Transcript SICKLE CELL DISEASE - Virginia Osteopathic Medical Association

SICKLE CELL DISEASE
JOHN M KAUFFMAN JR DO
ASSOCIATE DEAN FOR POSTGRADUATE AFFAIRS
VIA COLLEGE OF OSTEOPATHIC MEDICINE
Goals and Objectives
• At the conclusion of this program, the attendee will
have a better understanding of:
• The genetics and transmission of Sickle Cell Disease
• The Diagnosis and pathophysiology of Sickle Cell
Disease
• The management of the complications of Sickle Cell
Disease
• The current treatment of Sickle Cell Disease
Sickle Cell Disease: A Case
• A 22yo AA woman is transferred to your
hospital with respiratory failure. You are asked
to see her in the emergency department. In
the ED the patient is in obvious distress with a
RR of 45 and an O2sat of 72%. Her ABG
revealed 7.34/44/59/23/76% on 3 liters O2 by
nasal canula.
Sickle Cell Disease: A Case
• The patient had been diagnosed with Sickle
Cell Anemia at age 6 and was hospitalized for
a sickle cell crisis at age 12. 24 hours prior to
admission in your hospital she was seen in
another ED with severe pain (10/10) in her
back thighs and knees. She was nauseated and
had vomited once. She denied chest pain,
SOB, fever, chills, abdominal pain, dysuria,
constipation or diarrhea.
Sickle Cell Disease: A Case
• Within 10 hours of admission to your hospital,
the patients O2 sat dropped to 40% and she
was intubated. Her ABG revealed:
7.35/44/80/22/94% on the vent with 100% O2
TV=350, and 22cm of peep.
• What is your diagnosis?
Definitions
• Sickle-Cell Disease: A group of blood disorders
caused by a mutation in the hemoglobin gene.
• Common Sickle Cell Diseases Include:
• Sickle Cell Anemia
• Hemoglobin SC Disease
• Sickle Beta Thalasemia
• Sickling and sickle cell disease also confer some
resistance to malaria
Definitions
• Sickle-Cell Anemia : Sickle-cell anemia is the
name of a specific form of sickle-cell disease in
which the individual is homozygous for the
mutation that causes HbS. Normal hemoglobin is
called hemoglobin A, but people with sickle cell
anemia have only hemoglobin S, which in the
homozygous form, turns normal, round red blood
cells into abnormally curved (sickle) shapes.
Sickling decreases the cells' flexibility and
predisposes the carrier to potentially serious
complications. Sickle-cell anemia is also referred
to as "HbSS", "SS disease", "hemoglobin S" etc.
Sickle Cell Anemia
Definitions
• Sickle Cell Trait: condition in which a person has
one abnormal allele of the hemoglobin beta gene
( heterozygous), but does not display the severe
symptoms of sickle cell disease that occur in
individuals who have two copies of the abnormal
Hb S allele ( homozygous)
• About 2 million Americans have sickle cell trait.
The condition occurs in about 1 in 12 African
Americans.
Sickle Cell Disease
• Sickle cell disease (SCD) is the most common
genetic disorder identified in African
Americans,
• Also found in people from South and Central
America, the Mediterranean and the Middle
East.
Sickle Cell Disease
• In the United States, it’s estimated that sickle
cell anemia affects around 50,000 people,
mainly African Americans. The disease occurs
in about 1 out of every 700 African American
births.
• Before the era of Hydroxyurea, the average life
expectancy was in the 40’s
Clinical Hallmarks of
Sickle Cell Disease (SCD)
• Vaso-occlusion
• Hemolysis
Diagnostic Testing:
• Cellulose acetate electrophoresis is a standard
method of separating Hb S from other
hemoglobin variants. However Hb S, G, and D
have the same electrophoretic mobility with
this method.
Diagnostic Testing:
• Citrate agar electrophoresis seperates Hb S
from Hb D and G
• Thin-layer isoelectric focusing and high
performance liquid chomatography (HPLC) are
highly accurate tools for the diagnosis of sickle
or other hemoglobin variants
Diagnostic Testing
• In Summary: Cellulose acetate electrophoresis
with either citrate agar electrophoresis or a
solubility test allows a definitive diagnosis of
sickle cell syndrome
• Alternatively, thin layer isoelectric focusing
will separate Hb S, D, and G and can replace
the two electrophoretic methods.
