these patients develop progressive liver disease secondary to
hepatic accumulation of protoporphyrin. Liver transplantation
can become necessary.
Therapy is often beneficial with oral β-carotene1 (up to 400 mg/
day for adults). This leads to a harmless slight orange-yellow dis-
coloration of the skin and often effective sun protection. Ideally,
the β-carotene dose should be adjusted to a plasma level between
11 and 15 mmol/L.
1 an individualized intravenous opiate regimen, as well as sup-
Not FDA approved for this indication.
References
American Porphyria Foundation Home page. Available at: http://www.
porphyriafoundation.com (accessed August 5, 2015).
Anderson KE, Bonkovsky HL, Bloomer JR, Shedlofsky SI: Reconstitution of hematin
for intravenous infusion, Ann Intern Med 144:537–538, 2006.
Anderson KE, Bloomer JR, Bonkovsky HL, et al: Recommendations for the
diagnosis and treatment of the acute porphyrias, Ann Intern Med 142:439–450,
2005.
Anderson KE, Sassa S, Bishop DF, et al: Disorders of heme biosynthesis: X-linked side-
roblastic anemia and the porphyrias. In Scriver CR, Beaudet AL, Sly WS, et al, edi-
tors: The Molecular and Metabolic Bases of Inherited Disease, 8th ed., vol. 1, New
York, 2001, McGraw-Hill, pp 2961–3062.
Badminton MN, Elder GH: Management of acute and cutaneous porphyrias, Int J
Clin Pract 56:272–278, 2002.
Balwani M, Desnick RJ: The porphyrias: advances in diagnosis and treatment, Blood
120(23):4496–4504, 2012. https://doi.org/10.1182/blood-2012-05-423186 Epub
2012 Jul 12. Review. Erratum in: Blood. 2013;122(17):3090.
Bissell DM, Anderson KE, Bonkovsky HL: Porphyria, N Engl J Med 377(9):862–872,
2017.
Chemmanur AT, Bonkovsky HL: Hepatic porphyrias: Diagnosis and management,
Clin Liver Dis 8:807–838, 2004.
European Porphyria Initiative. Home page. Available at: http://www.porphyria-
europe.com/ (accessed August 5, 2015).
Kauppinen R: Porphyrias, Lancet 365:241–252, 2005.
VI Hematology
Puy H, Gouya L, Deybach JC: Porphyrias, Lancet 375:924–937, 2010.
SICKLE CELL DISEASE
Method of
Enrico M. Novelli, MD; Mark T. Gladwin, MD; and Lakshmanan
454 Krishnamurti, MD
CURRENT DIAGNOSIS
• Sickle cell disease (SCD) is diagnosed by neonatal screening in
the United States.
• Persons with congenital hemolytic anemia should be tested for
SCD by hemoglobin electrophoresis regardless of their ethnic
background.
• Infection with parvovirus B19 should be suspected in children
presenting with acute anemia and reticulocytopenia.
• Human leukocyte antigen (HLA) class I and II testing should be
performed in all patients with SCD and unaffected siblings to
identify candidates for hematopoietic stem cell transplant.
• Transcranial Doppler screening for primary prevention of stroke
is indicated in children with homozygous SCD.
• Acute chest syndrome is diagnosed in patients presenting
with fever, hypoxemia, and a radiographic pulmonary
infiltrate.
• Screening for iron overload by ferritin, quantitative liver
magnetic resonance imaging (MRI), cardiac MRI, or liver
biopsy is indicated in all patients who have received
more than 10 lifetime transfusions.
• Pulmonary hypertension screening by transthoracic
echocardiogram is indicated in all patients with
homozygous SCD.
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CURRENT THERAPY
• All children with SCD should receive penicillin prophylaxis.
• High fever should be treated empirically with coverage for
Streptococcus pneumoniae pending results of blood cultures.
• Children with high transcranial Doppler velocity need to be
placed on a chronic transfusion regimen to keep the hemo-
globin (Hb) S less than 30%.
• Painful vaso-occlusive episodes warrant prompt treatment with
portive care and incentive spirometry.
• Preoperative transfusion should aim at a target hemoglobin
level of 10 g/dL regardless of the HbS percentage and is indi-
cated in all patients with SCD undergoing major surgery.
• Therapy with hydroxyurea is indicated in all patients at all ages
with HbSS disease and HbSβ-thalassemia, and in patients with
HbSC with a severe phenotype on a case-by-case basis.
• Erythropoietin-stimulating agents can be used in conjunction
with hydroxyurea to prevent or ameliorate reticulocytopenia
and in patients with underlying renal insufficiency.
• Iron chelation is indicated in all patients with findings of iron
overload.
• Treatment of acute chest syndrome includes parenteral antibi-
otics to cover atypical microorganisms and transfusion, with
exchange transfusion reserved for the most severe cases.
• Patients with pulmonary hypertension should receive optimal
hematologic care (maximal hydroxyurea and/or chronic trans-
fusion therapy) and specific therapy for pulmonary hyperten-
sion in severe cases, with coordination and referral to a
pulmonary hypertension specialist.
• Stem cell transplantation should be offered to all patients who
have a matched donor and display a severe phenotype.
Epidemiology
SCD affects 70,000 to 100,000 persons in the United States and
millions worldwide. The hemoglobin (Hb) S mutation arose in
West-Central Africa approximately 7300 years ago and then prop-
agated to vast tropical and subtropical areas due to the selective
pressure of malaria infection. It is predominantly found in persons
of African, Mediterranean, Arab, or Indian ancestry. In the United
States, approximately 1 in 15 African Americans harbors the HbS
(sickle hemoglobin) mutation and 1 in 400 is affected by the dis-
ease. Most patients with SCD in the United States are homozygous
for HbS (SS), with heterozygous HbSC being the second most com-
mon abnormality. Conversely, in Mediterranean countries, HbS/β-
thalassemia is the most common SCD syndrome, and in the Arab
peninsula HbSS in combination with hereditary persistence of fetal
hemoglobin (HPFH) is particularly prevalent.
Pathophysiology
SCD consists of a group of inherited hemoglobinopathies charac-
terized by a qualitatively abnormal hemoglobin molecule that
affects the structure and integrity of the red blood cells (RBCs).
SCD is an autosomal recessive disease due to homozygosity for
HbS, characterized by a single base substitution in the β-globin
gene of the hemoglobin tetramer, leading to an amino acid substi-
tution (valine to glutamic acid), or coinheritance of HbS with other
abnormal hemoglobins such as hemoglobin C, D, E, and O or β-
thalassemia.
HbS is less soluble than normal hemoglobin (HbA) in the deox-
ygenated state and polymerizes when sickle RBCs are exposed to
hypoxic conditions in the microcirculation. In the classic patho-
physiologic explanation of SCD, sickled RBCs containing HbS
polymers are less deformable and remain trapped in the microcir-
culation, causing end-organ ischemia and necrosis. Compounding
this mechanism, more recent literature has emphasized the role of
cellular adhesion, abnormal cytokine levels, ischemia-reperfusion
injury, oxidative damage, sterile inflammation, and an abnormal
endothelial milieu. HbS polymers also lead to deformity and fragil-
ity of the RBC membrane, with resulting intra- and extravascular
hemolysis.
Patients with SCD suffer from severe chronic hemolytic anemia
and acute episodes of RBC trapping and destruction in the micro-
vasculature (vaso-occlusive episodes). Vaso-occlusive episodes are
the hallmark of SCD and are characterized by more intense epi-
sodic vaso-occlusion, often with increasing hemolysis, and are
due to exogenous or endogenous factors that acutely alter the rheo-
logic properties of the RBCs. The main determinants of RBC sick-
ling and vaso-occlusion are hypoxemia, RBC dehydration, RBC
concentration, high HbS relative to fetal hemoglobin (HbF), and
blood viscosity; these can occur in a multitude of clinical settings.
Most common clinical inciting events leading to vaso-occlusive epi-
sodes are dehydration due to inadequate replacement of fluid
losses, thermal changes, surgical stress, exposure to low oxygen
tension, infections, and psychological stressors.
Epidemiologic studies indicate that the risk of vaso-occlusive epi-
sodes and acute chest syndrome is related to high steady-state
hemoglobin levels, leukocytosis, and low HbF levels. These find-
ings are consistent with pathogenic mechanisms of altered red cell
rheology, higher viscosity, HbS polymerization, and inflammatory
cellular adhesion. Interestingly, the epidemiologic risk factors asso-
ciated with chronic vascular complications such as pulmonary
hypertension, cutaneous leg ulceration, priapism, systemic systolic
hypertension, renal failure with proteinuria, and possibly stroke
are different and include a low steady-state hemoglobin level,
increased hemolytic intensity, iron overload, and markers of low
nitric oxide bioavailability. One hypothesis is that SCD is driven
by two overlapping but different mechanisms of disease: on one
hand, vaso-occlusion causes vaso-occlusive episodes and acute
chest syndrome, and on the other hand, hemolytic anemia leads
to endothelial dysfunction and chronic vasculopathy. Both are
caused fundamentally by HbS polymerization.
Prevention
See “Evidence-Based Management of Sickle Cell Disease: Expert
Panel Report, 2014” at http://www.nhlbi.nih.gov/health-pro/
guidelines/sickle-cell-disease-guidelines for detailed, consensus
guidelines on prevention and treatment.
Bacterial Infections
Before the antibiotic era, most patients with SCD succumbed to
bacterial sepsis from encapsulated organisms. A landmark multi-
center, randomized, double-blind, placebo-controlled clinical trial
of prophylaxis with oral penicillin in children with sickle cell ane-
mia published in 1986 showed that bacterial prophylaxis started at
birth reduced by about 80% the incidence of infection in the pen-
icillin group, as compared with the group given placebo. This study
became the foundation for universal screening of SCD. Results of
the Penicillin Prophylaxis in Sickle Cell Study II (PROPS 2) trial
show that prophylaxis can be safely discontinued at age 5 years
as long as there is no history of prior serious pneumococcal infec-
tion or surgical splenectomy and in the setting of appropriate com-
prehensive care. All children should also receive both the 13-valent
pneumococcal conjugate (Prevnar 13) and 23-valent pneumococ-
cal polysaccharide (Pneumovax) vaccines, and adults should
receive Pneumovax. Vaccinations for H. influenzae and N. menin-
gitidis are also indicated.
Neurologic Events
Stroke is a devastating complication of SCD and affects predomi-
nantly children with HbSS and abnormal transcranial Doppler
(TCD) results. Silent cerebral infarcts are MRI-detectable abnor-
malities that also carry a high risk of morbidity, including overt
stroke and cognitive impairment. There is conclusive evidence that
chronic transfusions are effective in the primary and secondary pre-
vention of both overt and silent strokes in SCD. The first landmark
trial (STOP) published in 1995 showed that the first stroke can
be prevented by placing children with abnormal TCD on prophy-
lactic monthly transfusions with a target HbS of less than 30%.
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Transfusions were later found to also have a beneficial effect on
reducing the incidence of the recurrence of silent cerebral infarcts,
as shown by the SIT trial. The importance of continuing transfu-
sions for more than 30 months was underscored by the STOP 2
trial, where TCD abnormalities recurred and the incidence of silent
cerebral infarctions on MRI was higher in the transfusion-halted
group. The enthusiasm over the beneficial effects of transfusions
was tempered by the concerns about the side effects of long-term,
possibly indefinite use of this therapeutic strategy. There has been,
therefore, an interest in exploring whether hydroxyurea (Droxia,
Siklos) could represent an alternative to transfusion in high-risk
children. Specifically, the SWiTCH trial explored the hypothesis
that hydroxyurea and phlebotomy could maintain an acceptable
stroke recurrence rate and significantly reduce the hepatic iron bur-
den as compared to a prophylactic chronic transfusion regimen.
Unfortunately, the trial was terminated early because of a signifi-
cantly higher stroke recurrence rate in the hydroxyurea arm com-
pared to the transfusion arm, with equivalent hepatic iron burden
in both groups. Thus the issue of when, if ever, it is safe to discon-
tinue transfusions for the secondary prevention of stroke is still
unknown. Conversely, as shown by the results of the TWiTCH
trial, another study halted prematurely by the National Institutes
of Health, hydroxyurea is not inferior to chronic transfusions in
lowering TCD velocities in children at high risk but without a his-
tory of stroke, thereby suggesting that this drug may be equally
effective in the primary prevention of neurologic complications.
Clinical Manifestations
Multiple genetic and epigenetic factors affect the SCD phenotype.
Patients homozygous for HbS (SS) or compound heterozygous for
HbS and a nonfunctional β0-thalassemia allele tend to display the
most severe manifestations. On the other end of the spectrum,
hereditary persistence of HbF (HPFH), particularly common in
Sickle Cell Disease
Saudi Arabia, or coinheritance of β-thalassemia mitigates the phe-
notype. While the net effect of high HbF levels on the phenotype of
SCD is beneficial, coinheritance of one or two α-thalassemia alleles
has a more complex effect. α-thalassemia is present in approxi-
mately 30% of patients with SCD and is associated with higher
hemoglobin, lower mean corpuscular volume (MCV), and
decreased rate of hemolysis. These effects are protective toward
stroke and leg ulcers, but lead to increased rates of vaso-occlusive
episodes, osteonecrosis, and acute chest syndrome because of
increased blood viscosity related to the higher hemoglobin level. 455
Patients with HbSC and HbS/β+-thalassemia have an intermediate
severity phenotype (Table 1). Haplotypes of polymorphic sites in
the β-globin gene cluster in chromosome 11 have been associated
with different disease severity and rates of complications. Other
yet unidentified genetic factors predispose certain patients to
develop a particularly severe hemolysis with brisk reticulocytosis
and a high rate of specific complications that include leg ulcers, pri-
apism, and pulmonary hypertension.
Hematology
This section describes the main clinical manifestations of SCD in
each organ system (Figure 1 and Table 2).
TABLE 1 Severity of the Main Sickle Cell Syndromes
GENOTYPE CLINICAL SEVERITY HEMOGLOBIN (g/dL)
HbSS Usually marked 6–10
0
HbS-β -thalassemia Moderate to marked 6–10
HbS-β+-thalassemia Mild to moderate 9–12
HbSC Mild to moderate 10–15
HbSS-HPFH Mild
Abbreviations: HbSC ¼ heterozygous phenotype; HbSS ¼ homozygous phenotype;
HPFH ¼ hereditary persistence of fetal hemoglobin.
 Stroke, meningitis Retinal Retinopathy
infarction Obstructive
Acute chest Anemia, sleep apnea
syndrome leukocytosis
Pulmonary
Sickle
Splenic Indirect hyperbilirubinemia hypertension
hepatopathy
sequestration Cardiomegaly
Splenic Isosthenuria,
Papillary Functional
infarction chronic renal failure
necrosis asplenia

