036
Dense sickle cells (%) 11 13 .004
Shown are mean values after 2 years of study. Baseline values, which were not 
significantly different, are not shown.
Hb F, Fetal hemoglobin; MCV, mean corpuscular volume; PCV, packed cell 
volume; PMN, polymorphonuclear leukocyte.
Adapted from Charache S, Terrin ML, Moore RD, et al: Effect of hydroxyurea on 
the frequency of painful crises in sickle cell anemia. Investigators of the 
Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 
332:1317, 1995, with permission.
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 555
group incompatibilities between the recipient and donor pool, which 
often differ in ethnicity.70,71 Antibodies against the C and E antigens 
of the Rh group, Kell (K) and Lewis, Duffy (Fya, Fyb), and Kidd 
(Jk) are common.70 In the Stroke Prevention Trial in Sickle Cell 
Anemia, the routine use of WBC-reduced RBCs matched for E, C, 
and Kell decreased the allosensitization rate compared with historical 
data from 3% to 0.5% per unit transfused and decreased the rate of 
hemolytic transfusion reactions by 90%.72 Therefore, the recom-
mended approach to preventing alloimmunization is to reduce leu-
kocytes and perform limited phenotype matching for all patients 
(ABO, C, D, E, and Kell) and extended phenotype matching for 
patients with alloantibodies.67 The management of a delayed hemo-
lytic transfusion reaction and transfusional iron overload are dis-
cussed under Exacerbations of Anemia later.
Transmission of HIV, hepatitis B and C, and human T-cell 
leukemia/lymphoma virus-1 has diminished with improved screening 
of banked units but remains an issue. In addition to better screening 
programs, the use of leukocyte-depleted RBC transfusions can reduce 
this hazard.73
Stem Cell Transplantation
At this time, allogeneic stem cell transplantation remains the only 
curative option for SCD. The largest series to date has been in a 
pediatric population with severely symptomatic SCD failing to 
respond to HU. Using myeloablative conditioning and human leu-
kocyte antigen (HLA)–matched or one-mismatch (two cases) sibling 
donors, with bone marrow as the source of stem cells in the majority, 
there was a 10% mortality rate with 90% overall survival and 82% 
event-free survival at a median follow-up of 54 months.74 Similar 
results were obtained when related, HLA-matched umbilical cord 
blood was used as the source of stem cells.75 According to these results, 
stem cell transplant is a therapeutic option for the severely symptom-
atic child with an HLA-matched sibling donor. In adults, incorpora-
tion of rapamycin (to induce immunologic tolerance) into 
nonmyeloablative stem cell transplant protocols has enabled stable 
mixed hematopoietic chimerism with associated full-donor erythroid 
engraftment and normalization of blood counts. The attainment of 
tolerance may allow extension of these potentially curative approach 
to alternative donor sources, an active area of research.76,77 The issue 
of the cost-effectiveness of bone marrow transplantation (BMT) gains 
perspective from the comparative costs in the United States of 
$150,000 to $200,000 for an uncomplicated BMT versus up to 
$112,000 annually for conventional medical care of a chronically 
transfused, iron-overloaded patient.78
Education
Education regarding the nature of the disease, genetic counseling, and 
psychosocial assessments of patientsand their families are best accom-
plished during routine visits. Parents of small children are instructed 
regarding early detection of infection and palpating enlarging spleens.
Phlebotomy
As mentioned, an Hb level of more than 10 to 11 g/dL (hematocrit 
30%) in the presence of substantial amounts of Hb S (>30%) is 
associated with hyperviscosity. Some data indicate that phlebotomy 
to reduce the hematocrit and viscosity (and which may also address 
iron-overload) can decrease the frequency of crises in Hb SC or Hb 
S–β+ disease.79 In Hb SS disease, phlebotomy has successfully been 
used in combination with HU (which increases the Hb level) in 
secondary stroke prevention in patients previously treated with 
chronic transfusion.80 Phlebotomy alone has also been used in Hb SS 
disease with baseline Hb levels of more than 9.5 g/dL with favorable 
results on the frequency and duration of pain crises. This benefit may 
have resulted from decreased hematocrit and viscosity and from a 
and exchange transfusion, the target Hb level is 10 to 11 g/dL (hema-
tocrit, 30%).66,67 Transfusing to a higher Hb or hematocrit level is 
avoided because a hematocrit level greater than 30% is associated 
with hyperviscosity if there is a substantial proportion of Hb S in the 
blood. In exchange transfusion, an additional objective is to achieve 
an Hb S percentage of less than 30% (or sometimes <50%). In 
partial-exchange transfusion, a proportion of the patient’s diseased 
RBCs are removed before transfusion of normal donor RBCs; this 
can be done manually through phlebotomy followed by transfusion 
or concurrently using an automated device. In patients who need 
chronic transfusions, partial exchange is recommended because of the 
reduced iron burden of this approach. Partial exchange is also indi-
cated if the baseline Hb level is more than 10 g/dL. Simple transfu-
sion in this instance risks exacerbating the clinical condition through 
increased viscosity. For critical illness, exchange transfusion is also 
preferred. Although the target Hb S level should be less than 30% in 
exchange transfusion, decreasing Hb S levels to less than 50% may 
suffice depending on the severity of the complication being treated.