• However, thin-layer isoelectric focusing still
requires a confirmatory solubility test for Hb S
Newborn Screening
• Mandated in all 50 states and the District of Columbia.
• Most states use either thin-layer isoelectric focusing
(IEF) or high performance liquid chromatography
(HPLC) as the initial screening test.
• Both methods have extremely high sensitivity and
specificity for sickle cell anemia. Specimens must be
drawn prior to any blood transfusion (false negative)
• Extremely premature infants may have false positive
results when adult hemoglobin is undetectable
Screening Programs
• Selective screening of infants of high-risk
parents
• Universal testing of newborns
• Selective screening misses up to 20% of AA
newborns with SCD
• sickle cell diagnoses doubled when screening
was changed from targeted to universal
Hemoglobin Patterns
Laboratory Findings in
Sickle Cell Disease
• Chronic Hemolysis with mild to moderate anemia
(Hct 20-30%)
• Reticulocytosis of 3-15% (.5-1.85% RBCs)
• Unconjugated hyperbilirubinemia
• Sickled RBCs on peripheral smear
• Low serum erythropoietin secondary to
progressive renal disease
• Folate and Iron deficiency secondary to increased
utilizaton of folate and urinary excretion of iron
Peripheral Blood Smear
• Sickled red cells
• Polychromasia indicative of reticulocytosis
• Howell-Jolly bodies secondary to splenic
infarcts
• Normochromic, normocytic RBCs
Findings in Sickle Cell Disease
• The Cooperative Study of Sickle Cell Disease
looked at Lab Data in 2600 people with SCD
• Mean WBC counts elevated especially in
children < age 10
• Thrombocytosis seen individuals < age 18
• Serum Alk Phos elevated until puberty
TIMING OF SCREENING
• Test all newborns at the time of birth
• Verify screening results at first office visit
• Perform confirmatory tests no later than 2
months of age.
Most common types of
sickle cell disease
• Hemoglobin SS disease (also called Sickle Cell
Anemia)
• Hemoglobin Sickle-C disease
• Sickle Beta-Thalassemia.
Hemoglobin
• Hemoglobin: Definition and Structure
• Hemoglobin carries oxygen from the lungs to
tissues and CO2 from the tissues to the lungs for
excretion.
• Hemoglobin molecule consists of two parts:
• Porphyrin group or heme
• Protein or globin portion.
• Globin is made up of four polypeptide chains
attached to the porphyrin ring
• Four types: alpha, beta, delta and gamma.
Hemoglobin Molecule
Sickle Cell Hemoglobin
• In normal Hemoglobin A, glutamic acid is on the 6th
position of the beta chain, while in sickle-cell disease,
this glutamic acid is replaced by valine (point mutation)
leading to the formation of sickle cells.
• Polymerization: the two beta chains fit into each other
forming a longitudinal polymer (or lock and key)
causing the cell to become deformed and very rigid
leading to vessel occlusion.
• Polymerization: activated by infections, hypoxia,
acidosis, physical exercise, vasoocclusion due to cold as
well as dehydration.
Sickle Cell Hemoglobin
In sickle cell hemoglobin (HbS) glutamic acid in
position 6 (in beta chain) is mutated to valine.
This change allows the deoxygenated form of
the hemoglobin to stick to each other.
Normal Adult Hemoglobin
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Primarily Hemoglobin A
2 alpha chains and 2 beta chains
Beta chain synthesis begins early in fetal development
Sixth week of gestation, hemoglobin A composes about
7% of the total hemoglobin; the percentages slowly
increase throughout the pregnancy
• Thirtieth week there is a switch from gamma chain to
beta chain production.
Fetal Hemoglobin
• At birth babies have mostly fetal or F
hemoglobin
• falls to the normal level of less than 3 to 5% by
the time the infant is 5-6 months of age
• Adults have less than 2% fetal hemoglobin.
• Fetal hemoglobin is made up of two alpha and
two gamma chains.
STRUCTURAL FORMULA FOR
NORMAL HEMOGLOBIN
• A Major Adult Hemoglobin
2 Alpha Chains + 2 Beta Chains
• F Fetal Hemoglobin
2 Alpha Chains + 2 Gamma Chains
• A2 Minor Adult Hemoglobin
2 Alpha Chains + 2 Delta Chain
HEMOGLOBINOPATHIES
• Hemoglobinopathy: disease or trait caused by
a defect in the genetic code for hemoglobin
synthesis
• Over 600 known hemoglobin variants
reported
• Vast majority of abnormal hemoglobin result
from the mutation of a single polypeptide
chain.
