Sickle Cell Anemia

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Sickle Cell Anemia

• Emergency management of acute neurologic events
  in children
• Dr. Mary-Lou OByrne
• September 25, 2003

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OUTLINE

• Case presentation
• Sickle Cell Anemia fundamentals
• Genetics
• Pathogenesis
• Crises
• Sickle Cell Disease Care Consortium guidelines
• Therapies
• Prevention

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CASE (C.F.)

• 6 ½ year old black Canadian with known Sickle
  Cell Disease
• Well for 3 years
• Prior hx of splenic sequestration events
• Admitted to PLC x 3 in first 3 years of life
• Meds Pen V and Folate
• Immunizations UTD

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Presentation (C.F.)

• Well at bedtime
• _at_ 2300 woke crying with bilaterally painful legs
• Mother is rubbing her legs when pt stops crying,
  stiffens, and has a large emesis
• Generalized tonic seizure x 5 minutes
• EMS called

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On arrival in E.D.

• Eyes closed but will open eyes to voice commands
• c/o headache and abd pain
• Oriented to place and self
• PERL, marked nystagmus, diplopia on lateral gazes
  w/ RgtL lat rectus palsy
• Ataxia, unable to sit
• Vomiting with any mvmt
• Marked dysmetria
• DTR symmetric and brisk, Plantars downgoing

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Exam contd

• Chest clear, sats 85 in R/A, RR 20
• CVS HR 60-80, murmur noted
• ABD liver 4 cm down, Spleen not palp
• MSK no tenderness, swelling or erythema

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Investigations

• CXR mild cardiomegaly
• Hgb 73
• WBC 16.0 gt 9 to 12 in hospital
• Plt 529
• CBG pH 7.41 pCO2 38 pO2 191
• Lytes N INR 1.2 PTT 23
• Type and screen done
• CT head done immediately and normal

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Treatment in E.D.

• IV normal saline at maintenance
• O2
• ICU consulted
• Admitted onto clusters w/in 2 hours of arrival

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Course in Hosp

• Resolution of most of her neurologic findings
  within a few hours
• I phoned neurology after my shift and they had
  not been consulted yet
• Hematology consulted later in day
• ECHO and ECG confirmed mild rt and left
  ventricular enlargement and norm ventricular func
• MRI/MRA done and abnormal

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T2 Axial MRI
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MRI (FLAIR) vs. CT
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Course in Hospital

• Exchange transfusion in ICU on fourth day
• Sickle cells 84 to 34
• Residual left cerebellar signs on discharge
• Follow up w/ brain injury team, hematology for
  possible chronic transfusion Rx

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Sickle Cell Anemia
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Normal RBC vs. Sickle Cells
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Sickle Cell Anemia

• Hereditary hemoglobinopathy
• 8 of black Americans heterozygous for HbS
• 1910 Herrick first described sickled cells
• Heterozygote (40 HbS) protects against
  falciparum malaria
• African descent gt Hispanic, Arabians, Indians and
  whites
• 1973 life expectancy 14.3 years
• 1994 life expectancy 42 years men / 48 years
  women
• Most American states screen all newborns
• (1625 Afro-American births)

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Sickle Cell Anemia

• Structurally abnormal hemoglobin
• Normally tetramer of 4 globin chains
• 96HbA (alpha2 beta2)
• 3 HbA2 (alpha2 delta2)
• 1 HbF (alpha2 gamma2)
• SCD HbS is abnormal Beta chain
• Valine replaces glutamine on beta-globin
• Charge at site altered, allows polymerization of
  Hb
• Copolymerization w/ HbSgtCgtD etc

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SCD point mutation
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Pathogenesis

• On deoxygenation HbS aggregates and polymerizes
  (like viscous gel)
• Sickling is initially reversible w/ O2
• HbS returns to depolymerized state
• Recurrent sickling gt memb damage and
  irreversible sickling
• RBCs lose K H2 O and gain Ca
• Dehydrated cells

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Pathogenesis - 2

• HbF (fetal alpha2 gamma2) inhibits
  polymerization of HbS
• Newborns protected until 5-6 months
• Coexistent alpha-thalassemia is protective b/c it
  reduces the conc of Hb in a RBC
• Acidosis reduces O2 affinity of Hb and
  deoxygenates HbS
• HbS causes
• 1)chronic hemolytic anemia
• 2)occlusion of small blood vessels
• gt ischemic tissue damage

