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© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
in the clinic
Sickle Cell
Disease
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
Common Genotypes of Sickle Cell Disease
 Sickle cell trait (“HbAS”)
 Person carries sickle hemoglobin gene (HbS) and
also has some normal hemoglobin (HbA)
 HbS ≤40% total hemoglobin; usually no symptoms
 Cells don’t deform when deoxygenated
 Sickle cell anemia (sickle-cell disease, “HbSS”)
 HbS homozygosity; most / all HbA replaced with HbS
 Most common + most severe of sickle cell variations
 Complications due to sickled cells shape + thickness
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
Other Common Genotypes of Sickle Cell Disease
 HbSC disease
 Compound heterozygosity for HbS and HbC genes
 HbSE disease
 Compound heterozygosity for HbS and HbE genes
 HbS-β-thalassemia disease
 Compound heterozygosity for HbS and a β0- or β+thalassemia gene

HbSO Arabia
 Compound heterozygosity for HbS and HbO Arabia

HbSD Los Angeles (Punjab)
 Compound heterozygosity for HbS and HbD
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
Who should be screened for sickle cell
anemia and sickle cell trait?
 All U.S. newborns
 Test also detects sickle cell trait carriers
 At risk individuals pregnant or planning pregnancy
 Determining who is at risk can be difficult
 Maternal & paternal family history: best guide for
determining individual HbS screening
 Individuals with hyphema or hematuria
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What screening and diagnostic tests are
available?
 To detect HbS: high-performance liquid chromatography
 In newborns, children, adults
 Some labs use isoelectric focusing
 When genetic counseling needed: DNA-based test
 Establishes parental globin gene mutations
 If positive: DNA-based testing of chorionic villus samples or
amniotic fluid cells
 Before considering prenatal Dx, counsel parents:

On risks of procedure and consequences of positive Dx

On likelihood of affected fetus and options for termination
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
 Pathophysiology includes:
 Abnormal erythrocyte volume regulation
 Impaired nitric oxide bioavailability
 Reperfusion injury
 Inflammation and oxidant damage
 Abnormal intercellular interactions
 Endothelial injury
 Leukocyte and platelet activation
 HbS gene most prevalent in persons of African, Arabian,
and Asian-Indian ancestry
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
CLINICAL BOTTOM LINE: Screening…
 Screening can lead to prompt diagnosis
 Screening helps prevent serious complications
 Screening provides information for family planning
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What should prompt consideration of
undiagnosed sickle cell disease?
 Suspicious symptoms
 Frequent, unexplained pain
 Splenomegaly
 Stroke at young age
 Pneumonia with anemia requiring transfusion
 Osteonecrosis in femur heads and humerus
 Rare complications
 Leg ulcers, priapism, nephropathy+renal failure, severe anemia
 Complications occurring with advancing age
 Sickle retinopathy, liver disease
 Infections
 Major cause of death in children and adults
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What should be looked for on the physical
exam when sickle cell disease is suspected?
 Swelling and tenderness over affected areas and low-grade
fever (in acute, painful episodes)
 Consolidation, rales, rhonchi, wheezing (acute chest syndrome)
 Cardiac enlargement and systolic murmurs (common)
 Enlarged liver
 Asplenia, no splenic dullness on percussion
 Splenomegaly (in HbSC disease and HbS–β-thalassemia)
 Sickle retinopathy
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What lab tests should be ordered in the
evaluation of possible sickle cell disease?
 In untreated sickle cell anemia
 Erythrocytes (normocytic or macrocytic); microcytosis
 Sickle solubility test
 High-performance liquid chromatography
 After diagnosis established
 Baseline CBC and reticulocyte counts
 Red cell antigen phenotyping
 Blood urea nitrogen, creatinine, urine albumin, electrolytes,
bilirubin, lactate dehydrogenase, serum ferritin, alanine
transaminase, aspartate transaminase, alkaline phosphatase
 Chest radiographs and pulmonary function tests
 Pulse oximetry
 Echocardiography to estimate the TRV
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What are complications of sickle cell trait?