The volumes required for simple and exchange transfusions (Table 
40-6) are particularly important for transfusing children. For normal-
size adults, the general rule is that each unit of RBCs infused increases 
the Hb level approximately 1 g/dL.68
Episodic simple transfusion should be considered for blood 
volume replacement in aplastic crisis and splenic sequestration crises 
and for protection when there is a more than 20% decrease in Hb 
from baseline from severe illness such as septicemia or severe vasooc-
clusive crisis or hyperhemolysis or Hb levels of less than 5 g/dL. 
Episodic simple or exchange transfusion should be considered for 
acute chest syndrome, priapism, and preoperatively. The choice of 
simple versus exchange transfusion is determined by the pretransfu-
sion total Hb level and the severity of the illness.
In the preoperative setting, simple transfusion to increase the total 
Hb level to 10 g/dL was effective in preventing perioperative com-
plications and was associated with fewer transfusion-associated com-
plications than an aggressive exchange transfusion regimen to decrease 
Hb S levels to less than 30%.69 The efficacy of preoperative partial-
exchange transfusion in patients with Hb SC disease undergoing 
abdominal surgery suggests that this type of transfusion be performed 
preoperatively in this group of patients.
Chronic partial-exchange transfusion is indicated in primary and 
secondary prevention of cerebral thrombosis as discussed in the 
section on neurologic complications.
Transfusion complications include alloimmunization, delayed 
hemolytic transfusion reactions (discussed in Exacerbations of 
Anemia), iron overload, and transmission of viral illness. The inci-
dence of alloimmunization is between 19% and 30% and usually 
occurs with fewer than 15 transfusions.70 Some patients seem to toler-
ate multiple transfusions without developing alloantibodies, but 
others are readily allosensitized. The high rate of alloimmunization 
in transfused sickle cell patients is partly attributable to minor blood 
Table 40-6 Transfusion Formulas
Dilutional effects of transfusion on Hb S: PRBC volume (PRBCV) (mL) = 
(Hctd − Hcti) × TBV × HctrpB
Manual partial-exchange transfusion:* Hb Sf = 1 − (PRBCV × Hctrp)(TBV 
× Hcti) + (PRBCV × Hctrp) × Hb SiC
Automated exchange transfusion: Exchange volume (mL) = (Hctd − Hcti) × 
TBVHctrp − (Hcti + Hctd)2D
RBC volume (mL) = Hcti × TBV
Hctd, desired hematocrit; Hcti, initial hematocrit; Hctrp, hematocrit of 
replacement cells (usually 0.75); Hb Si, initial Hb S; Hb Sf, final Hb S; PRBC, 
packed red blood cells; TBV, estimated total blood volume in milliliters 
(children, 80 mL/kg; adults, 65 mL/kg; nomograms are available).†
*In these formulas, Hct and Hb S are fractions (e.g., 40% = 0.4).
From Nieburg and Stockman, with permission. Copyright 1977, American 
Medical Association.
†From Linderkamp et al, with permission. Copyright 1977, Springer-Verlag.
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Part V Red Blood Cells556
States are deferoxamine (via continuous intravenous or subcutaneous 
infusion) or deferasirox (orally), both of which appear to have similar 
efficacy, although the oral route of administration and toxicity profile 
may favor deferasirox.91,92
Newer U.S. Food and Drug Administration (FDA)–approved 
methods of quantitating iron burden by Ferriscan of the liver93 can 
avoid the need for liver biopsies. T2-weighted MRI of the heart 
indicates hemosiderosis of cardiac tissue, and when the results are 
abnormal, aggressive chelation is mandated.94
Alternatives to Hydroxyurea for Hb F Induction
Alternatives to HU for pharmacologic induction of Hb F that are 
being studied in clinical trials include the methyltransferase inhibitor 
5-aza-2′-deoxycytidine (decitabine) and histone deacetylase inhibi-
ters.95 These classes of agents act on chromatin processes that regulate 
gene transcription.
The methyltransferase inhibitors 5-azacytidine and 5-aza-2′-
deoxycytidine have produced the largest increases in Hb F of any of 
the pharmacologic reactivators of Hb F that have been tested.96,97 
Responding patients include those who did not respond to HU, 
consistent with a different mechanism of action. Although improve-
ments in a number of surrogate clinical endpoints have been dem-
onstrated, larger studies to confirm safety and clinical effectiveness 
with chronic use are required. In the United States, 5-azacytidine and 
decitabine have been approved by the FDA for the treatment of 
myelodysplastic syndrome.
The efficacy of the class of agents known as histone deacetylase 
inhibitors in Hb F reactivation has been reviewed.97-99 However, the 
absence of large clinical trial data, practical issues with administration 
and stability of some agents, and the lack of FDA approval for many 
drugs in this class are limitations.
