Sickle cell anemia:

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Sickle cell anemia Current issues
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
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Sickle Cell Disease

• Inherited as autosomal recessive
• Point mutation in beta globin gene (?6 Glu
  Val)
• Gene occurs in 8 of African-Americans

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Pathophysiology of sickle cell disease

• ?6 Glu Val
• Deoxy Hb S polymer forms with low O2, depends on
  Hgb S concentration, low pH, high temperature,
  high 2,3-DPG
• Under a variety of circumstances, different
  organs are susceptible
• spleen, renal medulla (papillary necrosis),
  many other complications

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Sickle cell anemia No apparent risks

• Erythroleukemia
• Atherosclerotic disease/Coronary artery syndromes

Aorta
Coronary artery
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Sickle Cell Anemia Clinical Effects

• Chronic hemolytic anemia
• Gallstones (bilirubin)
• Risk of red cell aplasia (Parvovirus)
• Decreased vascular tone
• Susceptible to infection
• Functional asplenia
• Infarcted tissue
• Numerous manipulations
• Vaso-occlusion

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Chronic hemolytic anemiaClinical manifestations

• Cholelithiasis
• Calcium bilirubinate (radiopaque)
• 80 of patients gt30 years old
• Aplastic crisis
• Normocytic anemia with reticulocyte count lt 0.5
• Absent erythroid precursors in bone marrow
• Caused by Parvovirus B19
• Immunocompetent patients with chronic hemolysis

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Vascular beds susceptible to injury

• Brain
• Lung
• Ankle
• Erectile vasculature of the penis

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Mechanism of Lung Injury
Regional Pulmonary Hypoxia
? Sickling, ? Vascular adhesion, production of
vasoactive substances ? Reoxygenation
followed by reperfusion injury ? Progressive
tissue damage with altered pulmonary vascular
tone, vascular proliferation in the muscle wall
and hypercoagulable state causing pulmonary
thrombosis and progressive loss of the vascular
bed ? Obliterative Pulmonary Vasculopathy with
pulmonary hypertension
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End-stage vascular lung disease
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Role of NO (Nitric oxide) ? Produced by
endothelial cells (blood vessels) ? Has
vasodilative and cytoprotective effects that
counter the processes induced by hypoxia ?
However, in sickle cell disease, levels of both
arginine (the substrate for NO) and NO are low,
diminishing the benefits of NO Why is NO low in
Sickle Cell Disease? Intravascular hemolysis
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Depletion of NO in sickle cell anemia

• Sildenifil
• Increase effect of NO on cellular function

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Infectious complications of Sickle cell anemia

• Related to absent spleen
• Pneumococcus infections
• Hemophilus infections
• Dramatically improved with the use of
  prophylactic penicillin in childhood
• Related to frequent instrumentation
• Staphyloccocal infections
• Related to tissue infarction
• Osteomyelitis

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Auto-splenectomyin sickle cell disease
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Sickle Cell Anemia Vaso-occlusion Unique
pathophysiologic feature

• Causes acute and chronic organ damage
• Acute complications
• Sickle cell vaso-occlusive pain crisis
• Hepatic crisis
• Splenic crisis
• Priapism
• Chronic organ damage
• Stroke
• Chronic lung disease with pulmonary
• hypertension
• Renal failure
• Avascular necrosis of bone

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Sickle Cell Anemia Vaso-occlusive Events (Pain
Crisis)

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

• 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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Pain in Sickle Cell Disease

• Sickle cell crisis
• Periodic, self-limited episodes of pain
• Occurs in all age groups

Platt, O. et. al. N Engl J Med 32511-16 (1991)
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Sickle cell vaso-occlusive crisis

• Serious complication of sickle cell anemia
• Risk of acute event (lt48 hours)
• Acute chest syndrome
• Splenic sequestration
• Massive hemolysis
• Risk of sudden death

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Sickle Cell Anemia Painful Events Management
Principles

• Correct fluid/electrolyte abnormalities use
  hypotonic fluid and limit volume to avoid
  overhydration
• Treat any underlying illness
• Opioid analgesics (meperidine is not recommended)
• Blood transfusion is not indicated for an
  uncomplicated pain episode
• Incentive spirometry should be used during waking
  hours

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Prevention of Painful Episodes

• Hydroxyurea increases Hgb F
• Reduces the frequency of painful episodes, acute
  chest syndrome, RBC transfusions and
  hospitalizations
• Non-pharmacologic approaches have not been
  evaluated
• Prophylactic transfusions showed a decreased
  incidence of painful crisis in pregnancy

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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 90 of admissions
• Average hospital charges are 2000-2500/admission
  (2000)

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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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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 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 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 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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Acute Chest Syndrome Prevention and Treatment

• Incentive spirometry
• Treat possible underlying infection
• Bronchodilators and supplemental oxygen
• RBC transfusion therapy
• Simple transfusion
• Exchange transfusion for
• Multiple lobes involved
• Rapidly progressing
• Worsening hypoxia

