Sickle Cell Disease and Trait: What Every Primary Care Physician Needs to Know

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Sickle Cell Disease and Trait What Every
Primary Care Physician Needs to Know
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Objectives

• Pathophysiology of sickle cell disease
• Inheritance of sickle cell disease
• Health maintenance for sickle cell disease
• Management of acute illness

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• The Management of a child with sickle cell
  disease is best when overseen by a comprehensive
  sickle cell disease center.
• If unavailable, care should be provided in
  consultation with a pediatric hematologist.

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Sickle Cell Disease

• Pathophysiology

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What Is Sickle Cell Disease?

• An inherited disease of red blood cells
• Affects hemoglobin
• Polymerization of hemoglobin leads to a cascade
  of effects decreasing blood flow
• Tissue hypoxia causes acute and chronic damage

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Why Do Cells Sickle?

• Glutamic acid is substituted for valine
• Allowing the polymerization of sickle hemoglobin
  when deoxygenated

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Normal Vs. Sickle Red Cells

• Sickle
• Sickle-Shaped
• Rigid
• Lives for 20 days or less

• Normal
• Disc-Shaped
• Deformable
• Life span of 120 days

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Hemolysis and Vaso-occlusion

• Vaso-occlusion
• Occurs when the rigid sickle shaped cells fail
  to move through the small blood vessels, blocking
  local blood flow to a microscopic region of
  tissue. Amplified many times, these episodes
  produce tissue hypoxia. The result is pain, and
  often damage to organs.

Hemolysis The anemia in SCD is caused by red
cell destruction, or hemolysis, and the degree of
anemia varies widely between patients. The
production of red cells by the bone marrow
increases dramatically, but is unable to keep
pace with the destruction.
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Hemolysis and Vaso-occlusion(continued)

• Chronic Manifestations
• Anemia
• Jaundice
• Splenomegaly
• Functional asplenia
• Cardiomegaly and functional murmurs
• Hyposthenuria and enuresis
• Proteinemia
• Cholelithiasis
• Delayed growth and sexual maturation
• Restrictive lung disease
• Pulmonary Hypertension
• Avascular necrosis
• Proliferative retinopathy
• Leg ulcers
• Transfusional hemosiderosis

• Acute Manifestations
• Bacterial Sepsis or meningitis
• Recurrent vaso-occlusive pain (dactylitis,
  muscoskeletal or abdominal pain)
• Splenic Sequestration
• Aplastic Crisis
• Acute Chest Syndrome
• Stroke
• Priapism
• Hematuria, including papillary necrosis

Potential cause of mortality
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Sickle Cell Disease SCD Genotype
Genotype
Genotype prevalence

• Sickle cell anemia (SS)
• Sickle Hb C disease (SC)
• Sickle S beta plus(Sß thalassemia )
• Sickle Beta zero(Sß thalassemia)

• 65
• 25
• 8
• 2

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Historical Distribution of Hemoglobin Variants
Hemoglobin S
Hemoglobin C
Hemoglobin D
Malarial Regions of Africa and Asia Alpha
thalassemia occurs in all these regions as well
Hemoglobin E
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Prevalence/Incidence of SCD

• In African-Americans the incidence of SCD is 1 in
  375 for HbSS, 1 in 835 for HbSC and 1 in 1,667
  for Sickle beta-thalassemia. In addition, 1 in 12
  African-Americans are carriers for the disorder
• In other U.S. populations, the prevalence of
  sickle cell disease is 1 in 58,000 Caucasians 1
  in 1,100 Hispanics (eastern states) 1 in 32,000
  Hispanics (western states) 1 in 11,500 Asians
  and 1 in 2,700 Native Americans

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Sickle Cell Pedigree

• Parents with sickle cell trait hemoglobin AS
• Probability of child with hemoglobin AA 25
• Probability of child with sickle cell trait AS
  50
• Probability of child with sickle cell disease SS
  25

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Sickle Cell Disease

• Newborn Screening

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Newborn Screening for Sickle Cell Disease

• 47 states, Washington DC, Puerto Rico, and the
  Virgin Islands provide mandatory universal
  newborn screening
• Specimen must be drawn prior to transfusion
• Prevention of pneumococcal septicemia
• Early Detection and treatment of splenic
  sequestration

Linkage to timely diagnostic, parental education,
and comprehensive care markedly reduces morbidity
and mortality in infancy and childhood.
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Interpreting Newborn Screening ResultsSickle
Hemoglobinopathies

• Screening Results Associated Disorder
• FS SS or Sßthalassemia
• FSC SC
• FSA S ß thalassemia
• FSE S Hemoglobin E
• FS Variant S Variant

Confirmatory testing requires hemoglobin
separation by electrophoresis (cellulose acetate
and citrate agar), isoelectric focusing, and/or
high performance lipid chromatography. Solubility
testing should never be used for confirmation.
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Interpreting Newborn Screening Results
Hemoglobinopathy Carriers
Newborn Screening Result Associated
Carrier State FAS Sickle Cell
Trait FAC Hb C Carrier FAE Hb E
Carrier FA Variant Hb Variant Carrier
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Sickle Cell Disease