 Most carriers can’t concentrate urine normally
 Due to renal medullary abnormalities
 Important to hydrate adequately
 Increased risk hematuria
 Due to papillary necrosis (usually benign and self-limited)
 2-fold higher risk thromboembolic disease
 4-fold higher risk pulmonary embolism
 Splenic infarction rare
 Preop screen: needed w/ open-heart or complicated intrathoracic procedures where hypoxia intrinsic to procedure
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
Which patients with sickle cell disease
should be referred to a specialist?
 General internist, pediatrician, or family physician can
manage routine maintenance + common complications
 Consult appropriate specialists as needed
 All patients with sickle cell disease: hematologist with
expertise in hemoglobinopathies (annually)
 Pulmonary complications: pulmonologist or cardiologist
 Severe acute chest syndrome: hematologist and critical
care specialist
 Pregnancy: high-risk obstetrician and hematologist
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
CLINICAL BOTTOM LINE: Diagnosis and
evaluation…
 Suspicious symptoms: undiagnosed sickle cell disease
 Frequent, unexplained pain
 Splenomegaly
 Stroke at young age
 Pneumonia with anemia requiring transfusion
 Osteonecrosis in femur heads and humerus
 H&P and lab tests used to confirm diagnosis and
evaluate patient
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What drugs should be considered for the
primary treatment of sickle cell anemia?
 Hydroxyurea
 Only FDA-approved drug for primary Rx
 Begin early, before irreversible vasculopathy and organ
damage develop
 Reduces of acute painful events and acute chest syndrome
 Reduces mortality 40% and reduces hemolysis
 Fewer hospitalizations, reduced medical costs
 Improved physical capacity
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What is the role of blood transfusion?
 Simple transfusions reduce HbS levels more gradually
 Require only peripheral venous access and rapidly available
 Lower alloimmunization risk; greater hyperviscosity risk
 Exchange transfusions reduce HbS levels more rapidly
 Take more time to start and more complicated venous access
 Lower hyperviscosity risk; higher alloimmunization risk
 Preop: simple transfusion can reduce postop complications
 Stroke: exchange transfusion can reduce recurrence
 Acute chest syndrome
 Patient may not need transfusion if no hypoxia + chest
infiltrates minor, fever minimal, blood count changes small
 Don’t use repeated transfusion to manage routine crisis
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What is the role of bone marrow
transplantation in sickle cell anemia?
 Transplantation mortality rate: ≈5%
 Event-free survival: 84%
 Rejection or disease recurrence: ≈10%
 When successful, disease is “cured”
 Patient no longer anemic
 Long-term, stable engraftment sufficiently eliminates the
phenotype of sickle cell disease
 Myeloablative stem cell transplantation largely limited to
children <16 yrs old with severe disease
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What are the features of sickle cell anemia
over a patient's lifetime?
 Major clinical features in the first decade…
 Severe life-threatening infection
 Acute chest syndrome
 Splenic sequestration
 Stroke; pain; dactylitis
 Major clinical features in young adulthood and beyond…
 Sickle vasculopathy likely to progress despite few symptoms
 Chronic organ damage leads to pulmonary vasculopathy
 Deteriorating pulmonary function and renal failure
 Late effects of cerebrovascular disease
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
How does pain manifest in sickle cell
disease?
Clinical Features of the Acute Painful Episode
 Some patients always in pain; others rarely
 Pain distribution and duration varies
 Pain most often occurs in back, chest, extremities, joints
 Cause unclear: unrelated to “new sickling”; blood film unhelpful
 Physical findings limited
 Frequent episodes associated with poor prognosis
 Directly related to packed cell volume; indirectly related to HbF
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
How should pain be managed?
 Most pain successfully managed at home
 Many patients can sense the beginning of an episode
 Use nonopioid analgesics, then oral opioids if needed
 Up fluid intake, use rest, warm baths, heating pads, massage
 Pain requiring medical intervention
 Usually treated in the hospital ED
 Initiate parenteral opioids and adjust dosage as needed
 Individualize Rx (analgesic doses can vary considerably)
 Monitor for oversedation, hypoxia, and low respiratory rate
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
How are episodes requiring further treatment
and continuously increased use and dose of
opioids managed?
