Title: Sickle cell anemia:
1 Sickle cell anemia Current issues
Morey A. Blinder, M.D. Associate Professor of
Medicine and Pathology Immunology
2Hemoglobinopathy and Thalassemia Disorders of
the Globin Genes
Hgb A tetramer
3Discovery of Sickle Cells
4Peripheral Blood Smear
5Sickle Cell Disease
- Inherited as autosomal recessive
- Point mutation in beta globin gene (?6 Glu
Val) - Gene occurs in 8 of African-Americans
6Pathophysiology 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
7Sickle cell anemia No apparent risks
- Erythroleukemia
- Atherosclerotic disease/Coronary artery syndromes
Aorta
Coronary artery
8Sickle 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
9Chronic 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
10Vascular beds susceptible to injury
- Brain
- Lung
- Ankle
- Erectile vasculature of the penis
11Mechanism 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
12End-stage vascular lung disease
13Role 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
14Depletion of NO in sickle cell anemia
- Sildenifil
- Increase effect of NO on cellular function
15Infectious 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
16Auto-splenectomyin sickle cell disease
17Sickle 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
18Sickle 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.
19Sites 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
20Pain 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)
21Sickle 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
22Sickle 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
23Prevention 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
24Sickle 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)
25Avascular 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
26Addiction and pseudo-addiction
- Addiction (abuse)
- Overwhelming involvement with obtaining and using
mind-altering drug - Pseudo-addiction
- Relief seeking behavior misidentified as
addictive behavior
27The 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
28Treating 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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30SummaryPain 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
31Acute 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
32Acute chest syndromeIncidence by hemoglobinopathy
33Acute 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
34Acute 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
35Treatment Approaches in Sickle Cell Anemia
- Replacement of red blood cells
- Pharmacologic elevation of Hgb F
- Hydroxyurea
- Replacement of abnormal gene
- Bone marrow transplant
36Indications 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
37Equivocal indications for RBC transfusions in
sickle cell disease
- Sickle cell pain episode
- Asymptomatic anemia
- Priapism
- Skin ulcers
- Eye surgery
- Pregnancy
38Improved Survival with RBC transfusions
- Survival
- Hgb SS and S b thalassemia 40-50 yrs.
- Hgb SC disease 55-65
- b thalassemia major 20-30
39Iron 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
40Hemosiderosis 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
41Prevention 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
42Complications of Iron Overload
- Cardiac failure
- Liver cirrhosis/fibrosis/cancer
- Diabetes mellitus
- Infertility
- Arthritis
Andrews NC. N Engl J Med. 19993411986-1995.
43Deferasirox 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.
44Phase 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.
45Summary 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)
.
46ICL670 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.
47Sickle 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
48Comparative 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
49Baseline characteristics
50Average iron intake during the study
51Mean daily dose
52Patient disposition
53Change in serum ferritin from baseline to
end-of-study, by dose
54Change in LIC from baseline to end-of-study, by
dose
55Deferasirox 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
56Deferasirox 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
57Treatment 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
58Sickle cell diseaseEffect of hydroxyurea
59Effect of Hydroxyurea on Hgb F
60Effect of Hydroxyurea on Pain Crisis
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62Summary
- 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