Priapism Cholelithiasis Delayed Avascular

puberty necrosis
Bone marrow,
infarction,
osteomyelitis
Acute Chronic
Skin ulcers
complications complications

Figure 1 Acute and chronic complications of sickle cell disease.

TABLE 2 Landmark Randomized Clinical Trials in Sickle Cell Disease

YEAR OF
PUBLICATION TITLE MAIN FINDINGS
1986 Prophylaxis with oral penicillin in children with 84% reduction in incidence of infection and no deaths from pneumococcal
sickle cell anemia: A randomized trial septicemia in the penicillin group
1995 Multicenter Study of Hydroxyurea in Sickle Cell Reduced incidence of painful crises, ACS, and transfusion in the
Anemia (MSH) hydroxyurea group
Survival benefit in follow-up study
1995 Preoperative Transfusion in Sickle Cell Disease A conservative transfusion regimen was as effective as an aggressive regimen
Study in preventing perioperative complications in patients with sickle cell
VI Hematology

anemia
1996 Multicenter investigation of bone marrow HCT is safe in SCD with survival and event-free survival at 4 y of 91% and
transplantation for sickle cell disease 73% and can lead to cure
1998 Stroke Prevention Trial in Sickle Cell Anemia Transfusion reduces the risk of a first stroke by 92% in children with sickle
(STOP) cell anemia who have abnormal results on transcranial Doppler
ultrasonography
2005 Optimizing Primary Stroke Prevention in Sickle Cell Discontinuation of transfusion for the prevention of stroke in children with
Anemia (STOP 2) sickle cell disease results in a high rate of reversion to abnormal blood-
456 flow velocities on Doppler studies and stroke
2009 Improving the Results of Bone Marrow Nine of 10 adults who received nonmyeloablative allogeneic hematopoietic
Transplantation for Patients with Severe stem cell transplantation for severe sickle cell disease achieved stable,
Congenital Anemias mixed donor–recipient chimerism and reversal of the sickle cell
phenotype, without acute or chronic GVHD.
2011 Pediatric Hydroxyurea Phase III Clinical Trial Children ages 9–18 mo randomized to receive hydroxyurea irrespective of
(BABY HUG) disease severity for 2 y had decreased pain episodes, dactylitis, ACS,
hospitalization, leukocyte count, and transfusion and increased
hemoglobin as compared to children receiving placebo.
2014 Silent Infarct Trial (SIT) Children with silent cerebral infarcts and normal TCD velocity who were
randomized to chronic transfusion therapy had a 58% relative risk
reduction in the recurrence of silent cerebral infarct or stroke as compared
to those in the observation arm.

Abbreviations: ACS ¼ acute chest syndrome; GVHD ¼ graft-versus-host disease; HCT ¼ hematopoietic cell transplantation; SCD ¼ sickle cell disease; VOE ¼ vaso-occlusive
crisis.

