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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.