Preclinical studies suggest that the “imid” class of drugs (analogues 
of thalidomide such as pomalidomide) could have a potential role in 
Hb F reactivation.100
Preventing Red Blood Cell Dehydration With Ion 
Channel Inhibitors
Polymerization of Hb S is related to the Hb S concentration within 
the cell. Therefore, a therapeutic strategy could be to reduce the 
intracellular Hb S concentration by improving cellular hydration. 
Potential therapeutic options to maintain RBC hydration for which 
there are preliminary clinical data include cetiedil citrate, imidazole 
inhibitors of the Gardos pathway,101 novel Gardos channel inhibi-
tors,102 or magnesium supplements, which inhibit potassium chloride 
cotransport.103
It also is possible to reducethe Hb concentration by reducing the 
Hb content with iron deficiency. It has been observed that spontane-
ous or induced iron deficiency (see Phlebotomy above) sufficient to 
reduce the serum ferritin, MCV, and mean cell Hb concentration 
(MCHC) resulted in variably improved Hb S polymerization, RBC 
survival, level of anemia, and clinical status.104
Anticoagulation or Antiplatelet Therapy
Although there is clear evidence of activation of the coagulation 
system in SCD, the role of thrombogenesis in vasoocclusive crisis 
remains unclear.105 Similarly, there have been no thorough evaluations 
of the role of antiplatelet or antithrombotic agents for the treatment 
of SCD. D-dimer levels (a degradation product of cross-linked fibrin) 
increase during acute vasoocclusive crisis.106
Minidose heparin, 5000 to 7500 units every 12 hours, adminis-
tered to four patients for 2 to 6 years reduced hospitalization and 
emergency department time by 75%, and pretreatment pain fre-
quency recurred after heparin was discontinued.107 Larger clinical 
studies will be required to better understand the risks and benefits of 
decrease in intracellular Hb concentration from iron deficiency.81 One 
approach to phlebotomy is to remove approximately 10 mL/kg of 
blood over 20 to 30 minutes followed by infusion of an equal volume 
of normal saline. This is repeated every 2 weeks until the target Hb 
level of 9 to 9.5 g/dL is achieved.
Erythropoietin or Darbepoetin
The chronic hemolytic anemia of SCD is partially compensated by 
vigorous reticulocytosis. A decrease in compensatory reticulocytosis 
will exacerbate already existent anemia and can be expected to increase 
clinical risk. Accordingly, chronic relative reticulocytopenia (defined 
as Hb <9 g/dL and absolute reticulocyte count <250,000 × 109 L−) 
was identified as a significant risk factor for early mortality in a pro-
spective cohort study of SCD patients.82
In the general population, evaluation of EPO levels is usually 
prompted by the combination of anemia and abnormal serum creati-
nine level. EPO levels are then interpreted in relationship to the Hb 
level to assess for the possibility of EPO deficiency. In patients with 
SCD, this approach to diagnosis has pitfalls. Patients with SCD are 
already anemic; therefore, gradual anemia exacerbation is easily 
missed, and clinicians must weigh many possible causes in the context 
of complex, multisystem SCD pathology. Furthermore, patients with 
SCD have low serum creatinine levels at baseline. Therefore, a sub-
stantial increase in serum creatinine from baseline may nonetheless 
remain below the threshold defined as abnormal for the general 
population, potentially disguising the presence of renal damage that 
is sufficient to decrease renal endocrine function. Furthermore, EPO 
levels are not readily interpreted in the individual SCD patient: EPO 
levels in SCD are generally low for the level of hemoglobin.83 One 
contributing factor could be increased uptake by the massive com-
pensatory reticulocytosis. However, EPO levels are lower in SCD 
adults than in children,83 and EPO levels are inappropriately lower in 
patients with chronic relative reticulocytopenia.19 Hence, EPO defi-
ciency should be considered as a possible cause of progressive anemia 
in patients with absolute reticulocyte counts below 250,000 × 109 L− 
even if their serum creatinine levels are in the normal range. The 
cumulative published experience of EPO use in SCD is limited (52 
patients).84 Although EPO by itself has been reported to increase Hb 
F levels, the most important role for EPO may be as replacement 
therapy for EPO deficiency that causes relative reticulocytopenia and 
progressive anemia. EPO replacement can also facilitate enhanced 
HU dosing and Hb F augmentation.84 In using recombinant human 
EPO, caution must be exercised not to elevate the hematocrit to levels 
that result in hyperviscosity. Also, the reticulocyte fraction is the 
most adhesive, and it is possible that EPO could exacerbate or trigger 
sickle cell crises.84 Patients with SCD may be relatively resistant 
to EPO and require doses higher than those used in other patients 
with chronic renal failure. The reasons for EPO resistance are unclear 
but may include increased inflammation-mediated suppression of 
erythropoiesis.85
Erythropoietin therapy is probably not indicated in patients 
receiving chronic transfusion therapy in whom encouraging endog-
enous Hb S containing erythropoiesis may be counterproductive.
