Objectives

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Sickle cell disease
Morey A. Blinder, M.D. Associate Professor of
Medicine and Pathology Immunology
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Hemoglobinopathy and Thalassemia Disorders of
the Globin Genes
Hgb A tetramer
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Discovery of Sickle Cells
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Peripheral Blood Smear
Sickle cell anemia
Normal
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Relative Frequency of Hemoglobin Variants
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Pathophysiology of sickle cell disease

• ?6 Glu Val
• Deoxy Hb S polymer forms with low O2,
• Causes irreversibly sickled cells
• Under a variety of circumstances, different
  organs are susceptible
• Bone, spleen, and kidney

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Sickle cell anemia No apparent risks

• Erythroleukemia
• Coronary artery syndromes

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Sickle Cell Anemia Clinical Effects

• Susceptible to infection
• Functional asplenia
• Infarcted tissue
• Numerous manipulations

• Chronic hemolytic anemia
• Gallstones (bilirubin)
• Risk of red cell aplasia (Parvovirus)
• Decreased vascular tone
• Vaso-occlusion
• Microinfarction

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Infectious complicationsClinical manifestations
Auto-splenectomy
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Sickle Cell Anemia Pathophysiologic features
Vaso-occlusion
Chronic hemolysis
Pulmonary hypertension Priapism Leg ulceration
Vasoocclusive crisis Acute chest
syndrome Avascular necrosis
Stroke
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Chronic hemolytic anemiaClinical manifestations

• Cholelithiasis
• Calcium bilirubinate (radiopaque)
• 80 of patients gt30 years old
• Aplastic crisis
• Change in vascular tone

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Pure Red Cell Aplasia

• Normocytic anemia with reticulocyte count lt 0.5
• Absent erythroid precursors in bone marrow
• Caused by Parvovirus B19
• Clinical syndromes
• Immunocompetent patients with chronic hemolysis
• Immunodeficient patients with persistent viremia

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Role of Nitric oxide (NO) in hemolytic anemia

• Produced in endothelial cells
• Vasodilator - counters the processes induced by
  hypoxia
• ? NO is low in sickle cell disease

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Depletion of NO in sickle cell anemia
Sickle cell disease Hemolysis Arginine NO
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Vasoocclusion Clinical manifestations
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Sickle Cell Pain Episodes

• Average duration 5-7 days
• 30-50 of patients seen in ED are admitted
• Pain episodes account for 80-90 of admissions
• Average hospital charges are 6000-6500/admission

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Sickle Cell Anemia Vaso-occlusive Events (Pain
Crisis)

• Precipitating factors
• Hypoxia
• Acidosis
• Fever
• Infection
• Dehydration
• Exposure to cold

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Causes of Pain Perceived factors

• Exposure to cold 34
• Emotional stress 10
• Physical exertion 7
• Pregnancy 5
• Alcohol consumption 4
• Not identified 40

Sergeant, G. et al., Brit J. Haemat 1994 87586.
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Sites of vaso-occlusive painn 183
Site Frequency Bilateral Lumbar spine
49 Abdominal pain 32 Femur 30 28 Knees
21 68 Sternum 18 Ribs 18 47 Shoulder 1
8 53 Elbows 17 45 Tibia/fibula 15 57 H
umerus 12 44 Thoracic spine
12 Hips 11 48 All over 1
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Sickle Cell Anemia Painful Events Treatment
Principles

• Quantitative assessment of pain
• Verbal pain scale ( 0 - absent to 10 worst)
• Correct fluid/electrolyte abnormalities
• Decrease IV fluids/ switch to PO when stable
• Treat any underlying illness
• Opioid analgesics

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Opioids and sickle cell pain

• Proposed starting dose of opioids (Intermittent)
• Morphine sulfate 2-10 mg (0.05-0.1mg/kg) IV,IM or
  SQ q2-4 hours
• Proposed starting dose of opioids (PCA)
• Loading Morphine sulfate 2-10 mg IV by PCA with
  10 min lock out rate to control pain
• Bolus 20 of initial dose as bolus dose
• Convert 2/3 of infused hourly dose to basal
  rate
• Maintenance
• Taper PCA basal rate convert to long-acting oral
  agents

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Adjunctive therapy for sickle cell pain

• Diphenhydramine 25-50 mg PO or IV
• Hydroxyzine 25-50 mg PO or IM
• Anxiolytics
• Benzodiazepines
• Antiemetics (Prochloroperazine 5-10 mg PO or IM)
• Sedative
• Laxatives
• Magnesium citrate
• Lactulose
• Other agents
• Heating pad
• Non-pharmacologic approaches (biofeedback,
  relaxation or diversion)

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Opioids and sickle cell pain

• Short acting agents
• Codeine, hydrocodone or oxycodone
  acetominophen
• Meperidine
• Hydromorphone
• Morphine

• Long acting agents
• Morphine SR
• Oxycodone SR
• Methadone
• Fentanyl patch

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Differential diagnosis of sickle cell pain
Causes other than vaso-occlusion

