Transcript Caribbean Pediatrics Hematology

Hedy Smith MD, PhD
Tufts Medical Center, Boston
CMPAA 2016
What is Sickle Cell Disease?
• A genetic disease that alters hemoglobin in red blood cells
• A – T base pair substitution in codon 6th of b globin gene
• Glutamic acid to Valine substitution
• Sickle Cell Disease is transmitted from both parents (silent carriers)
• Onset of symptoms is in childhood (around 6 months of age)
Sickle Cell Disease
A family of disorders of variable severity
• Hb SS (sickle cell anemia / SCA)
• HbSC
• Hb Sb thalassemia
• Hb SE
• Hb SD / O Arab
• Hb SS with hereditary persistence of fetal hemoglobin
A number of genes influence the Hb Sb globin gene
• Haplotypes
• SNPs
History of Sickle Cell Anemia (SCA)
J. B. Herrick. Describes a young black
male from the island of Grenada, who
suffered from chronic hemolytic anemia
with jaundice (Arch. Int. Med. 6: 517521, 1910).
Epidemiology
Epidemic – a Global
Health problem!
“We’ve known for 50 years what causes
sickle cell disease. Where’s the cure?”
No funding for SCD
Globe News – Boston 2016
SCD around the World
• W. Africa: >120,000 babies born annually with SCD
• Jamaica: 1:10 individuals with trait; 1:150 births with SCD
• Brazil: 1:35 with trait, 1:1000 with SCD
• US: 1:500 with SCD; >90,000 affected
Cause of Illness in SCD
Deoxygenation of sickle hemoglobin
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Globin chain precipitates in red cells
Loss of solubility
Red cell shape change
Increased blood viscosity
Blood vessel occlusion
Inflammation in Sickle Cell Disease
• Increase in white blood cells
• Increase in blood platelets
• Increased risk of blood clots
• Damage to the blood vessel (vasculopathy)
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Stroke
Eye disease (retinopathy)
Lung disease (pulmonary hypertension)
Heart disease
Kidney disease
Manifestations of Sickle Disease
• Anemia - red cell hemolysis
• Pain!!
• Organ ischemia & injury
• Death
Acute Complications of SCD
• Pain crisis – blood vessel occlusion with acute severe pain in bones
Acute chest syndrome (ACS)
• Low blood oxygen (SO2 <95%)
• Shortness of breath
• Fever (Temp >101°F)
• Abnormal chest X-Ray (looks like pneumonia)
• Risk of death
• Aplastic crisis (due to Parvo B19 infection)
• Splenic sequestration
Acute Complications of SCD
Infections – loss of spleen function
• Urinary tract infections / pyelonephritis
• Pneumonias
• Osteomyelitis (100x more common than normal)
Blood Clots (thrombosis) – prevalence 25%
Chronic Complications of SCD
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Pain
Avascular necrosis of hips, shoulders
Gallstones
Jaundice
Priapism
Leg Ulcers
Kidney Disease
Stroke / eye disease (retinopathy)
Headaches
Lung & Heart disease
Iron overload and alloimmunization due to blood transfusions
Management of SCD
Focus on Preventative care
• Neonatal Screening Programs – Jamaica, Brazil, US, Europe
• Will decrease mortality in children
• Identification of gene in families
• Family Education & Counselling
• Seek immediate medical care for fevers and breathlessness
• Prompt attention and intervention for sickle pain flares
Prevention Program
• Avoid extremes of temperature that trigger sickle crises
• Hydration – very important
• Healthy diet
• Avoid tobacco and illicit drugs
• Moderate exercise
• Weight management
• Good sleep habits
• Prompt medical attentions for fevers, chills, cough
• Compliance with medications – Folic acid, Hydroxyurea
Health Maintenance in SCD
• Antibiotic prophylaxis in childhood is mandatory
• TCD in children to determine risk of stroke
• Screening for neurocognitive impairment cause by silent strokes –
validates patient concerns
• advocate for reasonable accommodations in schools and work place