Iron Chelation
Early death is well described in association with iron overload from 
β-thalassemia and hereditary hemochromatosis.86,87 Similarly, iron 
overload is likely to be a problem in chronically transfused SCD 
patients, although the clinical significance may critically depend on 
the degree and duration of overload. Chelation guidelines for patients 
with SCD are similar to those for other chronically transfused, iron-
overloaded patients; iron chelation is indicated when the total body 
iron level is elevated (ferritin >2000 mcg/L, quantitative liver iron of 
2000 mcg/g dry weight, transfusion history >1 year of monthly trans-
fusions).88 Notably, the serum ferritin level may underestimate clini-
cally significant iron overload.89,90 Iron chelation options in the United 
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 557
immunoglobulin G conjugate), agents that increase the production 
of nitric oxide (NO) (glutamine), and herbal extracts with unknown 
mechanisms of action (Niprisan).112
Specific Complications and Their Management
Pain Crisis
Acute Pain Episode or Crisis
Acute pain is the first symptom of disease in more than 25% of 
patients and is the most frequent symptom after age 2 years.113 Pain 
is the complication for which patients with SCD most commonly 
seek medical attention.114 An episode of acute pain was originally 
called a “sickle cell crisis” by Diggs, who used the expression “crisis” 
to refer to any new rapidly developing syndrome in the life of a 
patient with SCD.115 The basic mechanism is believed to be vasooc-
clusion of the bone marrow vasculature causing bone infarction, 
which in turn causes release of inflammatory mediators that activate 
afferent nociceptors.116
Although a general correlation of vasoocclusive severity and geno-
type has been posited,117 there is tremendous variability within geno-
types and in the same patient over time. In one large study of patients 
with Hb SS disease, one-third rarely had pain, one-third were hospi-
talized for pain approximately two to six times per year, and one-third 
had more than six pain-related hospitalizations per year.118 Over a 
5-year period in the National Cooperative Study of SCD, 40% of 
patients had no painful episodes, and 5% of patients accounted for 
one-third of the emergency department visits. Pain is more frequent 
with the Hb SS genotype, low levels of Hb F, higher Hb levels,28 and 
sleep apnea.119 The frequency of pain peaks between ages 19 and 39 
years. After the age of 19 years, more frequent pain correlates with a 
higher mortality rate.28 Medical personnel who see patients only in 
the emergency department gain a biased view of SCD skewed by a 
frequently affected minority with severe disease.120,121
Pain may be precipitated by events such as cold, dehydration, 
infection, stress, menses, and alcohol consumption. Any underlying 
cause should be searched for and corrected, but the majority of 
painful episodes have no identifiable cause. Pain can affect any area 
of the body, most commonly the back, chest, extremities, and 
abdomen; may vary from trivial to excruciating; and is usually 
endured at home without a visit to the emergency department. There 
may be premonitory symptoms.121 The duration averages a few days,with hospital admissions typically lasting between 4 and 10 days. 
Painful episodes are biopsychosocial events caused by vasoocclusion 
in an area of the body having nociceptors and nerves.116 Pain is an 
effect and, as such, consists of sensory, perceptual, cognitive, and 
emotional components. Frequent pain generates feelings of despair, 
depression, and apathy that interfere with everyday life and promote 
an existence that revolves around pain. This scenario may lead to a 
chronic debilitating pain syndrome; fortunately, this is rare.
There is no specific clinical or laboratory finding pathognomonic 
of pain crisis. The diagnosis is established by history and physical 
examination. Changes in steady-state Hb values, sickled cells on blood 
smear, WBC counts, and so on are not reliable indicators. Numerous 
laboratory tests, leukocytosis, D-dimer fragments of fibrin, and 
markers of platelet activation have been found to lack specificity as 
indicators of acute vasoocclusion. Often patients can tell if they are 
having a typical pain crisis or something more sinister. It is thus good 
practice to ask the patient if it feels like usual pain crisis pain.
Initial medical assessment should focus on detection of triggers or 
medical complications requiring specific therapy, which include 
infection, dehydration, acute chest syndrome (fever, tachypnea, chest 
pain, hypoxia, and chest signs), severe anemia, cholecystitis, splenic 
enlargement, neurologic events, and priapism.122 Pain management 
should be aggressive to make the pain tolerable and enable patients 
to attain maximum functional ability. To make the patient pain free 
is an unrealistic goal and risks oversedation and hypoventilation, 
which must be avoided. A pain chart should be started and analgesia 
titrated against the patient’s reported pain together with medical 
heparin therapy for acute vasoocclusive crisis in SCD. Heparin has 
not been studied for acute arterial stroke in patients with SCD but 
has a role in SCD-associated dural venous sinus thrombosis.108 The 
management of stroke is fully discussed under Specific Complications 
and Their Management.
Acenocoumarol was administered in low doses that achieved a 
mean international normalized ratio (INR) of 1.64 and reduced the 
elevated levels of prothrombin activation fragment (fragment 1+2) to 
50% of pretreatment levels.109 Clinical endpoints were not measured. 