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Treatment Approaches in Sickle Cell Anemia

• Replacement of red blood cells
• Pharmacologic elevation of Hgb F
• Hydroxyurea
• Replacement of abnormal gene
• Bone marrow transplant

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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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Improved Survival with RBC transfusions

• Survival
• Hgb SS and S b thalassemia 40-50 yrs.
• Hgb SC disease 55-65
• b thalassemia major 20-30

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Iron overloadfrom blood transfusions

• Sickle cell anemia is the most common blood
  disorder to be treated with transfusion
• Each unit of RBCs adds 200-250 mg iron
• To maintain Hgb S level 30 need 150 ml/kg/year
  (1g/month)
• In thalassemic patients with similar transfusion
  burden, life span is 15-25 years

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Hemosiderosis in SCD a growing problem

• gt90 Hgb SS transfused at 21 years
• 37 adult Hgb SS lab diagnosis hemosiderosis
• 50 hospitalized adult SCD transfused
• Increased lifespan associated ? transfusion
• Indications for transfusion in children ?
• Compliance chelation limiting

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Prevention of Complications from RBC Transfusions

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

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Complications of Iron Overload

• Cardiac failure
• Liver cirrhosis/fibrosis/cancer
• Diabetes mellitus
• Infertility
• Arthritis

Andrews NC. N Engl J Med. 19993411986-1995.
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Deferasirox a New, Oral Iron Chelator

• Selected from more than 700 compounds tested
• Tridentate iron chelator
• An oral, dispersible tablet
• Administered once daily
• Highly specific for iron
• Chelated iron excreted mainly in feces (lt 10 in
  urine)

Clinical trial formulation or preparation
3 polar interaction sites in the binding
pocket. Nick H, Current Medicinal Chemistry.
2003101065-1076.
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Phase I Pharmacokinetic and Pharmacodynamic
Study Multiple Doses in Thalassemia Patients

• Randomized, double-blind, placebo-controlled
  sequential trial to assess
• Short-term safety (12-day exposure)
• Efficacy (iron balance)
• Pharmacokinetic/pharmacodynamic relationships
• 3 cohorts of 7 patients with ?-thalassemia
• 5 patients per cohort received active drug, 2
  received placebo
• Doses 10, 20, 40 mg/kg

Nisbet-Brown E, et al. Lancet. 20033611597-1602.
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Summary of Phase I Results

• Dose-response relationship (10 to 40 mg/kg)
• Iron excretion within therapeutic range (0.1 to
  0.5 mg Fe/kg/day)
• Iron excreted mainly in feces
• Acceptable safety profile
• Dose recommendation 10 to 20 mg/kg

Nisbet-Brown E, et al. Lancet, 20033611597-1602)
.
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ICL670 Phase I Safety Profile
Treatment-Related Adverse Events by Dose Level
ICL670 10 mg/kg 20 mg/kg 40 mg/kg
Preferred term Severity (n 5) (n 5) (n
7) Nausea Mild 2 1 Nausea Moderate
1 Diarrhea Mild 1 3 Abdominal pain Mild
1
Nisbet-Brown E, et al. Lancet, 20033611597-1602.

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Sickle cell study 109 objectives

• Primary objective
• Safety and tolerability
• Secondary objective
• Efficacy endpoints
• Change in liver iron concentration (LIC) assessed
  by magnetic susceptometry (SQUID)
• Change in serum ferritin
• Ratio iron excretion/intake

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Comparative Phase II trialin adult and pediatric
SCD patients
Deferasirox 530 mg/kg/day (n132)
Screening
andrandomization (21)
DFO 2060 mg/kg/day 5 times/week (n63)
1-year treatment and observation
SQUID
SQUID
SQUID
1 year treatment period Serum ferritin monitored
monthly
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Baseline characteristics
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Average iron intake during the study
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Mean daily dose
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Patient disposition
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Change in serum ferritin from baseline to
end-of-study, by dose
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Change in LIC from baseline to end-of-study, by
dose
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Deferasirox conclusions safety

• Deferasirox was generally well tolerated
• Most common AEs considered to be
  treatment-related were mild to moderate
  gastrointestinal side effects and rash
• Mild, non-progressive creatinine elevations were
  manageable with dose reduction
• Occasional increases in liver transaminases
• No agranulocytosis, growth failure, or bone
  abnormalities

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Deferasirox conclusions efficacy

• At baseline patients had evidence of clinically
  significant iron overload
• Deferasirox removed iron from the body in
  proportion to the amount of drug administered
• Deferasirox was efficacious at 20 and 30
  mg/kg/day for maintaining or reducing LIC and
  serum ferritin
• Similar effect as comparable doses of DFO

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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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Effect of Hydroxyurea on Pain Crisis
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Summary

• Without any homeruns 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 and lung disease
  constitute the majority of the morbidity
  associated with sickle cell anemia