Genetics of Sickle Cell Trait
• Heterozygous subject (sickle cell trait (A/S), an
abnormal gene is inherited from one parent
and it directs the formation of abnormal
hemoglobin.
• A normal gene is inherited from the other
parent and it directs the formation of normal
hemoglobin.
Example of an Inheritance Pattern for
Sickle Cell Trait
Genetics of Sickle Cell Disease
• Homozygous subject, identical abnormal
genes are inherited; one from each parent,
and the majority of the hemoglobin is
abnormal, such as in sickle cell anemia (S/S).
Example of an Inheritance Pattern for
Sickle Cell Trait
HEMOGLOBIN A/S
SICKLE CELL TRAIT
• GENOTYPE: AS
• Beta chain variant
• Each red cell contains a mixture of A (60%)
and S (40%).
• Amount of A in each cell is enough to prevent
sickling under most physiological conditions.
POPULATIONS AFFECTED
• African Americans: 8-10%
• Hispanic Americans: 2%
• Occurs frequently in Greeks, Italians, Saudi
Arabians, East indians and Middle Easterners
CLINICAL SYMPTOMS of
Sickle Cell Trait
• NOT associated with anemia.
• Offers some protection against malaria.
• Occasional hematuria and hyposthenia (impaired
renal concentrating ability)
• Splenic infarction reported to occur at altitudes
greater than 7,000 feet
• Greater risk for sudden death under extreme
conditions such as those that might occur during basic
training in the military.
• severe dehydration, malnutrition, physical
overexertion and exhaustion. This risk though
increased, is small.
PRECAUTIONS
• Avoid hypoxic situations: deep sea diving,
flying in unpressurized aircraft, strenuous
physical activity over a prolonged period of
time.
COUNSELING POINTS TO BE MADE
• Person is a healthy carrier
• Person is not sick.
• Sickle cell trait is not a disease.
• Sickle cell trait will not cause you to be anemic.
• There is a small amount of hemoglobin S, but not
enough to change the shape of the red blood cell.
• The red blood cells of a person with sickle cell
trait remain round and flexible.
SICKLE CELL ANEMIA
• GENOTYPE: S/S
• Hemoglobin S (90-100%)
• Hemoglobin F may be slightly elevated
SICKLE CELL ANEMIA
• Most common form of sickle cell disease
identified in African Americans
SICKLE CELL ANEMIA
Clinical Symptoms
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Most severe form of sickle cell disease
Clinical course variable
Severe anemia
Vaso-occlusion, pain episodes, organ damage
Aplastic episode, splenic sequestration,
increased risk for infection
• If HbF is greater than 10% there is a decreased
risk of stroke
SICKLE CELL ANEMIA
PRECAUTIONS
• Genetic counseling and screening to clarify
risk for child born with sickle cell disease
• Referral to High Risk OB Clinic for pregnancy.
• Avoid Hypoxia, dehydration
Clinical Manifestations of
Sickle Cell Disease
• Vasoocclusion and hemolysis are the
hallmarks of sickle cell disease
• Vasoocclusion results in recurrent painful
episodes (sickle cell crisis)
• Dactylitis (acute pain in the hands and feet) is
the most common initial symptom
Most Common Complications of
Sickle Cell Disease
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Acute Painful Crisis (Sickle Cell Crisis)
Acute Chest Syndrome
Stroke
Chronic Lung Disease
Avascular Necrosis
Leg Ulcers
Clinical Manifestations of
Sickle Cell Disease
• Hemoglobin S (HbS) results results form the
substitution of a valine for glutamic acid as the
sixth amino acid of the beta globin chain, that
produces a hemoglobin tetramer (alpha
2/beta S2) that is poorly soluble when
deoxygenated.
