Sickle cell disease

By:Anjali Narayanan Shajimol
Rajiv Gandhi University Of Science &
Technology

 Sickle cell disease is an inherited disease
mutations in the beta globin gene that helps make
hemoglobin
 Genetic disorders resulting from the presence of a
mutated form of hemoglobin, hemoglobin S (HbS)
 encodes valine instead of glutamine in the 6th position
in the β-globin molecule.

 SCD results from any combination of the sickle
cell gene with any other abnormal β-globin
gene
 there are many types of SCD.
 The most common types include sickle cell
anemia (Hb SS), the sickle beta-thalassemias
(Hb Sβ0 and Hb Sβ+), hemoglobin SC disease
(Hb SC)

 Patients with Hb SS and Hb Sβ0, in general,
have the most severe forms of SCD including
lower hemoglobin levels and more frequent
vasoocclusive and hemolytic complications.
 Sickle-C (Hb SC) disease is the second most
common form of SCD.
 Patients with this type of SCD generally have a
more benign clinical course than do patients
with Hb SS or sickle β0-thalassemia

EPIDEMIOLOGY
 It is seen worldwide but occurs most frequently in
Africans and less commonly in those of
Mediterranean, Latino, East Indian, and Arab
descent.
 It is estimated that 16% of the population in Africa
has a sickle hemoglobinopathy which is the
highest proportion worldwide.
 The Americas and the East Mediterranean region
represent the next highest proportion of sickle cell
hemoglobinopathy as delineated by the World
Health Organization

DIAGNOSIS
 The most commonly used procedures for newborn
diagnosis include thin layer/isoelectric focusing
and high-performance liquid chromatography
(HPLC).
 A confirmatory step is recommended, with all
patients who have initial abnormal screens being
retested during the first clinical visit and after 6 mo of
age to determine the final hemoglobin phenotype.

 In addition,complete blood cell count (CBC)
and hemoglobin phenotype determination is
recommended for both parents to confirm the
diagnosis and to provide an opportunity for
genetic counseling.

Sickle cell trait(Hemoglobin AS)
 Sickle haemoglobin (S) + Normal haemoglobin (A) in
RBC
 By definition among individuals with sickle cell
trait, the HbS level is <50%.
 Adequate amount of normal Hb (A) in red blood cell
 Carriers
 Often asymptomatic.
 Anemia and painful crises are rare.

 Rare complications of sickle cell trait are associated
with :
sudden death during rigorous exercise
splenic infarction at high altitude
hematuria
deep vein thrombosis
Renal medullary carcinoma is also associated with
sickle cell trait and occurs predominantly in young adults
and children.
 Avoidance of dehydration or extreme physical stress
should be advised.

 Sickle cell trait (AS) confers partial protection against
lethal Plasmodium falciparum malaria.
 patients who are homozygous for the sickle
gene(HbSS) and therefore suffer from sickle cell
anaemia (SCA) are highly susceptible to the lethal
effects of malaria.

 HbS polymerise on deoxygenation.
 polymers distort the red cell, which assumes an
elongated crescentic, or sickle, shape
 The sickling of red cells initially is reversible
upon reoxygenation.

 the distortion of the membrane that is
produced by each sickling episode leads to an
influx of calcium, which causes the loss of
potassium and water and also damages the
membrane skeleton.
 Over time, this cumulative damage creates
irreversibly sickled cells, which are rapidly
hemolyzed.

Three important variables influencing sickling red
cells:
1.The presence of hemoglobins other than HbS.
 In heterozygotes approximately 40% of Hb is HbS
and the remainder is HbA, which interacts only
weakly with deoxygenated HbS
 HbC has a greater tendency to aggregate with
HbS than does HbA, HbS/HbC compound
heterozygotes have a symptomatic sickling
disorder called HbSC disease.
 HbF interacts weakly with HbS

2.The intracellular concentration of HbS.
 Polymerization of deoxygenated HbS is strongly
concentration dependent. Thus, red cell
dehydration, which increases the Hb
concentration, facilitates sickling.
 The relatively low concentration of HbS also
contributes to the absence of sickling in
heterozygotes with sickle cell trait.

3.The transit time for red cells through the
microvasculature.
 The normal transit times of red cells through
capillaries are too short for significant
polymerization of deoxygenated HbS to occur.
 sickling in microvascular beds is confined to
areas of the body in which blood flow is sluggish.
 Sickling also can be triggered in other
microvascular beds by acquired factors that
retard the passage of red cells.

 inflammation slows the flow of blood by
increasing the adhesion of leukocytes and red
cells to endothelium and by inducing the
exudation of fluid through leaky vessels.
 These factors conspire to prolong the transit times
of sickle red cells, increasing the probability of
clinically significant sickling.