In a crossover study, 29 patients were treated with acenocoumarol to 
target an INR of 1.6 to 2.0. No effect on crisis frequency was noted, 
although again, there were significant reductions in markers of coagu-
lation system activation.110 In 37 acutely ill sickle cell patients with 
elevated D-dimers, the effect of low-dose warfarin therapy (1 mg 
without a target INR) in 12 of them was examined. In multivariate 
analysis, low-dose warfarin was the only variable associated with a 
significant decrease in D-dimer levels, suggesting a warfarin-induced 
decrease in thrombin activity.106 Therefore, oral anticoagulation, even 
at low doses, is associated with a decrease in laboratory markers of 
coagulation pathway activation in SCD; however, further clinical 
trials are required to understand the clinical risks and benefits.
Aspirin was compared with placebo in 49 pediatric SCD patients 
in a double-blind crossover study. The frequency and severity of crises 
were not affected by aspirin therapy.111 Cerebral thrombosis, which 
accounts for 70% to 80% of all cerebrovascular accidents (CVAs) in 
SCD, results from large-vessel occlusion (Fig. 40-9) rather than the 
more typical microvascular occlusion of SCD. In the United States, 
there is an ongoing clinical trial testing the safety and efficacy of 
aspirin in diminishing the incidence and progression of cognitive 
defects and overt or silent stroke in pediatric patients.
The management of stroke risk and stroke is fully discussed under 
Specific Complications and Their Management.
Experimental Therapies
A number of therapies are in the early stages of clinical evaluation 
and could have a role in disease modification of SCD. These include 
agents that directly address sickle erythrocyte adhesion to endothe-
lium (recombinant P-selectin glycoprotein ligand-1 [PSGL]–
Figure 40-9 Right common carotid arteriogram taken in anteroposterior 
projection demonstrating complete occlusion of the origin of the right ante-
rior cerebral artery (arrowhead). (From Stockman JA, Nigro MA, Mishkin MM, 
Oski FA: Occlusion of large cerebral vessels in sickle-cell anemia. N Engl J Med 
287:846, 1972.)
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Part V Red Blood Cells558
assessment of the patient’s overall clinical status, paying particular 
attention to avoiding oversedation. When clinicians consistently 
observe a disparity between patients’ verbal self-report of their pain 
and their ability to function, further assessment should be performed 
to ascertain the reason for disparity. Patients are often undertreated 
for pain because many physicians and other health care providers are 
overly concerned with the potential for addiction. Undertreatment 
of pain is no more desirable than overtreatment and oversedation; 
undertreatment can prolong the duration of a painful episode and 
can poison the relationship between the patient and the health care 
system. In assessing patient responses to conventional doses of anal-
gesia, it must be remembered that individuals with SCD metabolize 
narcotics rapidly.123
The pain pathway should be targeted at different points with dif-
ferent agents, avoiding toxicity with any one class (Table 40-7). The 
mainstays are nonsteroidal antiinflammatory drugs (NSAIDs), acet-
aminophen, and opioids. NSAIDs can be used to control mild to 
moderate pain and may have an additive role in combination with 
opioids for severe pain. The most potent NSAID is ketorolac. 
NSAIDs should be used with caution in those with a history of peptic 
ulcer, renal insufficiency, asthma, or bleeding tendencies. Within 
limits, use the agents that the patients know work for them and avoid 
meperidine (Demerol), which should only be used under very excep-
tional circumstances. Sedatives and anxiolytics alone should not be 
used to manage pain because they can mask the behavioral response 
to pain without providing analgesia.
Treatment of persistent or moderate to severe pain should be based 
on increasing the opioid strength or dose.122 One approach is to 
Table 40-7 Recommended Dose and Interval of Analgesics Necessary to Obtain Adequate Pain Control in Patients With Sickle Cell Disease
Dose/Rate Comments
Severe to Moderate Pain
Morphine Parenteral: 0.1-0.15 mg/kg every 3-4 hr
Recommended maximum single dose, 10 mg
PO: 0.3-0.6 mg/kg every 4 hr
Drug of choice for pain; lower doses in elderly adults and infants and 
in patients with liver failure or impaired ventilation
Meperidine Parenteral: 0.75-1.5 mg/kg every 2-4 hr
Recommended maximum dose, 100 mg
PO: 1.5 mg/kg every 4 hr
Increased incidence of seizures; avoid in patients with renal or 
neurologic disease and those who receive MAOIs
Hydromorphone Parenteral: 0.01-0.02 mg/kg every 3-4 hr
PO: 0.04-0.06 mg/kg every 4 hr
Oxycodone PO: 0.15 mg/kg/dose every 4 hr
Ketorolac IM: Adults: 30 or 60 mg initial dose followed by 15-30 mg; 
children: 1 mg/kg load followed by 0.5 mg/kg every 6 hr
Equal efficacy to 6 mg MS; helps narcotic-sparing effect; not to 
exceed 5 days; maximum, 150 mg first day, 120 mg maximum on 
subsequent days; may cause gastric irritation
Butorphanol Parenteral: Adults: 2 mg every 3-4 hr Agonist–antagonist; can precipitate withdrawal if given to patients who 
are being treated with agonists
Mild Pain
Codeine PO: 0.5-1 mg/kg every 4 hr
Maximum dose, 60 mg
Mild to moderate pain not relieved by aspirin or acetaminophen; can 
cause nauseaand vomiting
Aspirin PO: Adults: 0.3-6 mg every 4-6 hr; children: 10 mg/kg every 
4 hr
Often given with a narcotic to enhance analgesia; can cause gastric 
irritation; avoid in febrile children
Acetaminophen PO: Adults: 0.3-0.6 g every 4 hr; children: 10 mg/kg Often given with a narcotic to enhance analgesia
Ibuprofen PO: Adults: 300-400 mg every 4 hr; children: 5-10 mg/kg every 
6-8 hr
Can cause gastric irritation
Naproxen PO: Adults: 500 mg/dose initially and then 250 every 8-12 hr; 
children: 10 mg/kg/day (5 mg/kg every 12 hr)
Long duration of action; can cause gastric irritation
Indomethacin PO: Adults: 25 mg every 8 hr; children: 1-3 mg/kg/day given 3 
or 4 times
Contraindicated in psychiatric, neurologic, renal diseases; high 
incidence of gastric irritation; useful in gout
IM, Intramuscular; MAOI, monoamine oxidase inhibitor; MS, morphine sulphate; PO, oral.