Clinical Manifestations of
Sickle Cell Disease
• Sickle Cell Disease is used to describe those
conditions associated with “ Sickling”
• Patients who are homozygous for HbS have
the most severe form of the disease
Pathophysiology of Vasoocclusion
• Sickle cells (Hb SS) lose deformability when
deoxygenated
• Causes vascular obstruction and ischemia
• Critical factor underlying painful crises, acute
chest syndrome, functional asplenia, and
stroke
Pathophysiology of Vasoocclusion
• Membrane damage shortens the lifespan of
RBCs
• Causing chronic intravascular and
extravascular hemolysis
• Intravascular hemolysis causes:
• Decreased nitric oxide, Increased vascular
tone, and pulmonary artery hypertension
Pathophysiology of Vasoocclusion
• Damaged RBCs have irregular surfaces that
cause them to adhere to the vascular
endothelium
• promotes acute vascular occlusion leading to
a proliferative “lesion” made up of WBCs,
platelets, smooth muscle cells and coagulation
proteins
• Leading to strokes and possibly Pulm HTN
Gladwin and Vichinsky n engl j med November 20, 2008 359 (21): 2254
Acute Painful Crisis (Sickle Cell Crisis)
• Acute pain (previously know as “sickle cell
crisis”)
• Most common type of vasoocclusive events
• First symptom noted in over 25% of patients
• Most frequent symptom after the age of two
Clinical Manifestations of
Sickle Cell Disease
• Dactylitis (acute pain in the hands and feet)
most common symptom before the age of two
• Pain was the most common symptom after
the age of two
• Splenic sequestration is the third major
symptom
Clinical Manifestations of
Sickle Cell Disease
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Significant predictors of adverse outcome
Dactylitis before the age of 1
Hemoglobin level <7 g/dl
Leukocytosis in the absence of infection
Pulmonary Complications
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Acute Chest Syndrome
Bronchoconstriction/Asthma
Pneumonia
Pulmonary hypertension
Chronic lung disease
Acute Chest Syndrome
• Presentation: Chest pain, pulmonary infiltrate
and fever
• Most common form of acute pulmonary
disease in Sickle Cell Disease
• Most common cause of death in SCD
• Etiology: pneumonia, infarction/thrombosis,
fat embolus
Acute Chest Syndrome
• Presentation: Chest pain, pulmonary infiltrate
and fever
• Most common form of acute pulmonary
disease in Sickle Cell Disease
• Most common cause of death in SCD
• Etiology: pneumonia, infarction/thrombosis,
fat embolus
Gladwin and Vichinsky n engl j med November 20, 2008 359 (21): 2254
Acute Chest Syndrome
• The Acute Chest Syndrome occurs in the
majority of patients with sickle cell disease at
least once during their lives
• Second most common cause of hospital
admission after “painful vaso-occlusive crises”
Acute Chest Syndrome
• The Acute Chest Syndrome is a lifethreatening disorder
• Leading cause of death in people with sickle
cell anemia.
• Defined as the presence of a new pulmonary
infiltrate on Chest Xray, with chest pain, fever,
cough, dyspnea, or an elevated WBC count in
a patient with sickle cell anemia.
Acute Chest Syndrome
• Caused by occlusion of the pulmonary vessels
by sickled red cells. Since hypoxia is the chief
stimulus for polymerization of hemoglobin S,
lung disease of any type poses a particular
threat to the patient with sickle cell anemia.
Four Major Precipitants of
Acute Chest Syndrome
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Infection
Bone Marrow Emboli
Thromboembolism
Atelectasis
Acute Severe Anemia
• Splenic Sequestration Crisis
• Aplastic Crisis
• Hyperhemoytic Crisis
Splenic Sequestration Crisis
• Vaso-occlusion within the spleen and pooling
of RBCs leads to a marked fall in Hg and an
increase in reticulocytes
Aplastic Crisis
• Transient cessation of erythropoiesis
secondary to infection with parvovirus
• Can also occur after infection with Strep
pneumoniae, salmonella, and EBV
Hyperhemolytic Crisis
• Associated with multiple transfusions
• Also associated with certain drugs, infections
and glucose-six-phostate dehydrogenase
deficiency
Growth and Development
• Growth retardation and delayed puberty are
common in children with SCD
Infection
• Impairment of the spleen
• Patients are susecptable to encapsulated
organisms such as Strep pneumo, and H flu
• Bacteremia
• Meningitis
• Pneumonia
• Osteomyelitis
Fever
• Medical emergency requiring immediate
attention and treatment with antibiotics
Cerbrovascular/ Neurologic Disease
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Stroke/ TIA
Intracranial Bleed
Spinal Cord Infarction/ Compression