Baseline or Steady-State Hematologic Abnormalities
Chronic intravascular and extravascular hemolysis causes a
chronic anemia of moderate to severe intensity in HbSS and
HbS/β0-thalassemia, with a hemoglobin range of 6 to 9 g/dL. In
HbSC and HbS/β+-thalassemia, the anemia may be mild or absent.
The anemia of SCD is usually normocytic in HbSS, with anisocy-
tosis and poikilocytosis and a population of small dehydrated
dense cells, irreversibly sickled cells, numerous reticulocytes, and
schistocytes. Reticulocytosis is common but not compensatory,
and nucleated RBCs are seen in acute exacerbations of the anemia
such as in splenic or hepatic sequestration. Baseline leukocytosis
with neutrophilia is also common and is a poor prognostic sign
associated with acute chest syndrome in adults and frequent
vaso-occlusive episodes in children. Preclinical studies have shown
that leukocytes are not simply a marker of disease activity and
acute phase but also have a direct pathogenic role in cellular
adhesion and vaso-occlusion. The platelet count is commonly
elevated in SCD, particularly in patients who are autosplenecto-
mized as a result of repeated splenic infarction, and platelet acti-
vation is increased. In the subset of patients with HbSC and

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HbS/β+-thalassemia who retain a functional spleen and develop
splenomegaly, features of hypersplenism may instead be observed
with resulting mild pancytopenia.
Hematologic Indices During Vaso-Occlusive Episodes
In acute vaso-occlusive episodes the total Hb decreases as a result
of hemolysis (by 1.6 g/dL in acute chest syndrome). The lactate
dehydrogenase (LDH), reticulocyte count, and other markers of
hemolysis such as aspartate transaminase (AST) and indirect bili-
rubin are elevated in steady state, and in many—but not all—
patients are further increased during vaso-occlusive episodes. Hap-
toglobin levels are chronically depressed in SCD and typically not
measurable, even in steady state, in patients with HbS homozygos-
ity. In patients with HbSC, vaso-occlusive episodes may be due to
increased blood viscosity and RBC sickling, and worsening hemo-
lysis might not be readily appreciated.
Splenic sequestration crises occur mostly in childhood and are
characterized by anemia disproportionate to the degree of hemoly-
sis, reticulocytosis, and acute splenomegaly. Splenic sequestration
and repeated episodes of splenic infarction eventually lead to auto-
splenectomy, although some patients develop splenomegaly.
Splenic infarction usually manifests with left upper-quadrant pain
and may be massive, involving more than 50% of the splenic tissue.
In severe vaso-occlusive episodes, massive bone marrow infarc-
tion can also occur. In these instances, the peripheral blood smear
reveals a leukoerythroblastic picture with immature neutrophilic
forms, nucleated RBCs, and teardrop cells. Fat emboli syndrome,
a life-threatening complication of vaso-occlusive episodes, can then
develop as bone marrow fat embolizes to peripheral capillary beds,
leading to multiorgan failure.
Red Blood Cell Alloimmunization
RBC alloimmunization is a common complication of transfusional
therapy in SCD and occurs in approximately 30% of patients. It is
primarily due to the disparate expression of RBC antigens in Afri-
can Americans as compared to the donor pool, which is mostly
composed of Caucasians. Alloimmunization complicates RBC
matching and leads to delayed hemolytic transfusion reactions.
Alloantigens that become undetectable by indirect Coombs test
2 months after exposure to mismatched blood have the potential
to result in future false-negative cross-matching results. A subset
of heavily alloimmunized patients with SCD undergoes life-
threatening hemolytic reactions upon exposure to mismatched
RBC units. In these hyperhemolytic crises, there is intense hemoly-
sis of transfused and nontransfused RBCs and acute anemia. Treat-
ment of hyperhemolytic crises is empirical and includes
erythropoietin-stimulating agents (ESA), parenteral steroids, and
intravenous immunoglobulins (Gammagard).1
Iron Overload
Hemosiderosis is the other major complication of transfusional
therapy in SCD and is characterized by iron deposition in the heart,
liver, and endocrine glands, leading to organ failure and significant
morbidity and mortality. It commonly occurs in patients who have
received more than 10 lifetime transfusions or more than 20
packed RBC units. Liver biopsy is the gold standard for diagnosis
but it is an invasive and uncomfortable procedure. Hepatic and
myocardial iron quantitation by MRI is supplanting liver biopsy
as the preferred test to diagnose iron overload and monitor therapy
with iron chelators, although when this is not available diagnosis
often rests on the finding of an elevated ferritin and transferrin sat-
uration in the appropriate clinical setting.
Hemostatic Activation and Thrombosis
Numerous studies have shown that arterial and venous thrombosis
are common in SCD and include pulmonary embolism, in situ pul-
monary thrombosis, and stroke. In SCD, alterations at all levels of
the hemostatic system have been described: patients with sickle cell
1
Not FDA approved for this indication.
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disease exhibit increased basal and stimulated platelet activation,
increased markers of thrombin generation and fibrinolysis,
increased tissue factor activity, and increased von Willebrand fac-
tor (vWF) antigen and thrombogenic ultralarge vWF multimers
with depressed ADAMTS13 activity. Interestingly, hemostatic acti-
vation is amplified during vaso-occlusive episodes, as shown by
increases in multiple markers of thrombosis as compared to steady
state, suggesting a link between hemolysis and thrombosis.
Neurology
Ischemic stroke is common in SCD, with the highest incidence
between 2 and 5 years of age. Patients may develop overt stroke
from large vessel occlusion (5%–8% of patients with HbSS) or
silent infarcts from focal ischemia detectable by MRI without
symptoms of acute stroke (20%–35% of patients with HbSS).
The pathophysiology of stroke in SCD is unclear, although genetic
factors and an unbalance between oxygen demand and supply have
been postulated. Multiple epidemiologic studies have shown that
the risk factors for ischemic stroke in adult patients include HbSS
genotype, severity of anemia, systolic hypertension, male gender,
and increasing age. Patients with repeated strokes are at risk for
development of anatomic abnormalities and Moyamoya pattern
of vascularization, which predisposes to both ischemic and hemor-
rhagic stroke later in life. The highest incidence of intracerebral
hemorrhages occurs in patients older than 20 years.
Both overt and silent strokes have a negative impact on IQ and
cause cognitive impairment measurable by psychometric testing.
Children and adults with SCD can develop cognitive impairment
and subtle signs of accelerated brain aging and vascular dementia
even in the absence of focal ischemia by MRI, with a low hemato-
crit being a predictor of neuropsychological dysfunction. These
abnormalities are probably due to chronic and diffuse, as opposed
to focal, cerebral anoxia and may be unmasked by psychometric
Sickle Cell Disease
testing.
Ophthalmology
Retinal abnormalities are common in SCD and are often asymp-
tomatic until the occurrence of ophthalmologic emergencies. Ret-
inal disease is due to arteriolar occlusion, with subsequent
vascular proliferation, neovascularization, retinal hemorrhage
(stage IV), and detachment (stage V). Patients with HbSC are more
prone to retinal complications, possibly as a result of increased
blood viscosity. 457
Nephrology
Renal abnormalities are common in SCD and manifest primarily as
hematuria, proteinuria, and renal tubular acidosis. Hematuria is
usually due to papillary necrosis and is an acute finding that
requires supportive care and carries a good prognosis. Rarely,
gross hematuria requires urologic consultation. Tubular functional
defects include an inability to concentrate the urine (hyposthe-
nuria) and renal tubular acidosis. Hyposthenuria often manifests
with enuresis in childhood, and it is clinically relevant because it
predisposes patients to an increased risk of dehydration. Renal
tubular acidosis similar to type IV renal tubular acidosis is a com-
mon finding in SCD and may lead to hyperkalemia, an important
consideration in patients already predisposed to hyperkalemia with
intravascular hemolysis and whenever therapy with angiotensin-
converting enzyme inhibitors is entertained.
Hyperphosphatemia and hyperuricemia are also often observed
in SCD. Microalbuminuria may be detected in early adulthood and
tends to progress to nephrotic range proteinuria. Focal segmental
glomerulosclerosis is the most common glomerular abnormality
and it is probably due to glomerular sickling and infarction. There
are currently no approved therapies to prevent progression to end-
stage renal disease, which occurs in up to 20% of patients and at a
median age of 37 years. Renal replacement therapy is often needed
in older adults with SCD. Serum creatinine and 24-hour creatinine
clearance are not adequate for screening and monitoring of pro-
gression of kidney disease, because tubular secretion of creatinine
is preserved and glomerular hyperfiltration is common in SCD,
 leading to a relatively low creatinine and a high glomerular filtra-
tion rate even in patients with underlying kidney impairment. Test-
ing for microalbuminuria, plasma cystatin C levels and
hemoglobinuria may instead be used as screening tools for chronic
kidney disease.
Leg Ulcers
Leg ulcers occur in 10% to 20% of patients with HbSS and have
been associated with a chronically high hemolytic rate. They are
usually located over the malleolar areas and are exquisitely painful,
debilitating, disfiguring, and nonhealing. Vascular and plastic sur-
gery consultation are recommended and aim at excluding local vas-
cular problems that can complicate management of the ulcers and
at providing prompt debridement and skin grafting. Although
hydroxyurea is associated with development of leg ulcers in
patients with myeloproliferative disorders, there is no such link
with leg ulcers in SCD. Whereas wound healing may be impaired
with hydroxyurea use, patients who develop an increase in fetal
hemoglobin and have reduced sickling as a result of hydroxyurea
therapy might have a net benefit in terms of tissue oxygenation and
perfusion. Transfusional therapy, including exchange transfu-
sional therapy, topical nitrates,1 and nutritional zinc7 or
L-arginine7 supplementation, have shown benefit in anecdotal
reports, but the evidence is inconclusive.
Gastroenterology
Nausea, vomiting, and dyspepsia in SCD are related to delayed gas-
tric emptying and gastrointestinal motility disorders, autonomic
neuropathy, or medical therapy. Opiates are often responsible
for acute nausea and vomiting, whereas other medications such
as hydroxyurea and deferasirox (Exjade) are occasionally respon-
sible for chronic symptoms. Gastroparesis may be due to damage
of the microvasculature of autonomic nerves (vasa vasorum) from
repeated episodes of sickling.
VI Hematology
The liver may be episodically affected by hepatic sequestration
crises, heralded by direct hyperbilirubinemia, right upper quadrant
pain from distention of the hepatic capsule, acute anemia, and reti-
culocytosis or by sinusoidal vaso-occlusion leading to severe epi-
sodes of intrahepatic cholestasis. Supportive therapy and
transfusions are indicated for hepatic vaso-occlusive complica-
tions. Exchange transfusion may be the preferred modality for
hepatic sequestration with the goal of preventing reythrocytosis
458 once the pooled RBCs are released back into the circulation. Eleva-
tion of liver injury tests may be drug-induced (hydroxyurea, defer-
asirox), but also related to hepatic sickling, particularly if it occurs
during a vaso-occlusive episode.
Infectious Disease
Patients homozygous for HbSS develop functional asplenia during
childhood. This is due to repeated episodes of splenic infarction
leading to fibrosis and autosplenectomy. As a result, children are
susceptible to overwhelming bacterial sepsis from encapsulated
organisms such as S. pneumoniae, H. influenzae, and N. meningi-
tidis. High pediatric mortality from sepsis was therefore common
before a landmark study published in 1986 demonstrated the ben-
efit of penicillin prophylaxis instituted at birth. Vaccination for
encapsulated organisms is also standard of care in children and
adults. In spite of preventive measures, the incidence of life-
threatening bacterial infections is increased in SCD, and high fever
should be treated empirically as in splenectomized patients, with
coverage for penicillin-resistant S. pneumoniae pending blood cul-
ture results. Patients with indwelling venous catheters are at risk of
catheter-related bacteremia.
Viral infections with bone marrow–tropic viruses such as
Epstein-Barr virus, citomegalovirus, and predominantly parvovi-
rus B19 place patients at risk for myelosuppression, which can fur-
ther worsen chronic anemia. In children, infections with parvovirus
1
Not FDA approved for this indication.
7 1
Available as dietary supplement.
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B19 are responsible for transient red cell aplasia and severe aplastic
crises, characterized by acute anemia and reticulocytopenia due to
intra marrow destruction of erythroid precursors. Treatment of
these episodes includes transfusion and intravenous immunoglob-
ulins,1 besides supportive measures.
Pulmonology
A subset of patients with vaso-occlusive episodes develop acute
chest syndrome, the major pulmonary complication of SCD. Acute
chest syndrome is a lung injury syndrome defined by fever, pleuritic
chest pain, oxygen desaturation, and multilobar radiographic infil-
trates associated with severe vaso-occlusive episodes, infection, and
bone marrow fat embolization (Figure 2). It usually develops 2 to 3
days after hospitalization for vaso-occlusive episodes and is often
misdiagnosed as nosocomial pneumonia or aspiration pneumonia,
particularly because it displays a predilection for the lower lobe of
the lungs. Although pneumonia often accompanies acute chest syn-
drome, proper diagnosis is important because acute chest syn-
drome warrants simple or exchange transfusion in addition to
antibiotic therapy and supportive measures. Common infectious
pathogens identified in cases of acute chest syndrome include Chla-
mydia pneumoniae, Mycoplasma pneumoniae, and Legionella
pneumophyla, thus dictating inclusion of a macrolide in the antibi-
otic cocktail. Pulmonary embolism with resulting infarct is also in
the differential diagnosis of acute chest syndrome and may occur
concurrently in 17% of patients. If not recognized and treated
promptly, acute chest syndrome leads to pulmonary failure and
carries a high mortality.
Airway hyperreactivity is common in children with SCD and
needs to be actively diagnosed and aggressively treated because
it is associated with worse SCD outcomes. Children with
chronic respiratory symptoms should be tested for bronchial
hyperresponsiveness.
Chronic complications of SCD include pulmonary fibrosis and
pulmonary hypertension. Pulmonary hypertension (PH) is an
emergent complication of SCD and is associated with a high mor-
bidity and mortality. Multiple epidemiologic studies have shown
that a high baseline hemolysis rate, low hemoglobin, increasing
age, a history of leg ulcers, liver dysfunction, iron overload, and
kidney failure are risk factors for the development of pulmonary
hypertension. Three epidemiologic studies and a randomized clin-
ical trial have shown that an elevated tricuspid regurgitant jet
velocity (TRV) measured by Doppler echocardiography is a com-
mon occurrence in SCD with 30% of the patients having a TRV of
2.5 m/sec (2 standard deviations [SDs] above the normal mean) or
higher, and 10% of the patients having a TRV of 3.0 m/sec (3 SDs
above the normal mean) or higher. These have proved to be valu-
able cutoff values, as a TRV of less than 2.5 m/sec, when combined
with an N-terminal pro B-type natriuretic peptide (NT-proBNP)
value less than 160 has a high negative predictive value for PH.
A TRV of 3.0 m/sec or higher confers a positive predictive value
for having PH by RHC of 60% to 75% and a relative risk for death
of 10.6. Controversy exists on the significance of an intermediate
TRV value of 2.5 to 2.9 m/sec, as it is unclear how accurately it pre-
dicts RHC-diagnosed PH. In three subsequent studies, patients
with intermediate or high TRV values had a prevalence of PH
by RHC ranging from 25% to 65% depending on what specific
cutoff value was used as the criteria to perform a RHC (2.5 vs.
2.8) and on whether patients with evidence of end-organ damage
were included or excluded. It is, however, worrisome that regard-
less of the prevalence of PH, patients with an intermediate TRV are
as a whole at increased risk of death (relative risk 4.4). One screen-
ing approach is to consider RHC in all patients with TRV of 3.0 or
higher and in patients with intermediate TRV values of 2.5 to
2.9 m/sec if the NT-proBNP is greater than 160 pg/mL or the 6-
minute walk is less than 333 meters or there is a high clinical pretest
probability of having PH (mosaic perfusion pattern on CT scan,
low DLCO, significant dyspnea on exertion, etc.). It is likely that
Not FDA approved for this indication.
Figure 2 Vicious cycle of acute chest syndrome (ACS). Vaso-occlusive crises are characterized by increased intraerythrocytic polymerization of
deoxygenated hemoglobin S, leading to red blood cell sickling, cellular hyperadhesion, hemolysis, and vaso-occlusion in the microvasculature. These