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Screening for depression and anxiety
Annual eye exams – treat retinopathy before blindness
Heart ultrasound (ECHO) – pulmonary HTN, heart disease
Vaccinations (Hepatitis B, Haemophilus influenza, Meningococcus,
Pneumococcal, HPV)
• Dental care (aseptic pulp necrosis) – fluoride rinses
Health Maintenance in SCD
Screen for iron overload - annual serum ferritin measurements
• chelation therapy if ferritin >1500
Chelators
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Deferoxamine (SQ)
Exjade (oral)
Jadenu (oral)
Deferiprone (oral; iron overload in the heart)
Indications for RBC transfusion in SCD
•Transfuse for disease complications
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Stroke
Acute retinal vessel occlusion
Acute Chest Syndrome
Organ failure (e.g. hepatic congestion, kidney injury)
Surgery with general anesthesia
• Symptomatic severe anemia
• Inappropriate to transfuse for
• chronic steady state anemia
• uncomplicated pain episodes
• uncomplicated pregnancy
• minor surgeries done under local anesthesia
Recognize Sleep Disorders
• Screen for Obstructive Sleep Apnea (OSA)
• Screen for and treat concurrent Asthma
Reproductive Health in SCD
• Puberty is often delayed by 1.5 – 2 years
• Menstruation may be associated with pain flares – often need to induce
menstrual arrest
• Contraception should be addressed & pregnancies counselled and planned
- high risk!
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Screening of partners for sickle and other abnormal hemoglobin traits
Discontinue Hydroxyurea ahead of pregnancy (birth defects)
Increased risk of miscarriages
Increased risk of pre-eclampsia and pre-term deliveries
Risk of maternal mortality
Growth retardation of fetus (small birth weights)
High risk obstetrician
Therapeutic Landscape - Where are we?
Can we target the complex pathophysiology of sickle disease with
drug(s)?
Can we contemplate cure for severe SCD?
Targeting Red Cell Sickling
Enhance Fetal Hemoglobin production
• Hydroxyurea
• dosed @ 25mg/kg/d or MTD
• NIH guidelines - use in children @ 9months
• TWiTCH trial – HU reduced risk of stroke
in children (increased blood flow)
• Decitabine
• Vorinostat
• Butyrates (HQK-1001)
Therapy for SCD
Reducing Red Cell Destruction (Hemolysis)
GBT-440 – Phase 1/2
• Single daily oral dose
• Drug that enhances hemoglobin affinity for oxygen
Targeting Inflammation in SCD
Prasgruel – clinical trial failed
Statins (Atorvastatin)
Omega -3
Antibodies to Selectins
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SelG1 (P-selectin antibody)
Rivapansel – pan selectin
(Phase III study ongoing)
• Regadenoson
• NKTT120 (anti-iNKT)
Gene Therapy in SCD
Current Clinical Trial:
BM CD34+ from SCD patients are
transduced ex-vivo with the Lenti/βAS3FB lentiviral vector. Gene engineered
The transduced cells are then infused into
the patient.
Bone Marrow Transplant in SCD
NIH Experience – ablating diseased bone marrow and replacing it with
stem cells from HLA matched sibling donor
• NIH: >40 adult patients transplanted; ~80% with full engraftment, no graft
rejection, no fatalities {JAMA 2014;312(1), 48-56}
• Thousands now transplanted world-wide (adults & children), 94% survival; some >20
years
"Our patients have had a remarkable change in their lives," said John F.
Tisdale, M.D., the trial’s principal investigator in the NIH Molecular and
Clinical Hematology Branch. "They are no longer being admitted to the
hospital for frequent pain crises, they have been able to stop chronic pain
medications, go back to school and work, get married and have children."
Sickle Cell Disease: NIH Health Information
CONTACT US
NIH Office of Communications and Public Liaison
Building 31, Room 5B64
Bethesda, MD 20892-2094
[email protected]
Tel: 301-402-7337
Thank You!
Hope by Nazaire
Hope !