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Pathogenesis - 3

• RBC lasts 17 - 20 days
• of sickled cells correlates to degree of
  anemia/hemolysis
• No correlation b/w sickling and microvascular
  events
• Non-sickled cells with memb damage adhere to the
  endothelium of the microvessels.
• Lowest O2 is in microcirculation

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Pathogenesis - spleen

• Early childhood spleen enlarged w/ congestion,
  sickled RBC in splenic cords and sinusoids
• Erythrostasis gt thrombosis/infarction and tissue
  hypoxia
• Scarring gt shrinkage gtautosplenectomy by
  adolescence
• By age 5y 95 have functional asplenia

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Autosplenectomy
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Immunodeficiency

• Impaired splenic function
• Defects in alternative complement pathway impairs
  opsonization of encapsulated bacteria
• Increased susceptibility to Salmonella
  osteomyelitis (bone necrosis)
• Pneumococci and Haemophilus influenzae
  septicemia/meningitis most common causes of death
  in SCD children

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Crises

1. Dactylitis
2. Splenic sequestration
3. Aplastic anemia
4. Acute painful events
5. Acute chest syndrome
6. Neurological events

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Dactylitis

• Common presentation of SCD in children lt2 yrs
• Swollen, tender hands and feet
• Usually bilateral
• Ischemia/necrosis of bone
• Full resolution expected
• Humeral gt femoral heads prone to necrosis in
  older children/adults
• gt50 dev avascular necrosis of femoral head by
  35yr

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Dactylitis
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Splenic sequestration

• 30 incidence in young children
• Rapid, severe worsening of anemia w/ good
  reticulocytosis
• Enlarging, tender spleen
• Hypovolemic shock
• 15 mortality, 50 recurrent
• Often concurrent with viral illnesses
• Parents taught to palpate for spleen
• Rx fluid resuscitation. O2 transfusion

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Aplastic anemia

• Young children very sensitive to Parvovirus B19
  marrow suppression (68)
• Supraphysiologic oxygen decreases erythropoietin
  production and decreases retic w/in 2 days
• Supportive transfusions until retic return

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Acute painful events

• Most frequent symptom after age 2 yrs
• Vaso-occlusion vs. shunting of blood flow
• Rx hydration, O2 and aggressive narcotic use.
  Avoid Demerol (incr dependence and possible
  seizures)
• Cause usually not identified
• Peripheral/extremities in younger pts and
  proximal (back, chest, abdomen) in adults

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Acute Chest Syndrome

• s/s dyspnea, cough, chest pain
• Occasionally abd pain, fever, tachypnea,
  infiltrate on CXR, leukocytosis
• Major danger is hypoxemia
• Affects 30 of SCD w/ Mortality 10 (higher in
  adults)
• Vaso-occlusion or infection (S. pneum, H.
  influenzae, Mycoplasma, Chlamydia, Legionella and
  viruses)
• Rx oxygen, urgent partial exchange transfusion,
  intubation, ?extracorporeal mb oxygenation,
  incentive spirometry, /- bronchodilators
• May follow febrile illness in children and
  painful event in adults (w/ fat emboli)

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Acute CNS events

• Overt CVA 5 of children w/ SCD
• Greatest incidence in 5-10 year olds
• Silent infarcts in 17 before age 20
• Correlates with
• seizures
• lower painful event rate
• incr leukocyte ct gt11.8
• incr pocked RBC (gt3.5 considered evid of splenic
  dysfunc)
• SEN betaS globin gene haplotype
• Cooperative Study of Sickle Cell Disease in USA
• Followed patients for 20 years, from 6 months of
  age
• (Pediatrics March 1999)

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Stroke

• Watershed perfusion areas in most occult CVA
• Most strokes are ischemic, rarely hemorrhagic
• Anterior vessels of Circle of Willis show
  progressive narrowing w/ eventual occlusion,
  collateral vessel dev and occ moyamoya

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(C.F.) MRA
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Circle of Willis
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SICKLE CELL DISEASE IN CHILDREN AND
ADOLESCENTSDIAGNOSIS, GUIDELINES FOR
COMPREHENSIVE CARE, AND CARE PATHS AND PROTOCOLS
FOR MANAGEMENT OF ACUTE AND CHRONIC COMPLICATIONS