Adapted from Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter 
Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 332:1317, 1995.
administer morphine 0.1 mg/kg intravenously or subcutaneously 
every 20 minutes until pain is controlled. The patient should be 
checked at 20-minute intervals for pain; respiratory rate, depth, 
and quality; and sedation until the patient is stable with adequate 
pain control. Subsequently, the patient should receive a maintenance 
dose of 0.05 to 0.15 mg/kg intravenously or subcutaneously every 
2 to 4 hours. A rescue dose of 50% of the maintenance dose can 
be considered on an as-needed basis every 30 minutes for break-
through pain.
During maintenance with opioids, pain control; respiratory rate, 
depth, and quality; and oxygen saturation should be monitored 
approximately every 2 hours. If respiratory depression is noted, omit 
the maintenance dose of morphine. For severe respiratory depression 
or oxygen desaturation, administer naloxone. Incentive spirometry 
and mandatory time out of bed are helpful in patients with chest pain 
to decrease the risk for hypoventilation. Adjuvant medications to 
consider include NSAIDs, acetaminophen, antiemetics, and antihis-
tamines. Laxatives or stool softeners should be prescribed in keeping 
with close monitoring for constipation.
After 2 to 3 days, consider decreasing the dose and switching from 
parenteral to oral administration of opioids. For adult patients whose 
pain requires several or many days to resolve, a sustained-release 
opioid preparation is appropriate and provides a more consistent 
analgesia.
Hydration is a critical part of management. However, cardiac 
function may be significantly impaired, especially in adult patients, 
and standard discipline must be followed with intravenous fluid 
management to avoid iatrogenic fluid overload. SCD patients cannot 
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 559
long-acting morphine preparations similar to those used in cancer 
patients) is important to maintain the psychosocial functioning of 
patients who do have complications that cause chronic pain. Also 
consider agents such as amitriptyline or antiseizure medications124 
that can address neuropathic components and help decrease the sleep 
impairment and depression that can occur with chronic pain. If the 
patient is not taking a disease-modifying agent such as HU, consid-
eration should be given to initiating such therapy.
Chronic Anemia
Chronic hemolytic anemia is one of the hallmarks of SCD. Sickle 
erythrocytes are destroyed randomly, with a mean life span of 17 
days.125 The overall hemolytic rate reflects the number of ISCs.126 The 
degree of anemia is most severe in sickle cell anemia, and Hb S–β°-
thalassemia, milder in Hb S–β+-thalassemia and Hb SC disease,127 
and, among patients with sickle cell anemia, less severe in those who 
have coexistent α-thalassemia (Tables 40-8 and 40-1).128
As already noted, EPO deficiency from otherwise subclinical 
chronic renal damage may also contribute to a decline in Hb levels 
below baseline. The level of chronic anemia is a significant prognostic 
marker.19
The treatment options for the chronic anemia of SCD have 
already been mentioned. These strategies attempt to decrease hemo-
lysis by increasing Hb F (HU and the experimental approaches with 
EPO, decitabine, and histone deacetylase inhibitors) or decreasing 
the intracellular Hb S concentration by preventing RBC dehydration 
(Gardos channel inhibitors).
Exacerbations of Anemia
The rather constant level of hemolytic anemia may be exacer-
bated by additional events such as aplastic crises, acute splenic 
concentrate their urine and are at risk for dehydration when not 
taking adequate fluids (60 mL/kg/24 hr in adults). Intravenous 
hydration is indicated when the patient is not taking oral fluids 
adequately. Ideally, the urine specific gravity should be kept under 
1.010 by daily testing when in the hospital. Hb may decrease by 1 
to 2 g/dL in an uncomplicated pain crisis; blood transfusion is not 
routinely indicated for an uncomplicated pain crisis.