• Acute exacerbation of chronic pain (avascular
  necrosis)
• Inflammatory arthropathy
• Iron overload syndrome
• Addiction and pseudo-addiction
• Secondary gain - the difficult patient

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Avascular necrosis (osteonecrosis)of the femoral
head

• Occurs in all forms of sickle cell disease
• Age- dependent
• 33-50 of patients by age 35
• Associated with severe pain worse with weight
  bearing
• Radiographic findings and clinical findings may
  not correlate

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Osteonecrosis in sickle cell disease
Stage I Abnormal MRI Stage II Sclerosis with
lytic areas Stage III Flattened femoral head
widened joint space Stage IV Sclerosis
collapse of femoral head narrowed joint space
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Abdominal pain in sickle cell disease

• Right upper quadrant
• Acute cholecystitis
• Biliary colic
• Sickle cell hepatopathy
• Viral hepatitis
• Hepatic siderosis
• Other

• Left upper quadrant
• Splenic sequestration
• Splenic infarct
• Other

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Addiction and pseudo-addiction

• Addiction (abuse)
• Overwhelming involvement with obtaining and using
  mind-altering drug
• Pseudo-addiction
• Relief seeking behavior misidentified as
  addictive behavior

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The difficult patient withsickle cell disease

• Approximately 5 of patients account for 25-50
  of hospitalizations
• High use group has gt10 hospitalizations/year
• Hospital stay is longer (10 days vs. 6 days)
• Young, poor, unemployed, male
• Difficult interpersonal interactions
• May be associated with substance abuse
• Higher death rate

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Treating the difficult patient withsickle cell
disease

• Difficult and time consuming
• Guidelines
• Keep accurate account of opioids
• Set limits of consumption and time
• Designate specific provider to formulate plan in
  charge of plan
• Reduce opioids gradually
• Individualize care
• Consider detoxification/chemical dependency
  program
• Consider a contract

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SummaryPain and sickle cell anemia

• Sickle cell vaso-occlusive pain is the most
  common manifestation of sickle cell disease
• Morbidity and mortality from sickle cell anemia
  is directly related to pain episodes
• Advances in pain prevention and treatment have
  improved the quality of life of patients with
  sickle cell disease
• New approaches to pain prevention and treatment
  are likely to significantly help patients in the
  future

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Acute Chest Syndrome Clinical Findings

• Etiology - multifactorial
• Rib infarct causing splinting/atelectasis
• Pulmonary fat embolism
• Infection (mycoplasma, chlamydia, viral)
• Indistinguishable from pneumonia
• Pleuritic chest pain, fever, cough, tachypnea,
  hypoxia
• Laboratory diagnosis
• Worsening anemia
• Infiltrate on chest radiograph

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Acute chest syndromeIncidence by hemoglobinopathy
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Acute Chest Syndrome Prevention and Treatment

• High index of suspicion in hospitalized patient
• Incentive spirometry

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Acute Chest Syndrome Treatment

• Treat possible underlying infection (Cover
  community acquired and atypical infections)
• Bronchodilators and supplemental oxygen to
  correct hypoxia
• Adequate pain management Minimize splinting and
  avoid over-sedation
• Immediate RBC transfusion therapy
• Simple transfusion
• Exchange transfusion for
• Multiple lobes involved
• Rapidly progressing
• Worsening hypoxia

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Acute Chest Syndrome Outcome

• Complete recovery 91
• Weaned of supplemental O2 3.11.9 days
• Hospital discharge 5.42.3 days
• Chronic respiratory disease 3
• Death 6

Blood 1993
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Stroke in Sickle cell disease
Pathophysiology Blockage in one of the major
blood vessels to the brain. Proliferative
vasculopathy, with reduced vasodilitation in
response to hypoxia.
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Stroke in SSD
Stroke-free survival by genotype
Ohene-Frempong et al, Blood 1998 91 288-94.
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Stroke in SSD
Pathophysiology Distal internal carotid,
proximal MCA and ACA are stenotic or occluded in
SS patients with stroke. Proliferative
vasculopathy, with reduced vasodilitation in
response to hypoxia. Most common sites of
ischemic stroke are parenchymal areas supplied by
ACA and MCA, and the border zones between their
distal circulations. Mortality 24-40
hemorrhagic, lt5 ischemic
Ohene-Frempong et al, Blood 1998 91 288-94.
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Stroke in SSD - SS Genotype
75 are ischemic at ages lt20 75 are
hemorrhagic at ages 20-29
Ohene-Frempong et al, Blood 1998 91 288-94.
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Treatment of acute event

• Simple transfusion

• Exchange transfusion
• Acute or impending cerebrovascular episodes,
  whether caused by infarction, hemorrhage,
  hypoxemia, or transient ischemia, are absolute
  indications for exchange transfusion.

