Transcript Sickle Cell Disease

Sickle Cell Disease
Introduction
• Vaso-occlusive phenomena and hemolysis
are the clinical hallmarks of Sickle Cell
Disease (SCD)
• Inherited disorder due to homozygosity for
the abnormal hemoglobin, hemoglobin S
(HbS)
• HbS results from substitution of valine for
glutamic acid as sixth amino acid of the
beta globin chain, which produces a
hemoglobin tetramer that is poorly soluble
when deoxygenated.
• Polymer assumes elongated rope-like fiber
form in the classic sickle shape
• Sickle cell shape results in decrease cell
deformability.
• Changes also occur in red cell membrane
structure and function, disordered cell
volume control and increase adherence to
vascular endothelium.
Overview
• Disorder most severe in patients with SCD
(homozygosity for HbS), of intermediate
severity in hemoglobin SC disease (HbSC,
combined heterozygosity for hemoglobin S
& C), and generally benign in those with
sickle cell trait (heterozygosity for Hbs).
• Patients with homozygous SCD are
typically anemic and often lead a life of
painful episodes.
• Clinical signs and symptoms begin at an
early age.
Prevalence of symptoms at age
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Six month of age - 6%
Twelve months of age - 32%
Two years of age - 61%
Six years of age - 92%
eight years of age - 96%
Predictors of adverse outcome
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Dactylitis before age one
Hemoglobin concentration < 7 g/dl
Leukocytosis in absence of infection
An adverse outcome, defined as stroke,
frequent episodes of pain, recurrent acute
chest syndrome or death occurred in 18%
with these predictors,(392 infants/10yrs).
Laboratory findings
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Moderate anemia
Reticulocytosis 3-15%
High MCV
Unconjugated
hyperbilirubinemia
• Elevetaed LDH
• Low haptoglobin
• Folate & iron deficit
• Peripheral smear
shows sickle cells
• Polychromasia
• Howell-jolly bodies
• Elevated WBC
• Elevated Platelets
• Low than after 18 yrs
high creatinine
Acute Severe Anemia
• Acute fall in haptoglobin.
• Patients present with pallor, weakness and
lethargy.
• Fatalities not uncomon.
• Due to the Splenic sequestration crisis,
aplastic crisis or hyperhemolytic crisis.
Splenic sequestration crisis
• Vaso-occlusion in the spleen and pooling of
blood in the spleen produce fall in
hemoglobin, reticulocytosis and rapidly
enlarging spleen.
• Risk of hypovolemic shock and 10-15%
mortality.
• Recurrent in 50% of survivors.
Aplastic crisis
• Arrest of erythopoiesis with falling
hemoglobin levels and absence of
reticulocytes.
• Associated with infection namely ParvoB19, EBV, Streptococcus and salmonella.
• Reticulocytes usually reappear in 2-14 days.
Hyperhemolytic crisis
• Sudden exacerbation of anemia with
reticulocytosis.
• Cause unknown.
• Rare
Major Clinical Manifestations
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Acute painful episodes
Multiorgan failure
Psychosocial issues
Growth &
development
• Infection
• Bacteremia
• Meningitis
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Bacterial pneumonia
Osteomyelitis
CVA
Bone complcations
Infarct and necrosis
Marrow infarct
Orbital compression
Arthritis
Major Clinical Manifestations
• Cardiac complications
• Myocardial infarct
• Dermatologic
complications
• Leg ulcers
• Hepatobiliary
complications
• Cholelithiasis
• Chronic liver disease
• Acute hepatic episodes
• Pregnancy
complications
• Fetal complications
• priapism
• Pulmonary
complications
Major Clinical Manifestations
• Renal complications
• Retinopathy
• Take a deep breath!
Acute painful crisis
• Precipitated by cold, infection, dehydration,
infection, stress, menses, hypoxemia,
alcohol or no identifiable cause.
• Can affect any area, but back, chest,
extremities and abdomen most frequent.
• Usually last 2-7 days.
• Frequency- 1/3 rarely, 1/3 2-6yr, 1/3>6yr
Acute chest syndrome
• Due to pneumonia, infarct due to in situ
thrombosis and embolic phenomena due to
fat embolism and bone marrow infarct.
• Manifestations are chest pain, infiltrate on
CXR and fever.
• Treat with O2, antibiotics, and exchange
transfusion to lower HbS to below 30%.
Management
• Treatment and prevention of the acute
manifestations of SCD.
• Therapies designed to interfere with the
polymerization process at different levels
General principals
• Regular Physician follow up.
• Establish base line labs and Physical
findings.
• Education regarding nature of disease,
genetic counseling and psychosocial
assessment.
• Immunize for Strep, influenza and Hep B
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Prophylactic penicillin until five years.
Folic acid 1md/day
TCD
Retinal evaluation
BCP
Hydroxyurea
Hdroxyurea
• Increases production of hemoglobin F.
• Reduces median crisis rate by 50%,
decreased acute chest syndrome and
transfusion.
• 40% reduction in mortality.
• Mild increase in acute myeloid leukemia
Pain management
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Narcotics - Morphine or dilaudid
Toradol
Inhaled nitric oxide
anticoagulation low dose INR 1.5
Poloxamer 188
Management of infection
• Prophylactic fever - Ceftriaxone
• Acute chest syndrome - Cefuroxime &
Erythromycin.
• Osteomyelitis - Cover salmonella and staph
until cultures available.
Transfusion therapy
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Aplastic crisis
Acute chest syndrome or sepsis
CVA
Priapism
Perioperative
Simple vs exchange
Do not raise Hgb > 10
Prophylactic preoperative
transfusion
• Increase hemoglobin to 10g/dl
• Reduces serious complications
• Orthopedic surgery still has 67% serious
complications and 17% sickle-related
Complications ( acute chest syndrome and
vaso-occlusive crises )
Transfusion complications
• Alloimmunization
• Iron overload
• Infection
Prognosis
• Median age of death for SCD in males is
42 for men and 48 for women
• Median age of death for Hb SC is 60 for
men and 68 for females
Causes of death
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Infection - 48%
Stroke - 10%
Complications of therapy - 7 %
Splenic sequestration - 7 %
Thromboembolism - 5%
Renal failure - 4 %
Pulmonary hypertension - 3 %
The future
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Gene therapy
Increase expression of Hb F
RNA repair
Hematopoietic cell transplantation