Sickle Cell Disease

processes are responsible for acute pain (pain crisis) and bone marrow necrosis. ACS typically occurs in a subset of patients 2 to 3 days after
hospitalization for a vaso-occlusive episode, and radiographically may present as new multilobar, basilar infiltrates on a chest x-ray. Fat embolization
from the necrotic marrow is a recognized cause of ACS and is diagnosed by identifying lipid-laden macrophages in the bronchoalveolar lavage.
Pulmonary infection is, however, the most common trigger of ACS and may be superimposed over existing pulmonary infarction. Hypoventilation
and molecular pathogens such as reactive oxygen species from ischemia-reperfusion injury and by-products of hemolysis may also play a role in
inducing or exacerbating lung injury. Finally, in situ pulmonary thrombosis has been frequently identified as a co-morbid condition in patients with
ACS and may be caused by endothelial and hemostatic activation. As a result of lung injury, ventilation-perfusion mismatches and shunting ensues,
with subsequent hemoglobin desaturation and hypoxemia. Tissue hypoxia in turn triggers further hemoglobin S polymerization and sickling in a
vicious cycle.

intermediate TRV values will need to be combined with other mea-
sures of right ventricular function and functional capacity such as
NT-proBNP, and 6-minute walk to derive a highly predictive com-
posite biomarker of PH. All studies have been concordant on the
high risk of death conferred by PH in SCD whether measured by
echocardiography, NT-proBNP, or RHC. Noninvasive trans-
thoracic Doppler echocardiography is recommended by the Amer-
ican Thoracic Society as a screening test in homozygous SCD
due to its safety, low cost, and availability. The definitive
diagnosis of PH, however, requires a confirmatory right heart
catheterization (RHC).
Right heart catheterization studies of patients with SCD and pul-
monary hypertension reveal a hyperdynamic state similar to the
hemodynamics characteristic of portopulmonary hypertension. It
is increasingly clear that pulmonary pressures rise acutely in
vaso-occlusive episodes and even more during acute chest syn-
drome. This suggests that acute pulmonary hypertension and right
heart dysfunction represent a major comorbidity during acute chest
syndrome, and right heart failure should be considered in patients
presenting with acute chest syndrome.
Cardiology
Similar to other conditions with chronic anemia, SCD is associated
with a hyperdynamic state, low peripheral vascular resistance, and
normal blood pressure or hypotension. In this setting, even mild
elevation of the blood pressure can indicate relative hypertension
and represent a risk factor for stroke. Because there are no studies
459
on the treatment of hypertension in SCD, general guidelines on
antihypertensive therapy are applied.
Coronary artery disease is rarely observed in SCD, although
many patients complain of chest pain during vaso-occlusive
episodes. In these instances, the usual workup for acute coronary
syndrome is recommended. It is possible that myocardial microvas-
cular occlusions are the predominant ischemic event in SCD.
Left-sided heart disease in SCD is primarily due to diastolic dys-
function (present in approximately 13% of patients), although sys-
tolic dysfunction and mitral or aortic valvular disease (2% of
patients) can also occur. The presence of diastolic dysfunction
alone in SCD patients is an independent risk factor for mortality.
Patients with both pulmonary vascular disease and echocardio-
graphic evidence of diastolic dysfunction are at a particularly high
risk for death (odds ratio, 12.0; 95% confidence interval [CI], 3.8-
38.1; P <0.001).
Cardiac dysfunction is a late complication and the major cause
of death in patients with iron overload. Heart failure and conduc-
tion defects are the most common abnormalities and warrant emer-
gent iron chelation treatment. Deferoxamine (Desferal),
deferasirox (Exjade), and deferiprone (Ferriprox) reduce cardiac
iron content and may be used in combination in severe cases.
Methadone (Dolophine) is associated with a risk of QTc prolon-
gation, which carries a risk of arrhythmias and sudden death, par-
ticularly in the setting of pulmonary hypertension and iron
overload. Frequent electrocardiographic (ECG) monitoring, as
well as dosage reduction or discontinuation, are warranted in this
group, particularly if the QTc is greater than 500 msec.