• Peter A. Lane, George R. Buchanan, John J.
  Hutter, Robert F. Austin, Howard A. Britton,
  Zora R. Rogers, James R. Eckman, Michael R.
  DeBaun, Winfred C. Wang, Prasad Mathew, Sarah
  Iden, Michael Recht, Jesse D. Cohen, Ernest
  Frugé, Leanne Embry, Lewis Hsu, Brigitta U.
  Mueller, Robert Goldsby, Charles T. Quinn, Marie
  Mann, and Michele A. Lloyd-Puryear
• for the Sickle Cell Disease Care Consortium
• Revised at the Annual Meeting of the Sickle Cell
  Disease Care Consortium, Sedona, AZ, November
  10-12, 2001

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• ACUTE STROKE OR NEUROLOGIC EVENT IN CHILD WITH
  SICKLE CELL DISEASE
• DEFINITION Stroke, defined as an acute,
  clinically apparent neurological event, occurs in
  8-11 of children with Hb SS. Common presenting
  symptoms and signs include hemiparesis,
  monoparesis, aphasia or dysphasia, seizures,
  severe headache, cranial nerve palsy, stupor, and
  coma. Stroke may occur without warning as an
  isolated event or may complicate other
  complications of sickle cell disease such as
  acute chest syndrome or aplastic crisis. Acute
  neurologic symptoms or signs require urgent
  evaluation and treatment.
• CONSULTS
• Hematology
• Neurology
• Physical Medicine and Rehabilitation
• MONITORING
• 1. Rapid triage - urgent hematology consultation
• 2. Hospitalize. Consider ICU admission and/or CR
  monitor first 24 hr and until stable.
• 3. Vital signs, neuro checks q 2 hr.
• 4. Record I O, daily weight.
• DIAGNOSTICS
• 1. Document duration of acute symptoms, any prior
  neurologic symptoms or trauma, and results of any
  previous CNS imaging studies (ie. CT, MRI, MRA,
  or TCD).
• 2. Document details of the neurologic exam.
• 3. Type and crossmatch for transfusion (see
  Medication/Treatment below). Consider
  requesting, if available, minor-antigen-matched,
  sickle-negative, and leukocyte-depleted RBC.
• 4. CBC, diff, platelet count, and reticulocyte
  count initially and as clinically indicated
  (compare with patient's baseline data).
• 5. RBC minor-antigen phenotype if not previously
  documented.
• 6. Consider screening coagulation profile.
• 7. Blood and urine cultures if febrile.

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ACUTE STROKE OR NEUROLOGIC EVENT IN CHILD WITH SCD

• DEFINITION Stroke, defined as an acute,
  clinically apparent neurological event, occurs in
  8-11 of children with Hb SS. Common presenting
  symptoms and signs include hemiparesis,
  monoparesis, aphasia or dysphasia, seizures,
  severe headache, cranial nerve palsy, stupor, and
  coma. Stroke may occur without warning as an
  isolated event or may complicate other
  complications of sickle cell disease such as
  acute chest syndrome or aplastic crisis. Acute
  neurologic symptoms or signs require urgent
  evaluation and treatment.

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DIAGNOSTICS

• 1. Document duration of acute symptoms, any prior
  neurologic symptoms or trauma, and results of any
  previous CNS imaging studies (ie. CT, MRI, MRA,
  or TCD).
• 2. Document details of the neurologic exam.
• 3. Type and crossmatch for transfusion (see
  Medication/Treatment below). Consider
  requesting, if available, minor-antigen-matched,
  sickle-negative, and leukocyte-depleted RBC.
• 4. CBC, diff, platelet count, and reticulocyte
  count initially and as clinically indicated
  (compare with patient's baseline data).
• 5. RBC minor-antigen phenotype if not previously
  documented.
• 6. Consider screening coagulation profile.
• 7. Blood and urine cultures if febrile.
• 8. Electrolytes initially and daily until stable.
• 9. MRI and MRA. If MRI/MRA not immediately
  available, CT without contrast to exclude
  intracranial hemorrhage with MRI/MRA later when
  available. Initiation of transfusion therapy
  should not be delayed by arrangements for imaging
  studies.
• 10. Consider CSF culture if febrile and no
  contraindication present

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FLUIDS, GENERAL

• 1. IV PO_at_ 1 x maintenance

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MONITORING

• 1. Rapid triage - urgent hematology consultation
• 2. Hospitalize. Consider ICU admission and/or CR
  monitor first 24 hr and until stable.
• 3. Vital signs, neuro checks q 2 hr.
• 4. Record I O, daily weight.