 Decision to initiate long-term opiate therapy
 Define cause of pain
 Determine pain intensity + effect on functioning, QOL
 Document evaluation and treatment plan
 Monitor closely
Causes of Persistent Severe Pain
 Progressive tissue damage
 Inadequate treatment
 Tolerance
 Hyperalgesia
 Changes at receptors
 Maladaptive behavior
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
How common is the acute chest syndrome
in sickle cell disease?
 Affects >50%
 Mortality higher in adults than children (<10% cases fatal)
 Second most common reason for hospitalization
 Features: fever, chest pain, cough, and lung infiltrates
 Causes: infarction, pulmonary infection, atelectasis,
embolism, in situ thrombosis
 Frequent postop complication, even after preop transfusion
 Fat embolism from necrotic bone marrow causes most
severe acute chest events
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
How is the acute chest syndrome in
sickle cell disease managed?
 Transfusions
 Antibiotics
 Hydration (avoid overhydration)
 Respiratory therapy with bronchodilators
 Incentive spirometry
 Maintenance of tissue oxygenation
 Oxygen: if hypoxic or tachypneic; in respiratory distress
 Opioids: balance pain relief w/ respiratory suppression risk
 Patients who deteriorate rapidly: admit to ICU
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What other conditions complicate sickle
cell anemia?
 Pulmonary vasculopathy & abnormal pulmonary function
 Infection
 Retinopathy
 Anemia
 Leg ulcers
 Priapism
 Renal disease
 Digestive system disease
 Neurocognitive dysfunction
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
As patients with sickle cell disease live
longer, what new health issues are emerging?
 Cardiomegaly and heart murmurs
 Contractility usually normal and overt CHF uncommon
 Hypertension
 Cause of ventricular hypertrophy and HF
 May contribute to sickle nephropathy and renal failure
 Chest pain
 Very common but MI unusual
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
Is pregnancy more complicated in women
with sickle cell disease?
 Most managed without regular transfusions
 Identify red cell phenotype & alloantibodies: so phenotypically matched blood can be used if needed
 Multiple-birth pregnancies benefit from transfusion
 Obstetric complications and C-section more common
 Prenatal testing needed
 Establish Hb phenotype and HbF level
 Blood counts; serum chemistries; hepatitis A,B,C; HIV testing
 Urinalysis; urine culture; rubella antibody titer; serum ferritin
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
Are patients with sickle cell disease at
particularly high risk during surgery?
 Surgery and anesthesia safe but not complication-free
 Blood transfusion: major issue preoperatively
 Preparation: hydration; optimization of pulmonary status
 Be vigilant toward detecting acute chest syndrome
Prevent acute chest syndrome after surgery with…
 Rapid mobilization
 Incentive spirometry and bronchodilators
 Close monitoring of oxygen saturation
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
How should end organ damage be
monitored, treated, and prevented?
 If patient stable  follow every 4 to 6 months
 Perform blood counts
 Monitor renal and liver function
 Test for baseline pulmonary function
 Obtain baseline and periodic estimation of TRV
 Periodically evaluate for sickle retinopathy
 Ophthalmologist visit
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
CLINICAL BOTTOM LINE: Treatment and
management…
 Sickle cell disease has protean manifestations
 Optimum care consists of:
 Direct drug therapy with hydroxyurea
 Prompt diagnosis
 Prompt treatment of complications
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What should patients be taught about
preventing disease complications?
 Good self-management can help prevent complications
 Awareness of acute pain episode beginning
 Use rest, hydration, warm baths to arrest development
 Avoidance extremes of temperature
 Cold, windy conditions associated with painful episodes
 Maintenance of good hydration
 Lower legs: protect from trauma, keep wellmoisturized
 To avoid leg ulcers
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
What should patients be taught about prenatal
screening and management of pregnancy?
 Discuss prenatal screening and its implications
 Preferably during planning
 At least in the first weeks of pregnancy
 Manage pregnancies in a high-risk obstetrics clinic
 Consult with a hematologist
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.
CLINICAL BOTTOM LINE: Patient
education…
 Teach patients to recognize the early signs of an acute crisis
 Encourage regular medical follow-up from a primary care
provider with access to a sickle cell center
© Copyright Annals of Internal Medicine, 2011
Ann Int Med. 155 (5): ITC3-1.