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 Endocrinology
Iron overload is a common cause of endocrinopathy in SCD and
thalassemia, with the hypophysis, gonads, and thyroid glands
being particularly affected. Patients with iron overload should
therefore undergo screening for endocrine dysfunction as it is man-
dated in thalassemia.
Patients with SCD are, however, at risk for specific endocrine
problems regardless of their iron status. Delayed growth and
puberty are relatively common, presenting in females with delayed
age of menarche by 2 to 3 years and in males with small testicular
size and hypospermia. Likely pathogenic factors include increased
catabolism, chronic hpoxemia, hospitalizations with prolonged
immobility, ischemic insults during vasooclusive episodes, and
chronic use of opiates.
Priapism
Priapism is the most common urogenital complication in patients
with the HbSS genotype. It is a sustained, painful erection in the
absence of sexual stimulation from occlusion of the penile blood
return. It is defined as stuttering if it lasts from minutes to less than
3 hours, and as prolonged if it lasts more than 3 hours. The latter is
considered a urologic emergency because of the risk of permanent
fibrosis and impotence, and requires a urologic consultation. Pseu-
doephedrine (Sudafed)1 may lead to detumescence in nonemer-
gency settings, whereas aspiration of the corpus cavernosum is
required in the emergency setting and is performed under conscious
sedation and local anesthesia. This is usually accompanied by
installation of epinephrine.1 Other supportive measures, such as
intravenous fluids and parenteral opiates, are usually indicated.
Penile shunts are employed as a last resort to prevent further epi-
sodes of priapism by increasing the cavernous blood flow using
native vessels or by creating an arteriovenous shunt. They invari-
ably result in impotence, which can be ameliorated by implantation
of an inflatable penile prosthesis. There are data showing that sil-
VI Hematology
denafil (Viagra)1 therapy can prevent priapism by altering vascular
smooth muscle tone through inhibition of phosphodiesterase 2
activity.
Diagnosis
The diagnosis of SCD rests on the hemoglobin electrophoresis or
high-performance liquid chromatography (HPLC), which allows
detection of most hemoglobin variants. In patients with microcyto-
460 sis α-globin gene sequencing may reveal coinheritance of an α-
thalassemia trait.
Neonatal Screening
Children with SCD have an increased susceptibility to bacteremia
due to S. pneumoniae, which can occur as early as 4 months of age
and carries a case fatality rate as high as 30%. Acute splenic seques-
tration crises also contribute to mortality in infancy. Diagnosis by
newborn screening and immediate entry into programs of compre-
hensive care, including the provision of effective pneumococcal
prophylaxis, can reach infants who might otherwise be lost to
the health care system and has been demonstrated to decrease mor-
bidity and improve survival. Currently, newborn screening and
follow-up of SCD are carried out in all 50 states in the United States
as well as in most developed countries and initiatives are under way
to introduce universal newborn screening in most sub-Saharan
African countries.
Late Diagnoses and Misdiagnoses
Rarely, patients who were born before the adoption of universal
screening or who were lost at the time of follow-up of positive neo-
natal screening results are only diagnosed late in life. This occasion-
ally occurs in patients with HbSC who might have normal
hemoglobin and hematocrit and a mild disease phenotype. Alterna-
tively, the disease may be misdiagnosed as iron deficiency in
patients with HbS/β+-thalassemia on account of their microcytosis,
1
Not FDA approved for this indication.
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which places them at risk of futile and potentially harmful pro-
longed trials of iron supplementation. Patients who have a low
HbS level (<40%) due to recent transfusion or who have only
mildly decreased hemoglobin (HbSC or HbS/β+-thalassemia)
may receive an erroneous diagnosis of sickle cell trait (carrier state).
Treatment
From the original description of SCD in 1910 to the 1970s, there
was no efficacious therapy for SCD, and most patients died within
the first 2 decades of life, with infectious complications being
responsible for the majority of pediatric fatalities. Several preven-
tive and pharmacologic milestones since then, and the realization
that care has to occur in a multidisciplinary setting, have pro-
foundly affected the natural history of the disease (Table 3).
Median age at death in resource-rich countries was 42 years in male
patients and 48 years in female patients with HbSS, according to
data from the Cooperative Study of Sickle Cell Disease in the
1980s (a pre-hydroxyurea setting), thereby still lagging approxi-
mately 2 to 3 decades behind that of the general African American
population. The following sections summarize the therapeutic
approach to the most important complications of SCD.
Vaso-Occlusive Episodes
Acute pain from vaso-occlusive episodes in SCD is extremely intense,
affects both children and adults, and is due to ischemia or necrosis of
the vascular beds. Most patients report severe pain in the bones and
joints of the extremities, as well as lower back, although acute ische-
mia and pain can affect unusual sites such as the mandibular area.
Occasionally, an affected limb displays the typical signs of inflamma-
tion, such as edema, warmth, and erythema, but a paucity of signs is
the norm. Imaging studies such as MRI and bone scan can reveal
signs of acute bone marrow infarction in a painful bony area, but
they are not routinely employed in the workup of a pain episode.
Intravenous opiates, as well as nonsteroidal antiinflammatory
drugs (NSAIDs), are the mainstay of treatment of a pain episode.
Even in opiate-naive patients with SCD, opioid dosages often
exceed those required for other indications. For instance, doses
of intravenous hydromorphone (Dilaudid) of 1 to 2 mg are typical
in adult patients. Most patients, however, are on an oral pain reg-
imen at home and have a history of multiple admissions for vaso-
occlusive episodes. In these cases, individualized care based on
prior effective regimens and the patient’s own perception of the
intensity of pain are recommended. After an attempt at controlling
the pain with three or four closely spaced opiate boluses is made,
patients who are in persistent discomfort or have evidence of
underlying complications triggering the vaso-occlusive episode
should be admitted and ideally placed on patient-controlled anal-
gesia. The American Pain Society has published guidelines for the
treatment of acute and chronic pain in SCD, followed by other
institutions in the past decade.
Common obstacles to prompt and effective care in SCD are the
health professional’s fear of overdosing the patient, as well as mis-
conceptions about addiction and pseudoaddiction. In general,
health care professionals tend to overestimate the prevalence of
opioid use disorder in SCD and tend to undertreat patients signif-
icantly, leading to patients’ frustration and anger when their pain
demands are not met (pseudoaddiction).
Nonpharmacologic therapies such as biofeedback, relaxation,
and localized heat may be effective and should be incorporated into
the management of pain episodes whenever possible. Care for
vaso-occlusive episodes should also include management of possi-
ble precipitating factors: dehydration and hypovolemia should be
corrected with hypotonic crystalloids, and an infection workup
should be initiated in patients with fever, hypoxemia, or leukocy-
tosis above baseline. Antiemetics and antipruritus therapy are also
usually required.
Prior experiences in multiple institutions have shown that a dedi-
cated facility for effective and rapid management of uncomplicated
vaso-occlusive episodes reduces hospitalizations and length of stay
and facilitates integration of care—psychological, socioeconomic,
and nutritional—in a multidisciplinary approach. This experience
 TABLE 3 Manifestations of Sickle Cell Disease with Key Prevention and Treatment Strategies
MANIFESTATION PREVENTION TREATMENT
Pneumococcal sepsis Penicillin, Prevnar/Pneumovax vaccination Antibiotic therapy for penicillin-resistant
Streptococcus pneumoniae
Splenic or liver sequestration — Exchange transfusion
Painful vaso-occlusive episode Hydroxyurea (Droxia), prevention of exposure to Intravenous fluids, parenteral opiates,
triggers supplemental oxygen
Acute chest syndrome Incentive spirometry during VOE, hydroxyurea Transfusion, broad-spectrum antibiotics with
atypical coverage
Iron overload Optimization of transfusion therapy Iron chelation with deferasirox (Exjade) or
deferoxamine (Desferal)
RBC alloimmunization Transfusion with leukoreduced RBCs —
CVA Chronic transfusion in children with high transcranial Exchange transfusion and thrombolytics in selected
Doppler velocity cases
Pulmonary hypertension Hydroxyurea?, treatment of predisposing conditions Hydroxyurea, chronic transfusion therapy, specific
such as obstructive sleep apnea, hypoxemia, therapy
thromboembolism
Kidney disease Antihypertensive therapy?, hydroxyurea?, ACE ACE inhibitors?, renal replacement therapy, kidney
inhibitors? transplant
Priapism Hydroxyurea? Pseudoephedrine (Sudafed),1 aspiration of corpus
cavernosum, sildenafil (Viagra)1
Leg ulcers Hydroxyurea?, chronic transfusion? Surgical debridement, surgical grafting