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MEDICATION/TREATMENT

• 1. Partial exchange transfusion or
  erythrocytapheresis to Hb 10 gm/dl and Hb S
  (patient's RBC) ?30 (may require transfusion
  medicine consult for erythrocytapheresis).
  Remove femoral or central venous catheter as soon
  as possible after exchange transfusion to reduce
  risk of thrombosis.
• 2. Simple transfusion with RBC to Hb
  approximately 10 gm/dl may be considered as an
  alternative to partial exchange transfusion for
  stable patients with Hb lt6-7 gm/dl (do not
  transfuse acutely to Hb gt10 gm/dl, Hct gt30).
• 3. Rx seizures if present.
• 4. Rx increased intracranial pressure if present.

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MEDICATION/TREATMENT

• 5. 02 by nasal cannula or face mask if needed to
  keep pulse ox ?92 or ? patient's baseline, if
  gt92. The etiology of a new or increasing
  supplemental 02 requirement should be
  investigated.
• 6. Consider hemoglobin electrophoresis after
  partial exchange transfusion or at discharge.
• 7. Cefotaxime or cefuroxime 50 mg/kg IV q 8 h if
  febrile. Substitute clindamycin 10 mg/kg IV q 6
  hr for known or suspected cephalosporin allergy.
  Strongly consider adding vancomycin 10-15 mg/kg
  IV q 8 hr for severe febrile illness or for
  proven or suspected CNS infection.
• 8. If applicable, continue prophylactic
  penicillin. Prophylactic penicillin should be
  discontinued while patient is receiving
  broad-spectrum antibiotics.
• 9. See other Clinical Care Paths for pain, acute
  chest syndrome, acute splenic sequestration,
  aplastic crisis, priapism, if present.

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DISCHARGE CRITERIA

• 1. Clinically and neurologically stable ?24 hr.
  after transfusions.
• 2. Afebrile ?24 hr. with negative cultures for ?
  24-48 hr. if applicable.
• 3. Taking adequate oral fluids and able to take
  oral medication if applicable.
• 4. Hematology, rehabilitation, and physical
  therapy follow-up organized.
• 5. Initiate chronic transfusion program (see p.
  27).

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CVA treatment

• Risk of recurrence is 70-90 and may be fatal
• Chronic monthly transfusion regimen to maintain
  HbS lt30
• Reduces recurrence by 90
• Continue until 18 years old
• Transcranial Doppler ultrasound to assess
  velocity of flow in circle of Willis every year
  to screen children
• Not readily available for children here
• MRI/MRA
• If velocity gt200 cm/sec, stroke risk is 10 per
  year
• start monthly transfusion therapy
• Reduces risk of stroke by 90
• Recommendation from the Stroke Prevention in
  Sickle Cell Anemia Trial (STOP)

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Stroke Rx Adult vs. Children

• CVA in adults to be treated as per non-SCD pts
• t-PA can be considered
• ASA and other antiplatelet drugs can be used
• t-PA data in children not available
• Most important in children to reverse the
  sickling
• Expect much better recovery in children post CVA

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New Therapies

• Hydroxyurea
• Chronic Transfusion therapy
• Bone Marrow transplant

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Hydroxyurea

• Increases fetal Hb (10 to 25)
• Decreases mortality in adults
• Early information on children suggest safe but
  efficacy data pending

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Chronic Transfusion Rx

• Essential in strokes and Acute Chest Syndrome
• Risks
• Iron overload
• Infection
• Alloimmunization (Afro-Amer dont express many
  of the minor red cell antigens present on
  Caucasian RBC)
• Does not reverse ischemic damage
• Does not prevent avascular necrosis of hum/fem

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Bone Marrow Transplant

• Very select population
• lt16 years old
• With an HLA-matched sibling
• 5 mortality
• Consider nonmyeloablative regime
• Stable stem cell chimera w/ phenotypic
  overexpression of the healthy graft can produce
  an asymptomatic pt

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Prevention

• Early diagnosis
• Vaccinations
• Penicillin to age 5-6 years or longer
• Folate
• Transcranial Doppler (or MRI)
• Chronic transfusion treatments
• Parental education

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