• Health Maintenance
• And
• Management

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Management

• Health maintenance
• Infection prevention
• Pain management
• Sickle emergencies
• Chronic disease management

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Health Maintenance

• Frequent visits every 3 to 6 months
• Immunizations
• Routine immunizations
• Hib- 6 months and older
• 23 valent Pneumovax at five years
• Penicillin prophylaxis beginning no later than
  two months
• Nutrition and fluids
• Folate supplementation is controversial

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Health Maintenance

• Physical exam with attention to
• Growth and development, jaundice, liver/spleen
  size, heart murmur of anemia, malocclusion from
  increased bone marrow activity, delayed puberty
• Lab evaluations
• CBC with differential and reticulocyte count,
  urinalysis, renal liver function

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Health Maintenance

• Special studies
• Brain- Transcranial doppler ultrasonography,
  MRI/MRA
• Lungs- Pulmonary function tests, Echo cardiogram
  for pulmonary hypertension
• Neurologic- neuropsychological testing

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Current Recommendations

• Penicillin Prophylaxis SS, SbºThalassemia
• 2 months to 3 years 125 mg PO BID
• Over 3 years 250 mg PO BID
• When to discontinue is controversial
• Penicillin Prophylaxis SC and Sb Thalassemia
• SC warrants penicillin prophylaxis similar to SS
• Sb Thalassemia penicillin prophylaxis can be
  safely discontinued at 5 years
• Routine use in infants and children is
  controversial
• Special Circumstances
• History of repeated sepsis, surgical splenectomy

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Eye Examination

• Retinal vessel disease
• Incidence 33 in hemoglobin SC
• Incidence 3 in SS
• Annual evaluation after age 10 years by
  ophthalmologist
• Laser photocoagulation for vessel disease

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Emergencies

• Fever/infection
• Acute chest syndrome
• Eye trauma (hyphema)
• Priapism
• Stroke
• Splenic sequestration
• Severe pain

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Fever and Infection

• Fever gt 38.5 C (101F)
• is an EMERGENCY
• Basic laboratory evaluation
• CBC with differential and reticulocyte count,
  blood, urine, and throat cultures, urinalysis,
  chest x-ray

• Indications for hospitalization IV antibiotics
• -Child appears ill
• -Any temperature gt 40C
• -Abnormal laboratory
• values
• Start IV antibiotics IMMEDIATELY if child appears
  ill or temperature gt 40C (DO NOT WAIT FOR LABS)

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Acute Chest Syndrome
A leading cause of death in sickle cell disease

• Clinically
• Acute onset of fever, respiratory symptoms, new
  infiltrate on chest x-ray
• Causes
• Infection
• Fat emboli
• Lung infarct

Since you cannot distinguish between acute chest
syndrome and pneumonia clinically there is no
change in treatment.
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Eye Trauma
Eye trauma is an emergency in ALL sickle
conditions(including sickle trait)

• Get sickle prep -rapid test- if sickle status
  unknown
• Complications if untreated
• -glaucoma,
• -optic nerve atrophy,
• -retinal artery blockage

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Priapism
Commonly occurs in children and adolescents with
SS or SC

• Treatment is difficult
• Opioid pain medication
• Intravenous fluids
• Aspiration and irrigation of the corpus
  cavernosum
• Surgery
• Blood Transfusions
• Impotence with severe disease or recurrent
  episodes

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Stroke
Any acute neurologic symptom other than mild
headache, even if transient, requires urgent
evaluation.

• Historically 8 to 10 of children with SS
• Silent Stroke in 22 of children with
  hemoglobin SS

Treatment Chronic transfusion therapy to
maintain sickle hemoglobin at or below 30
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Splenic Sequestration

• Sudden trapping of blood within the spleen
• Usually occurs in infants under 2 years of age
  with SS
• Spleen enlarged on physical exam, may not be
  associated with fever, pain, respiratory, or
  other symptoms
• Circulatory collapse and death can occur in less
  than thirty minutes

• Recurrence very common (50)
• Associated with high mortality (20)

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Splenic Sequestration

• Hemoglobin SS
• Incidence increased 6 and 36 months
• Overall incidence about 15
• Hemoglobin SC
• Incidence increased 2 and 17 years
• Mean age 8.9 years
• Can occur in adolescence and adulthood
• Incidence about 5

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Treatments For Splenic Sequestion

• Intravenous fluids
• Maintain vascular volume
• Cautious blood transfusion
• Treat anemia, sequestered blood can be released
  from spleen
• Spleen removal or splenectomy
• If indicated

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Pain Management

• Acute pain
• Hand-foot syndrome (dactylitis)
• Painful episodes vasoocculsion
• Splenic sequestration
• Acute chest syndrome
• Cholelithiasis
• Priapism
• Avascular necrosis
• Right upper quadrant syndrome