Abbreviations: ACE ¼ angiotensin-converting enzyme; CVA ¼ cerebrovascular accident; RBC ¼ red blood cells; TCD ¼ transcranial Doppler; VOE ¼ vaso-occlusive crisis.
1
Not FDA approved for this indication.

is the basis of the concept of the day hospital in SCD and relies on the overload, alloimmunization, transfusion reactions, and viral trans-

Sickle Cell Disease

need to provide prompt assessment and treatment of pain, safe dose
titration to relief, monitoring of adverse effects, and adequate dispo-
sition (emergency department, inpatient admission, home) in a clini-
cal environment familiar with SCD and the individual patient.
Chronic Pain
Chronic pain is common, and a study employing pain diaries com-
piled by patients shows that most patients with SCD experience pain
on an almost daily basis (PiSCES study). Patients who have success-
fully transitioned from pediatric to adult care, have a good support
system, and are distracted by their work or school schedules tend to
cope better and require less pharmacologic support. In many cases,
though, short-acting and long-acting opiates are required to
empower the patient to manage pain at home and minimize use
of the emergency department. Drugs for neuropathic pain, such as
gabapentin (Neurontin),1 may also be used in combination with opi-
ates. Recently, several US states have identified SCD as one of the
severe medical conditions for which medical marijuana use is
approved. While large, controlled studies of medical marijuana in
SCD are missing, the potential benefit of cannabinoids on the neu-
ropathic pain of SCD, opiate sparing, and the management of other
complications makes them an attractive therapeutic strategy.
Because analgesic care is life-long, consultation with pain
specialists is often valuable, particularly in patients for whom
more sophisticated pain regimens are needed. For instance, the
mu-opioid receptor partial agonist buprenorphine (Buprenex,
Butrans), opioid rotation, and methadone used as analgesic can
help reduce the total opiate requirements. Urine toxicology screens
are indicated and should be scheduled at regular intervals both to
document adherence with the therapy and to screen for use of illicit
substances.
Transfusional Therapy
In SCD, the benefits of transfusion in terms of improved hemody-
namics and oxygenation need to be balanced with the risks of iron
1
Not FDA approved for this indication.
mission of infectious agents. Leuko-reduced, sickle-negative RBCs
with extended phenotypic matching for Rh Cc, Ee, and Kell, which
account for 80% of detected antibodies, are required. By employ-
ing extended phenotypic matching, the rate of alloimmunization
decreased from 3% to 0.5% per unit, and the rate of delayed hemo-
lytic transfusion reactions decreased by 90% in the STOP study. In
previously immunized patients, a full RBC match also inclusive of
matching for the Duffy, Kidd, and S antigens is recommended. Indi-
cations for transfusion include hemoglobin less than 5 g/dL or less
than 6 g/dL with symptoms and any severe complication such as 461
stroke, aplastic anemia, splenic or hepatic sequestration, or acute
chest syndrome.
Prophylactic transfusions have been considered standard of care
before surgery (with the exclusion of minor procedures such as intra-
venous port placement); the benefit of preoperative transfusions in
preventing SCD-related complications in HbSS patients has also
been confirmed in a small randomized clinical trial (the TAPS study).
As to the type of transfusion strategy to be used, a clinical trial pub-
lished in 1995 showed that a conservative prophylactic transfusion
regimen to achieve a target hemoglobin of 10 g/dL and any HbS
value was as effective as an aggressive regimen to achieve a hemoglo-
bin of 10 g/dL and a target HbS value of less than 30% in preventing
postsurgical complications such as acute chest syndrome.
Exchange transfusion (erythrocytapheresis with RBC exchange)
is usually reserved for the most severe complications, which include
acute chest syndrome with impending pulmonary failure, acute
stroke and its prevention in children, multiorgan failure, and sepsis.
Box 1 summarizes the main indications for simple and exchange
transfusion in SCD as well as the areas of uncertainty.
Iron Chelation
Patients who have received more than 10 transfusions or 20 units
of packed RBCs should be screened for iron overload. Most
authorities recommend initiation of iron chelation based on a fer-
ritin level consistently greater than 1000 ng/mL, based on data
from the thalassemia literature, although liver iron quantitation
by MRI or biopsy should be obtained, when available, prior to
therapy and to monitor its effectiveness. In the United States, the

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 Nutritional Considerations
BOX 1 Indications for Transfusion Malnutrition, growth retardation, and stunting with findings of
low lean and fat body mass are highly prevalent in children and
No Indication
adolescents with SCD due to their increased caloric demands
Chronic steady-state anemia
and a hypermetabolic state. Macronutrient and micronutrient defi-
Uncomplicated painful episode
ciencies are common, and nutritional counseling is warranted.
Infections
Hypovitaminosis D and low bone mineral density are also preva-
Minor surgery without general anesthesia
lent in children and adults. Folic acid1 is indicated at the dose of
Aseptic necrosis of hip or shoulder
1 mg daily as in other hemolytic diseases, particularly where folate
Uncomplicated pregnancy
nutritional supplementation programs are absent. Strategies aimed
Unclear Indication at decreasing iron intake and absorption should be implemented
Intractable or frequent painful episodes early. There is also growing interest in antioxidant nutraceuticals,
Leg ulcers although there are no clear guidelines in these areas at present. The
Before receiving IV contrast dye small subset of patients who are overweight or obese is at risk for
Complicated pregnancy exacerbating or precipitating common orthopedic problems in
Cerebrovascular accident in adults SCD such as avascular necrosis of the femoral head and its resulting
Chronic organ failure disability. These patients should also receive targeted nutritional
counseling.
Simple Transfusion
Symptomatic anemia
Hydroxyurea
• High output cardiac failure
Since the pediatric hematologist Janet Watson suggested in 1948
• Dyspnea
that the paucity of sickle cells in the peripheral blood of newborns
• Angina
was due to the presence of increased HbF, there has been interest in
• Central nervous system dysfunction
developing therapies to modulate the hemoglobin switch from fetal
Sudden decrease in hemoglobin
to newborn life and prolong HbF production. Several antineoplas-
• Aplastic crisis
tic agents, including 5-azacytidine (Vidaza)1 and hydroxurea,
• Acute splenic sequestration
became the focus of attention after they were found to increase
Severe anemia (Hb 5 g/dL) with fatigue or dyspnea
HbF levels in nonhuman primates and individuals with SCD.
Preparation for surgery with general anesthesia
The landmark Multicenter Study of Hydoxyurea in Sickle Cell
Exchange Transfusion Disease (MSH) showed that the incidence of painful crises was
Acute cerebrovascular accident reduced from a median of 4.5 per year to 2.5 per year in
Multiple organ system failure hydroxyurea-treated patients with SCD. The rates of acute chest
Acute chest syndrome syndrome and blood transfusion were also reduced significantly.
Hepatic sequestration A follow-up for up to 9 years of 233 of the original 299 subjects
VI Hematology