Equianalgesic doses of oral opioids should be prescribed for home 
use when necessary to maintain the relief achieved in the emergency 
department or hospital ward. Care should be taken to appropriately 
taper opioids in patients who have received daily opioids over many 
days. In these patients, there may be physical opiate dependence, 
which is characterized by the onset of acute withdrawal symptoms 
upon cessation of opioid administration. For patients at risk for physi-
cal dependence, opiates should be titrated downward by 15% to 20% 
per day to zero. Physical dependence is a physiological problem, but 
addiction is a psychological problem characterized by craving—
behavior that is overwhelmingly directed at obtaining the drug; use of 
the drug for purposes other than pain control; and use of the drug 
despite negative physical, social, legal, or psychological consequences.
If the patient is not taking a disease-modifying agent such as HU, 
consideration should be given to initiating such therapy either as an 
inpatient or during follow-up in the outpatient setting.
Chronic Pain
Chronic pain in SCD usually (but not always) has an identifiable 
basis such as vertebral fractures, femoral head necrosis, early degen-
erative changes or osteoarthritis, or chronic skin ulcers. Most patients 
without such identifiable complications do not require chronic pain 
medications similar to those used for terminal cancer because the pain 
from a typical vasoocclusive crisis is episodic. Inappropriately main-
taining patients without chronic musculoskeletal degeneration on 
long-acting opiates can impair their overall psychosocial functioning. 
On the other hand, adequate analgesia with long-acting opiates (e.g., 
Table 40-8 Bacteria and Viruses That Most Frequently Cause Serious Infection in Patients With Sickle Cell Disease
Microorganism Type of Infection Comments
Streptococcus pneumoniae Septicemia Common despite prophylactic penicillin and pneumococcal vaccine
Meningitis Less frequent than in years past
Pneumonia Rarely documented except in infants and young children
Septic arthritis Uncommon
Haemophilus influenzae type b Septicemia
Meningitis
Pneumonia Much less common in recent years 
because of immunization with conjugate 
vaccine
Salmonella species Osteomyelitis
Septicemia Most common cause of bone and joint 
infection
Escherichia coli and other gram-negative 
enteric pathogens
Septicemia
Urinary tract infection
Osteomyelitis Focus sometimes inapparent
Staphylococcus aureus Osteomyelitis Uncommon
Mycoplasma pneumoniae Pneumonia Pleural effusions; multilobe involvement
Chlamydia pneumoniae Pneumonia
Parvovirus B19 Bone marrow suppression(aplastic crisis) High fever common; rash and other organ involvement infrequent
Hepatitis viruses (A, B, and C) Hepatitis Marked hyperbilirubinemia
Data from Buchanan GR, Glader BE: Benign course of extreme hyperbilirubinemia in sickle cell anemia: Analysis of six cases. J Pediatr 91:21, 1977.
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Part V Red Blood Cells560
and sometimes hypovolemia.134 The LDH level may remain stable or 
increase. Patients susceptible to this complication are those whose 
spleens have not undergone fibrosis—young patients with sickle cell 
anemia and adults with Hb SC disease or sickle cell–β+-thalassemia. 
Sequestration may occur as early as a few weeks of age and may cause 
death before SCD is diagnosed. In one study, 30% of children had 
splenic sequestration over a 10-year period and 15% of the attacks 
were fatal.135
The basis of therapy is to restore blood volume and RBC mass. 
Because splenic sequestration recurs in 50% of cases, splenectomy is 
recommended after the event has abated. Alternatively, chronic trans-
fusion therapy is used in young children to delay splenectomy until 
it can be tolerated safely. Because recurrence is possible during trans-
fusion therapy, parents should be trained to detect a rapidly enlarging 
spleen and to seek immediate medical attention in this event. Less 
common sites of acute sequestration include the liver and possibly 
the lung.136,137
Delayed Hemolytic Transfusion Reaction 
and Autoimmune Hemolytic Anemia
Approximately 30% of patients are predisposed to develop alloanti-
bodies, in part because of minor blood group incompatibilities 
in racially mismatched blood.71,72 The corollary is that the other 
patients can receive multiple transfusions without demonstrating 
alloantibodies. After alloimmunization, there is a subsequent 
decrease in antibody titer that can fall below serologically detectable 
levels. Therefore, antigen-positive RBCs appear compatible in 
cross-matching and are transfused. This can result in a delayed hemo-
lytic transfusion reaction produced by the amnestic response of the 
immune system (as opposed to the immediate hemolytic reaction 
that occurs with preformed antibody). The delayed hemolytic trans-
fusion reaction consists of an unexplained fall in Hb, elevated LDH 
level, elevated bilirubin above baseline, and hemoglobinuria, all 
occurring between 4 and 10 days after the RBC transfusion. Delayed 
hemolytic reactions and hyperhemolysis have been shown to occur 
in 11% of pediatric patients with SCD and a history of alloantibod-
ies.138 In SCD, the delayed hemolytic transfusion reaction can be 
particularly devastating because it can be accompanied by reticulocy-
topenia, which together with a bystander effect of destruction of 
recipient blood (not just donor blood) can result in unanticipated 
worsening of anemia to levels below that seen before transfusion.139 
In addition to the manifestations of a delayed hemolytic transfusion 
reaction as listed, patients may develop acute congestive heart failure, 
acute renal failure, or acute chest syndrome (accompanied by vasooc-
clusive pain crisis). Subsequent transfusions may further exacerbate 
the anemia.