Vestibular dysfunction
Sensory hearing loss
Bone Complications
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Bone infarction and necrosis
Osteomyelitis
Osteoporosis
Osteonecrosis (avascular or ischemic necrosis)
Bone marrow infarction
Pulmonary fat embolism (secondary to bone
marrow infarction)
Cardiac Complications
• Increased Cardiac Output (secondary to
chronic anemia)
• Myocardial Infarction (caused by increased
oxygen demand that cannot be met due to the
anemia and decreased oxygen carrying
capacity of the RBCs)
Dermatolgic Complications
• Leg Ulcers (secondary to vasoocclusion in the
skin
Hepatobiliary Complications
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Acute Hepatic Ischemia
Cholestasis
Hepatic sequestration crisis
Iron overload secondary to multiple
transfusions
• Acute and chronic cholelithiasis secondary to
pigmented gallstones
• Hepatitis C secondary to blood transfusion
Obstetrical Complications
• Fetal complications: Spontaneous abortion,
intrauterine growth retardation, fetal demise,
low birth weight secondary to compromised
placental blood flow
• Maternal complications: acute chest
syndrome, UTI, pyelonephritis, endometritis,
preeclampsia, thromboembolic events, which
occur in up to 50% of pregnancies
Renal Complications
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Hematuria
Proteinuria
Hypertension
Renal Infarction, Papillary necrosis
Nephrogenic DI
Focal Glomerulosclerosis
Renal Medullary carcinoma, seen in black
patients with sickle cell trait
Retinopathy
• Proliferative retinopathy
• Retinal artery occlusion
• Retinal detachment and hemorrhage
TREATMENT
• COMPREHENSIVE CARE —
• Upon diagnosis of SCD implement a
Comprehensive Care program for the affected
child and his\her family
• Because of the many manifestations of the acute
and chronic complications of SCD
• Critical to involve specialists with expertise
• Multidisciplinary teams: social workers,
psychologists, nurses, genetic counselors, and
nutritionists.
TREATMENT
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Universal screening of newborns
Prophylactic Penicillin
Improved medical care
Have reduced the mortality of Sickle Cell
Disease from 25% to less than 3%
TREATMENT
• Begin prophylactic penicillin 125mg BID by
2-3 months of age and continue until two to
three years of age. At this time increase dose to
250mg BID until the age of 5.
• After age 5 some clinicians elect to stop the
penicillin prophylaxis
• Immunize against, Streptococcus pneumoniae,
Haemophilus influenza,Hepatitis B and
influenza
TREATMENT
• Folic Acid 1mg daily
• Children 16 or younger should be evaluated
with transcranial doppler (TCD) to identify
those children at risk for cerebrovascular
accidents.
• Begin TCDs at age two and continue every 12
to 24 months.
• The risk of stroke can be reduced
TREATMENT
• Hydroxyurea
• Hematopoietic Stem-cell Transplantation
• Long Term Transfusion Therapy
Treatment
• Hydroxyurea: Only FDA approved therapy to
prevent episodes of pain in SCD. Interferes
with the sickle hemoglobin polymerization
process by increasing the production of fetal
hemoglobin
Cure
• Hematopoietic stem cell transplant. Limited to
individuals less than 16 years of age
Hydroxyurea
• Cytotoxic drug that can bind metals. Used in
polyc ythemia vera to decreas the elevated Hct
and platelet count
• Inhibits ribonucleotide reductase by bindings its
2 main iron molecules and inactivating a critical
tyrosyl radical that reduces the production of
RBCs with a high level of HbSS
• Favors production of fetal Hb which arises from
precursor cells that divide at a slower rate
Hydroxyurea
• A major breakthrough that shifts hemoglobin
production from sickle hemoglobin to fetal
hemoglobin by altering the bone marrow to
favor fetal hemoglobin production
Hydroxyurea
Hydroxyurea
• Dose: Single daily oral dose 15 mg/kg (adjust
for decreased creatinine clearance)
• Monitor CBC every 2 weeks
• Contraindicated in: pregnancy, breast feeding,
severe anemia, leukopenia and
thrombocytopenia
• Discontinue if CBC counts drop below the
acceptable range
Hydroxyurea
Hematopoietic Stem-cell Transplantation
• Still under careful investigation in the US
• Currently the only potential cure for SCD
SICKLE CELL DISEASE
• THE LITERATURE
References
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References
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National Guideline Clearinghouse. (2007). Hemoglobinopathies in pregnancy. Retrieved from http://www.guideline.gov
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