Retinal surgery
oral chelating agents deferasirox (Exjade) and deferiprone (Ferri-
prox) and the parenteral deferoxamine (Desferal) are available
and should be administered until the ferritin level is less than
500 ng/mL for three consecutive measurements. Patients on iron
chelation with deferasirox and deferoxamine require monitoring
462 of hepatic, renal, auditory, and visual toxicity, and particular cau-
tion has to be exercised in the setting of renal disease, because tran-
sient, reversible increases in serum creatinine as well as rare
instances of irreversible acute kidney injury have been reported
in patients with underlying renal insufficiency. Deferiprone has
been associated with agranulocytosis and neutropenia, mandating
close monitoring of the absolute neutrophil count during therapy.
Erythropoietic Stimulating Agents
Whereas a brisk reticulocytic response is common in SCD, patients
who develop renal failure or aplastic crises or who receive therapy
with hydroxyurea may experience a relative or absolute reticulocy-
topenia (<100,000 reticulocytes/mL) and a worsening of their
baseline anemia. In these situations, therapy with erythropoietic
stimulating agents (ESAs) may be beneficial.
Because of bone marrow expansion in patients with HbSS,
higher starting doses of erythropoietin (Epogen, Procrit)1 than in
patients without SCD and on the order of 300 U/kg three times
per week (or alternatively as a single dose of 900 U/kg once weekly)
may be considered. For darbepoetin (Aranesp),1 a reasonable start-
ing dose is 100 to 200 μg/weekly or every 2 weeks. ESAs can be
titrated by 20% to 25% increases in dose per week in patients
who do not respond adequately. Weekly monitoring of hematocrit
is essential to avoid overdosage and relative erythrocytosis, which
can lead to hyperviscosity and vaso-occlusive episodes.
showed a 40% reduction in mortality among those who received
hydroxyurea. This study led to the approval of hydroxyurea
(Droxia, Siklos) as the first disease-modifying therapy in adults
with SCD. More recent studies showed that hydroxyurea is safe
and effective in children and adults with SCD. The recently con-
cluded BABY HUG study showed that children 9 to 18 months
with HbSS disease randomized to receive 2 years of hydroxyurea
therapy, irrespective of the disease severity, had less dactilytis
and fewer pain episodes, hospitalizations, and transfusions than
children receiving placebo.
On the molecular and cellular levels, the benefits of hydroxyurea
are mostly related to increased intracellular HbF, which prevents
the formation of HbS polymers and sickling. In addition to this
mechanism, some patients on hydroxyurea who do not adequately
increase their HbF levels also display clinical benefits, suggesting
that hydroxyurea might have other beneficial rheologic properties.
Although the MSH study only included patients with HbSS, its
findings traditionally have been extrapolated to other sickle cell
syndromes such as HbSC and HbS/β-thalassemia. A report from
Greece, where S/β-thalassemia is highly prevalent, has confirmed
that hydroxyurea similarly reduces complications and mortality
in patients with HbS/β0-thalassemia, with a nonsignificant benefit
also observed in HbS/β+ thalassemia. Existing guidelines also rec-
ommend hydroxyurea in patients with HbSC disease, but there
is still no high level evidence to support this practice.
Hydroxyurea has been indicated at a dosage of 15 mg/kg
(7.5 mg/kg in patients with renal disease) in patients with frequent
pain episodes, history of acute chest syndrome, other severe vaso-
occlusive episodes, or severe symptomatic anemia, although
another sensible approach is to prescribe it to all patients with
HbSS regardless of their phenotype. Endpoints are less pain,
increase in HbF to 15% to 20%, increased hemoglobin level to
7 to 9 g/dL in severely anemic patients, improved well-being,
and acceptable myelotoxicity. The dosage can be increased by

1 1
Not FDA approved for this indication. Not FDA approved for this indication.

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Start therapy if one or more of the following conditions are present:
• frequent pain episodes
• history of acute chest syndrome
• other severe VOE
• severe symptomatic anemia
Starting dose: 15 mg/kg or 7.5 mg/kg if the patient has kidney
disease
Endpoints:
• less pain
• increase in HbF to 15%–20%
• increased hemoglobin level to 7–9 g/dL
• improved well-being
• acceptable myelotoxicity
Dose escalation: increase dose by 500 mg every other day every
8 weeks if no toxicity encountered to a maximum of 35 mg/kg
Lab monitoring:
• At time of initiation or escalation: check CBC/differential/reticulocyte
count every 2 weeks; serum chemistries every 2–4 weeks, percent
HbF every 6–8 weeks
• During maintenance: check CBC/differential/reticulocyte count
chemistries monthly, percent HbF every 3 months
Criteria to hold:
• ANC <2000
• Hb <9.0 g/dL and reticulocyte count <80,000 (alternatively start Epo)
• Platelet count <80,000
• Raising creatinine
• 2-fold elevation of AST or ALT over baseline
• 2 months prior to planned conception/pregnancy
Figure 3 Protocol for hydroxyurea treatment.
500 mg every other day every 8 weeks to a maximum of 35 mg/kg
if no toxicity is encountered. Considering the potential myelotoxi-
city, hepatotoxicity, and nephrotoxicity of this medication, labora-
tory monitoring needs to be performed every 2 weeks at the time of
initiation or escalation and monthly during maintenance therapy.
Laboratory studies should include a complete blood cell (CBC)
count, differential and reticulocyte count, and serum chemistries.
Measurements of HbF can be performed every 3 months. An ele-
vated MCV is a marker of adherence to the therapy.
Criteria for holding hydroyurea are listed in Figure 3. Patients
need to be counseled on the teratogenic potential, as demonstrated
in animal studies, as well as the risks of infertility and leukemogen-
esis, although a growing body of evidence shows that these risks
may have been overestimated in patients with SCD.
Other side effects that can affect compliance include, but are not
limited to, weight gain, alopecia, skin and nail hyperpigmentation
(melanonychia), nausea and vomiting, and mucosal ulcerations.
Because of the toxicity concerns as well as factors intrinsic to
long-term preventive therapy, hydroxyurea therapy has had low
effectiveness in spite of high efficacy, with underprescribing by
health care professionals and poor patient compliance being major
obstacles to its widespread adoption.
Therapy of Pulmonary Hypertension
Because evidence-based guidelines for managing pulmonary hyper-
tension in patients with SCD are not available, recommendations are
based upon the pulmonary arterial hypertension literature, case
reports, small open-label studies, and expert opinion. For patients
with mild pulmonary hypertension (tricuspid regurgitant velocity
[TRV], 2.5-2.9 m/sec), it is important to identify and treat risk fac-
tors associated with pulmonary hypertension such as rest, exercise
or nocturnal hypoxemia, sleep apnea, pulmonary thromboembolic
disease, restrictive lung disease or fibrosis, left ventricular systolic
and diastolic dysfunction, severe anemia, and iron overload. These
patients may benefit from aggressive SCD management, including
optimization of hydroxyurea dosage and initiation of a chronic
transfusion program in those who do not tolerate or respond poorly
to hydroxyurea. Consultation with a pulmonologist or cardiologist
experienced in pulmonary hypertension is also recommended.
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For patients with TRV 3 m/sec or more, we recommend follow-
ing the guidelines for TRV 2.5 to 2.9 m/sec. In addition, right heart
catheterization is necessary to confirm diagnosis and to directly
assess left ventricular diastolic and systolic function. We would
consider specific therapy with selective pulmonary vasodilator
and remodeling drugs if the patient has pulmonary arterial hyper-
tension defined by right heart catheterization and exercise limita-
tion defined by a low 6-minute walk distance.
FDA-approved drugs for primary pulmonary arterial hyperten-
sion include the endothelin receptor antagonists (bosentan [Tracl-
eer] and ambrisentan [Letairis]), prostaglandin-based therapy
(epoprostenol [Flolan], treprostinil [Remodulin, Tyvaso, Oreni-
tram], and iloprost [Ventavis]), the phosphodiesterase-5 inhibitors
(sildenafil [Revatio]), and riociguat [Adempas], the first member of
a new class of drugs, the soluble guanylate cyclase (sGC) stimula-
tors. No published randomized studies in the SCD population exist
for any of these agents, although a multicenter placebo-controlled
trial of sildenafil for pulmonary hypertension of SCD was stopped
early because of an unexpected increase in hospitalizations for
vaso-occlusive crisis in the treatment group receiving sildenafil.
Anticoagulation is indicated in patients who have evidence of
pulmonary thromboembolic complications and is supported by
evidence of benefit in other populations with pulmonary
hypertension.
Hematopoietic Stem Cell Transplantation
Despite improvement of supportive care in SCD, life expectancy
remains lower than for those not affected. In addition, quality of
life for patients with SCD is usually significantly impaired.
Although hydroxyurea can decrease acute complications of SCD
such as vaso-occlusive episodes and acute chest syndrome, no sat-
isfactory measures exist to prevent the development of irreversible
organ damage in adults. Further, therapy with hydroxyurea is life-
Sickle Cell Disease
long, and only 20% to 30% of eligible patients are prescribed or
actually take the drug.
Currently, allogeneic hematopoietic stem cell transplantation
(HCT) remains the only curative treatment. Indications for HCT
have been empirically determined from prognostic factors derived
from studies of the natural history of SCD. The most common indi-
cations for which patients with SCD have undergone HCT are a
history of stroke, recurrent acute chest syndrome, or frequent
vaso-occlusive episodes.
Allogeneic HCT after myeloablative therapy has been performed 463
in hundreds of pediatric and numerous adult patients with SCD.
The backbone of the preparative regimens have consisted of busul-
fan (Busulfex)1 14 to 16 mg/kg and cyclophosphamide (Cytoxan)1
200 mg/kg. Additional immunosuppressive agents used have
included antithymocyte globulin (Atgam),1 rabbit antithymocyte
globulin (Thymoglobulin),1 antilymphocyte globulin, or total lym-
phoid irradiation (Figure 4). Cyclosporine A (Neoral),1 alone or
with mercaptopurine (Purinethol)1 or methotrexate,1 has been
used for post-transplant graft-versus-host disease prophylaxis.
The outcome of HCT for patients with SCD from matched sib-
lings is excellent. Of 1000 recipients of HLA-identical sibling trans-
plants performed between 1986 and 2013 and reported to the
European Blood and Marrow Transplant, Eurocord and the Cen-
ter for International Blood and Marrow Transplant Research, the
5-year event-free and overall survival was 91.4% (95% CI 89.6%–
93.3%) and 92.9% (95% CI 91.1%–94.6%), respectively. Event-
free survival was lower with increasing age at transplantation
(hazard ratio [HR] 1.09; p<0.001) and higher for transplantations
performed after 2006 (HR 0.95, p ¼ 0.013). Twenty-three patients
experienced graft failure; 70 patients (7%) died, the most common
cause of death being infection. Stabilization or reversal of organ
damage from SCD has been documented after HCT. In patients
who have stable donor engraftment, complications related to
SCD resolve, and there are no further episodes of pain, stroke,
or acute chest syndrome. Patients who successfully receive
1
Not FDA approved for this indication.
 Nonmyeloablative Reduced intensity Myeloablative