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Pain Management

• Pain is an emergency
• Hospital evaluation
• Hydration 1.5 times maintenance unless acute
  chest syndrome suspected
• Assess pain level and treat
• Do not withhold opioids
• Frequently reassess pain control
• Assess for cause of pain/complications

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Pain Management

• Mild-moderate pain
• Acetaminophen
• Hepatotoxic
• Non-steroidal anti-inflammatory agents (NSAIDs)
• -Contraindicated in patients with
  gastritis/ulcers and renal failure
• -Monitor renal function if used chronically

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Pain Management

• Moderate-severe pain
• Opioids are first-line treatment
• Morphine sulfate or hydromorphone
• Meperidine NOT recommended
• (Metabolite causes seizures renal toxicity)
• Moderate or less severe pain
• Acetaminophen or NSAID's in combination with
  opioids
• Other adjuvant medications (sedatives,
  anxiolytics)
• May increase efficacy of analgesics

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Hand Foot Syndrome - Dactylitis

• Early complication of sickle cell disease
• Highest incidence 6 months to 2 years
• Painful swelling of hands and feet
• Treatment involves fluids and pain medication
• Fevers treated as medical emergency

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Renal Disease

• Renal findings
• Decreased ability to concentrate urine
• Decreased ability to excrete potassium
• Inability to lower urine pH normally
• Hematuria / papillary necrosis
• Risk factors for progressive renal failure
• Anemia, proteinuria, hematuria

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Gall Bladder and Liver

• Gall stones and biliary sludge
• Monitor by ultrasound every 1-2 years
• Cholestasis
• May progress, leading to bleeding disorders or
  liver failure
• Iron overload
• Due to chronic transfusions
• Chronic hepatitis

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Bone Disease Diagnosis and Treatment

• Avascular necrosis of hips and shoulders
• Index of suspicion
• Persistent hip or shoulder pain
• Plain film or MRI
• Treatment
• Conservative
• NSAIDs and 6 weeks of rest off affected limb
• Physical therapy

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Screening AVN

• Avascular Necrosis
• Hip Films
• Hip MRI
• Grading of AVN
• Grade I MRI
• Grade II Film/MRI
• Grade III Film
• Grade IV Film
• Grade V Film
• No grade for AVN of the shoulder

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Chronic Complications

• Anemia/Jaundice
• Brain Damage/Stroke
• Kidney failure
• Decreased lung function
• Eye disease (bleeding, retinal detachment)
• Leg ulcers
• Chronic pain management

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Anemia Jaundice

• Common and starting in the first year of life
• Decreased lifespan of sickle red cells
• Hemolysis
• Anemia
• Hyperbilirubinemia
• Reticulocytosis

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Stroke

• Intracranial hemorrhage
• More common in adults
• Sequela overt and silent strokes
• Paralysis overt stroke
• Neuropsychologic changes both overt and silent
  strokes
• Visual-spatial impairment
• Impaired memory
• Poor impulse control

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Renal Disease

• Proteinuria/Nephrotic syndrome
• 40 of SCD patients with nephrotic syndrome
  develop end-stage renal disease
• Occurs in 20 of all patients
• Occurs in 4.5 of all pediatric patients-
  increased in hemoglobin SS to 6.5
• Increased incidence with age
• Increased with anemia, increased MCV, and
  increased leukocyte count
• Renal failure common in adults

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Leg Ulcers

• Occurs in about 25 of all hemoglobin SS patients
• Predominantly males
• Incidence increased with
• Age
• Decreased hemoglobin
• Incidence decreased with alpha thalassemia
• Recurrence rate is 75

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Chronic Pain

• Pain lasting gt3 to 6 months
• Patients should receive comprehensive psychologic
  and clinical assessment
• Treatment
• Analgesics
• Hydroxyurea
• TENS units
• Relaxation techniques
• Physical and occupational therapy

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Adolescents and Transition of Care

• Young adults (gt20 years) with frequent pain
  crises at greatest risk for early death
• Barriers to care for young adults
• Lack of adult SCD providers
• Loss of medical coverage
• Developmental (level of independence, denial of
  chronic illness)
• Ineffective coping skills (passive versus active)

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Adolescents and Transition of Care

• Develop explicit plan for transition
• Team approach- pediatric and adult providers,
  social work, school/vocational staff, support
  groups
• Plan gradual transition (start 1 year before)
• Continue communication between pediatric adult
  providers after transition

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Genetic Counseling

• Who should receive counseling?
• -Parents of newborns with sickle disorders or
  traits
• -Pregnant women/ prenatal counseling
• What is the purpose of counseling?
• -Education
• -Informed decision-making
• Content should include
• -Genetic basis, chances of disease or trait
  (potential pregnancy outcome), disease-related
  health problems, variability/unpredictability of
  disease, family planning, average life span

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• Information about sickle cell disease can be
  found through the American Academy of Pediatrics
  or from the National Institute of Health on line
  at
• http//www.nhlbi.nih.gov/health/prof/blood/sickle/
  sc_mngt.pdf