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Treatment of Strokes with Transfusions

• Post stroke therapy
• Transfusion therapy (1976)
• 3 children were transfused following a stroke.
• Baseline angiogram demonstrate disease.
• At one year, repeated angiogram and noted almost
  complete resolution of arterial narrowing.
• 7 of 10 patients developed recurrent strokes when
  transfusions were stopped (Pediatrics 96(2)
  1980).
• Average time to recurrent stroke 3 months.

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When to Discontinue TransfusionsLater

• 10 patients with sickle cell disease and history
  of stroke.
• Transfused for an average of 9.5 years (5-12
  years), then stopped.
• Within 12 months of stopping therapy, 5/10
  patients had a recurrent ischemic event.

Journal of Pediatrics 118(3) 1991
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When to Discontinue TransfusionsSooner

• 9 patients with sickle cell disease and stroke.
• Transfusions were discontinued after an average
  of 6.3 years (1.5-16.5 years).
• No recurrent events.
• Average duration of follow-up was 9 years.

Journal of Pediatrics 131 1997
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Other Approaches to Long-term Management of a
Stroke Patient

• Target Hgb S to lt50 instead of lt30
  requirement?
• 15 patients with sickle cell disease and a
  history of stroke, ages 10-21.
• Following at least 4 years of chronic
  transfusions to maintain Hgb S lt 30, were
  changed to a threshold of lt50.
• Follow up 84 months - no strokes
• Hydroxyurea therapy

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Prevention of Stroke Who is at risk?

• Primary prevention
• Transcranial Doppler ultrasonography to predict
  stroke risk.
• 190 patients with Hgb SS disease ages 3 to 18.
• Flow velocity gt170 cm/sec through the middle
  cerebral artery deemed abnormal.

NEJM 326(9) 1992
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Blood transfusions to Prevent Strokes (STOP Trial)

• Blood transfusions prevent recurrent strokes.
• Prophylactically transfuse patients with abnormal
  transcranial doppler ultrasounds (gt200 cm/sec).
• 130 children
• 67 standard
• 63 transfusion (hemoglobin S)

Adams, RJ et. al. N.Engl.J.Med. 1998 3395-11
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STOP Trial Results

• Results 12 strokes
• 11 in standard cohort
• 1 in transfusion cohort
• (P lt .001)
• Risk of stroke was 92 lower in the transfusion
  group.

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Transcranial Doppler (TCD) STOP-2 Trial

• STOP-2
• Children with abnormal TCDs treated for 30 months
• Randomized to continued transfusions or not
• Continuing transfusion therapy reduced risk of
  stroke and reversion to high risk status by 50

Adams, RJ et. al. N.Engl.J.Med. 2005 3632769
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NHLBI Recommendations for Sickle Cell Disease
Stroke Management

• TCD screening for all children with SCD
• Transfusion therapy for children with abnormal
  TCD
• Continuing transfusions indefinitely in high-risk
  children
• Management of iron overload for children on
  chronic transfusions

Adams, RJ et al. NHLBI, NIH 2004
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Treatment Approaches in Sickle Cell Anemia

• Replacement of red blood cells
• Pharmacologic elevation of Hgb F
• Hydroxyurea
• Butyrate
• Replacement of abnormal gene
• Stem cell transplant
• Other - block sickling or sickle cell-
  endothelium interactions
• Polaxamer 188
• Gardos channel blockers

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Indications for RBC transfusionsin sickle cell
disease

• Indication Outcome
• Stroke Initial recovery
• decreased recurrence by 90
• Acute chest syndrome Rapid improvement
• Aplastic crisis May be life saving
• Pre-operative treatment Decrease post-operative
  
• (Hgb 10 g/dl) complications
• Symptomatic anemia Clinical improvement
• Splenic or hepatic sequestration Clinical
  improvement

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Equivocal indications for RBC transfusions in
sickle cell disease

• Sickle cell pain episode
• Asymptomatic anemia
• Priapism
• Skin ulcers
• Eye surgery
• Pregnancy

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Complications of RBC transfusionsin sickle cell
disease

• Complication Prevention
• Infectious complications Screening and testing
• Alloimmunization RBC screening
• Non-infectious non-immune Filtration/
• complications Pre-medication
• Iron overload syndrome None - treatment with
  chelator

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Treatment with Hydroxyurea

• Dose 15-35 mg/kg/day
• Dose-response in Hgb F
• Adverse effects
• Dose-limiting neutropenia
• Long-term effects uncertain
• Outcome
• Pain episodes decreased by gt 50
• Decreased incidence of acute chest syndrome
• Trend in improved survival

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Sickle cell diseaseEffect of hydroxyurea
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Effect of Hydroxyurea on Hgb F
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Summary

• Without any home runs the treatment of sickle
  cell disease has improved substantially
• Almost all patients live to adulthood
• Acute and chronic organ damage leads to
  progressive decline in quality of life
• Bone and joint disease, lung disease and renal
  failure constitute the majority of the morbidity
  associated with sickle cell anemia