• FLU/Mel/Alemtuzumab

Immunosuppression
• BU8/Flu/Alemtuzumab
• TB1200/Flu/ATG • BU8/Flu/ATG/TLI • BU16/CY200/ATG

• TB1200/Flu • BU8/Flu/ATG • BU16/CY200

Viral and fungal • BU8/Flu
infections • TB1200
EBV-associated
lymphoproliferation
Myelosuppression
Neutropenia
Infections
Mucositis

Figure 4 Spectrum of immunosuppression and myelosuppression in preparative regimens in hematopoietic stem cell transplantation (HCT) in sickle cell
disease (SCD). Most preparative regimens for HCT in SCD have employed a backbone of busulfan (BU) (Busulfex)1 and cyclophosphamide (CY)
(Cytoxan).1 Additional immunosuppressive agents include equine antithymocyte globulin (Atgam)1 or leporine antithymocyte globulin
(Thymoglobulin)1 (ATG), antilymphocyte globulin, total lymphoid or total body irradiation (TLI or TBI), fludarabine (Flu)1 (Fludara), and
alemtuzumab (Campath).1 Attempts to reduce the intensity of preparative regimens for patients with SCD have been based on one of two approaches.
The first is the use of reduced-intensity conditioning regimens to produce less myeloablation. These require donor marrow infusion for hematopoietic
recovery. The second is the use of nonmyeloablative regimens, which do not eradicate host hematopoiesis and allow hematopoietic recovery even
without donor stem cell infusion. (Adapted with permission from Krishnamurti L: Hematopoietic cell transplantation: A curative option for sickle cell
disease. Pediatr Hematol Oncol 24:569–575, 2007.)

allografts do not experience sickle-related central nervous system
complications and have evidence of stabilization of central nervous
system disease by cerebral MRI. However, the impact of successful
HCT on reversal of cerebral vasculopathy has been variable.
Current research is focused on improving the applicability of
HCT to a greater proportion of patients with SCD by the develop-
ment of novel conditioning regimens minimizing myeloablation
VI Hematology
trial. As in the case of L-glutamine, crizanlizumab was used with
and without concurrent hydroxyurea therapy. The pan-selectin
inhibitor rivipansel5 has shown similar promising results and is
currently undergoing phase III testing.
Modulation of Hemoglobin Oxygen Affinity
Deoxygenation of HbS leads to polymerization, sickling, and

(see Figure 4), the use of novel sources of hematopoietic stem cells
such as umbilical cord blood, extending HCT to adult recipients
and alternate donors such as matched unrelated donors and hap-
loidentical donors. The aim of these studies is to develop safe
and effective alternatives for patients without matched sibling
donors, thus increasing the applicability of curative therapy
for SCD.
hemolysis. Thus, strategies aimed at increasing the oxygen affinity
of HbS may be beneficial. Initial results of a phase IIa study of once
daily oral GBT440-007 (now voxelotor) showed improvement in
hemoglobin and reduction in daily pain in adolescents and adults
with SCD by increasing hemoglobin oxygen affinity and decreasing
HbS polymerization and sickling, and a phase III study is currently
under way.

New and Experimental Therapies Modulation of Nitric Oxide

464 The recent decade has witnessed a flourishing of new therapeutic
approaches for sickle cell disease. In 2018, pharmacologic
L-glutamine (Endari) has received FDA approval as the second
disease-modifying drug in SCD. A randomized, phase III multicen-
ter trail showed that patients in the L-glutamine group had signif-
icantly fewer pain crises and hospitalizations than those in the
placebo group. Of note, two-thirds of the patients in both arms
received concomitant hydroxyurea. Reassuringly, the drug had rel-
atively mild side effects incluging nausea and fatigue. L-glutamine
presumably acts by reducing oxidant stress in the sickle red blood
cells, although its effects on major disease parameters such hemo-
lysis are unclear.
Other therapeutic approaches are outlined in the following
paragraphs.
Modulation of Cellular Adhesion
Adhesive interactions between red blood cells, white blood cells
and platelets and between cells and endothelium are implicated
in the pathogenesis of vaso-occlusive episodes. Recently, several
compounds have been developed to target specific adhesion mole-
cules such as E-selectin and P-selectin. This is a particularly prom-
ising area of research that has yielded two compounds in advanced
phases of development. The P-selectin inhibitor crizanlizumab5 has
shown significant reduction of the rate of crises per year and longer
median time to the first crisis and second crisis when given as intra-
venous prophylaxis in a double-blind, randomized, phase II clinical
5 7
Investigational drug in the United States.
Nitric oxide (NO) is an active biogas and a free radical species that
mediates arterial relaxation, cellular adhesion to endothelium,
hemostasis, and blood viscosity. In SCD, NO bioactivity is
reduced as a result of decreased production due to endothelial per-
turbation and NO scavenging by cell-free hemoglobin generated
during intravascular hemolysis. Dietary supplementation with
L-arginine,7 a precursor of NO, and delivery of exogenous NO
or NO bioactivity to the microvasculature in SCD, should promote
dilatation of the terminal arterioles where obstruction to flow and
tissue damage occurs, improvement of lung ventilation and perfu-
sion is matching, decrease in pulmonary artery pressures, and inhi-
bition of platelet aggregation and cellular adhesion. Although two
recent clinical trials on L-arginine supplementation and inhaled
NO (DeNOVO trial) for vaso-occlusive episodes failed to show
a clinical benefit, optimization of timing and dosing, and novel
strategies to target the NO pathway might lead to valuable NO
therapeutics in the future.
Gene Therapy
The ultimate cure for sickle cell disease, gene therapy, is finally on
the horizon. A French group has reported that a patient has been
successfully treated with lentiviral-mediated insertion of an anti-
sickling beta globin gene into autologous stem cells. The trans-
duced cells were then transplanted into the patient who is free from
the hallmarks of sickle cell disease 15 months post-transplant.
5
Investigational drug in the United States.
Available as dietary supplement.

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Surgical Issues
Preoperative patient optimization includes prophylactic transfu-
sion, close monitoring of pulse oximetry, adequate analgesia based
on the patient’s opiate tolerance, and monitoring for sickle cell–
related complications.
Avascular necrosis (AVN) of the femoral heads, and more rarely
of the humeral heads, is the most common orthopedic problem in
SCD. Surgery is usually deferred until the pain and disability from
AVN become intolerable and usually involves total hip or shoulder
arthroplasty. This is usually a more involved procedure than in the
general population on account of the altered bone anatomy in
SCD. Patients with bone marrow expansion may experience thin-
ning of the cortical bone and prosthetic instability, whereas some
may suffer from the opposite problem of obliteration of the med-
ullary shaft by sclerotic bone in response to multiple necrotic
events.
Patients with SCD tend to develop pigmented gallstones and
cholelithiasis. Cholecystectomy is performed in patients with
SCD with cholelithiasis, right upper quadrant pain, and a positive
hepatobiliary iminodiacetic acid (HIDA) scan. In SCD, the rate of
intraoperative complications is higher and so is the rate of rever-
sion from laparoscopic to open cholecystectomy.
Splenectomy has been reserved for patients with massive splenic
infarction (>50% of the spleen volume); intractable, recurrent
splenic pain; and splenic abscess in the setting of splenic infarction.
It is important to limit splenectomy to these few specific circum-
stances, because overwhelming sepsis and acute pulmonary hyper-
tension have been reported in the postsplenectomy period in SCD.
Kidney transplantation has been successfully performed in
patients with SCD on chronic renal replacement therapy, although
survival at 7 years is lower than in African Americans without SCD
(67% vs. 83%). This difference is mostly due to vaso-occlusive
complications in the transplanted kidney, possibly exacerbated
by the higher hematocrit in the postoperative period from resump-
tion of endogenous erythropoietin production and increased blood
viscosity. It is therefore critical to closely monitor ESA therapy in
the post-transplantation period to prevent overdosing and relative
erythrocytosis. A chronic transfusion program to prevent intrare-
nal sickling and maximization of hydroxyurea therapy should also
be entertained, although its benefits need to be balanced against the
risk of HLA alloimmunization and rejection. Combined solid
organ and HCT protocols are being developed to overcome these
complications. Recently, lung transplantation has been successfully
performed in a SCD patient with severe pulmonary arterial hyper-
tension and pulmonary veno-occlusive disease.
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THALASSEMIA
Method of
Sarah A. Holstein, MD, PhD; and Raymond J. Hohl, MD, PhD
CURRENT DIAGNOSIS
• Complete blood count: anemia (very severe in β-thalassemia
major, mild in β-thalassemia minor and α-thalassemia trait), low
mean corpuscular volume, variable leukocytosis, thrombocyto-
penia (secondary to splenomegaly) or thrombocythemia (after
splenectomy)
• Peripheral blood smear: hypochromia, microcytosis,
anisocytosis, poikilocytosis, target cells, Heinz bodies, nucleated
red blood cells