sequestration, acute hepatic sequestration, chronic renal disease, or 
renal endocrine deficiency that may be present without overt renal 
failure, bone marrow necrosis, deficiency of folic acid or iron, delayed 
hemolytic transfusion reactions, autoimmune hemolytic anemia, or 
hyperhemolysis (hemolytic exacerbations) of unknown etiology. Lab-
oratory evaluations that are very useful in the evaluation of a patient 
with anemia exacerbation are the reticulocyte count, LDH, alloanti-
body screening, the direct antiglobulin (Coombs) test, and EPO level.
Aplastic Crises
Aplastic crises are transient arrests of erythropoiesis characterized by 
abrupt falls in Hb levels, reticulocyte number, and RBC precursors in 
the bone marrow without necessarily an increase in the LDH. 
Although these episodes typically last only a few days, the level of 
anemia may be severe because the hemolysis continues unabated in 
the absence of RBC production. Although the mechanisms that 
impair erythropoiesis in inflammation are operative in infections of all 
types (see Chapter 24), human parvovirus B19 specifically invades 
proliferating erythroid progenitors, which accounts for its importance 
in SCD (see Chapters 19 and 24).129 Parvovirus B19 (Fig. 40-10) 
accounts for 68% of aplastic crises in children with SCD,130 but the 
high incidence of protective antibodies in adults makes parvovirus a 
less frequent cause of aplasia in this age group (see also Infections later 
in this chapter). Other reported causes of transient aplasia are infec-
tions by S. pneumoniae, salmonella, streptococci, and Epstein-Barr 
virus. Bone marrow necrosis, which also may be the result of parvovi-
rus infection, characterized by fever, bone pain, reticulocytopenia, and 
a leukoerythroblastic response, also causes aplastic crisis.131,132
Inhaled oxygen therapy also causes transient RBC hypoproduc-
tion; supraphysiologic oxygen tensions curtail EPO production 
promptly and suppress reticulocytosis within 2 days.133
The mainstay of treating aplastic crises is RBC transfusion. When 
transfusion is necessitated by the degree of anemia or cardiorespira-
tory symptoms, a single transfusion usually will suffice because reticu-
locytosis resumes spontaneously within a few days. Transfusion may 
be avoided by keeping severely anemic patients on bed rest to prevent 
symptoms and by avoiding supraphysiologic oxygen tensions. A 
useful guideline for transfusion in the context of an aplastic crisis is 
the reticulocyte count. A patient having an aplastic crisis with a 
reticulocyte count that is recovering is less likely to require urgent 
transfusion than one with a normal or low absolute reticulocyte 
count.
Sequestration Crisis (Spleen or Liver)
Acute splenic sequestration of blood is characterized by acute exacer-
bation of anemia; persistent reticulocytosis; a tender, enlarging spleen; 
Figure 40-10 PARVOVIRUS. Bone marrow aspirate in a patient with sickle cell disease and aplastic crisis (A). Note the absence of red blood cell precursors 
except for the single, large degenerating pronormoblast (lower center). Such pronormoblasts contain large nuclear inclusions (B) as a result of replication of 
parvovirus B19. The same can be seen in the tissue sections of a bone core biopsy (C and D). The parvovirus can now be recognized immunohistochemically 
with an immunostain (E). 
A B C E
D
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Chapter 40 Sickle Cell Disease: Clinical Features and Management 561
Table 40-9 Organ-Related Infection in Sickle Cell Disease
Primary Sites of 
Infection
Most Common 
Pathogen(s) Other Pathogens Pathophysiology Prevention Management
Septicemia Streptococcus 
pneumonia
Haemophilus influenza type b
Escherichia coli
Salmonella spp.
Defective splenic function; 
deficiency of opsonic 
antibody
Vaccines*
Prophylactic penicillin
Empiric intravenous 
antibiotics for fever
Meningitis S. pneumoniae Same as for septicemia
Osteomyelitis and 
septic arthritis
Salmonella spp.
S. pneumonia
E. coli
Proteus spp.
Staphylococcus aureus
— Surgical drainage, 
intravenous antibiotics
Pneumonia Mycoplasma 
pneumoniae
Respiratory 
viruses
Chlamydia pneumoniae
S. pneumoniae
Vaccines* See pulmonary and therapy 
sections for management 
of acute chest syndrome.
*Against Streptococcus pneumoniae and Haemophilus influenzae type b.
serum opsonizing activity. Even before the anatomic autoinfarction 
of the spleen in patients with sickle cell anemia, defective