Two major consequences arise from the sickling of red
cells
 First, the red cell membrane damage and
dehydration caused by repeated episodes of
sickling produce a chronic hemolytic anemia. The
mean life span of red cells in sickle cell anemia is
only 20 days (one sixth of normal).
 Second, red cell sickling produces widespread
microvascular obstructions

CLINICAL MANIFESTATIONS OF SCD
FEVER
 People with SCA have an increased risk of
severe bacterial infection, resulting primarily
from reduced or absent splenic function.
 By 2 or 3 months of age, as their fetal
hemoglobin declines, infants with SCA begin to
develop splenic impairment. The result is an
extremely high risk of septicemia and
meningitis, primarily due to pneumocci and other
encapsulated bacteria

 In the event that Salmonella spp. or
Staphylococcus aureus bacteremia occurs, strong
consideration should be given to an evaluation
for osteomyelitis with a bone scan given the
increased risk of osteomyelitis in children with
sickle cell anemia when compared to the
general population.

SPLENIC SQUESTRATION
 Defined as sudden enlargement of the spleen
and reduction in hemoglobin concentration
by at least 2 g/dL below the baseline value.
 It is a major cause of acute anemia.
 During splenic sequestration, the reticulocyte
count and circulating nucleated red blood cells
are usually elevated, and the platelet count is
generally decreased because both red cells and
platelets are trapped in the spleen.

 It may occur as early as several months of age,
although it is more typical in children between
the ages of 1 and 4 years old
 sequestration events are less common in older
children and adults with HbSS.
 infants with HbSS, splenic sequestration may
present acutely with severe anemia and
hypovolemic shock.

 In people with hypovolemia due to severe acute
splenic sequestration, immediately provide IV
fluid resuscitation.
 Transfuse people who have acute splenic
sequestration and severe anemia to raise the
hemoglobin to a stable level, while avoiding over-
transfusion.

APLASTIC CRISIS
 Human parvovirus B19 infections result in
temporary red cell aplasia, limiting the
production of reticulocytes and causing profound
anemia.
 Tx:red blood cell transfusion when the patient
becomes hemodynamically symptomatic or has a
concurrent illness, such as acute chest syndrome.
 Patients with parvovirus-associated aplastic crisis
are contagious and infection precautions should
be taken to avoid nosocomial spread of the
infection

VASO OCCLUSIVE CRISIS
 A VOC is the hallmark acute complication for
persons with SCD and manifests as acute
severe pain.
 The first VOC may occur as early as 6 months
of age, often presenting as dactylitis.
 Acute sickle cell pain is characterized as
unremitting discomfort that can occur in any
part of the body but most often occurs in the
chest, abdomen, or extremities.
 Vasoocclusive crises within the femur may lead
to avascular necrosis of the femoral head and
chronic hip disease

 Pain may be precipitated by physical stress,
infection, dehydration, hypoxia, local or systemic
acidosis, exposure to cold, and swimming for
prolonged periods.
 The primary management of a VOC is analgesic
treatment, typically with opioids.
 Codeine in combination with other analgesics
appears to be the most common first-line oral
opioid treatment and plays an essential role in
home pain management regimens

 Alternative opioid drugs that are commonly
used to treat SCD related pain which include
hydrocodone/acetaminophen combinations,
oxycodone, morphine, and hydromorphone,
and fentanyl.

ACUTE CHEST SYNDROME
 The specific definition of what constitutes acute
chest syndrome (ACS) varies but usually refers to a
new pulmonary infiltrate accompanied by fever
and/or symptoms or signs of respiratory disease in
a patient with sickle cell disease (SCD).
 Children usually have fever and upper or middle
lobe involvement;
 whereas adults are often afebrile and present with
multilobe disease.
 The most common well-defined etiology is
infection

 Most common pathogens are S. pneumoniae,
Mycoplasma pneumoniae, and Chlamydia sp.
 Fat emboli has also been implicated as a cause of
ACS, arising from infarcted bone marrow, and
can be life-threatening if large amounts are
released to the lungs.
 Treatment of ACS may include broad spectrum
antibiotics, supplemental oxygen,
bronchodilators, and blood transfusions

RENAL EFFECTS
 Renal papillary necrosis due to medullary
infarction from obstruction of the blood supply
in the vasa recta affects up to 15–30 percent of
individuals with SCD.
 Signs and symptoms include flank pain and
hematuria.
 People with SCD often display a relative
inability to maximally concentrate the urine.

NEUROLOGIC COMPLICATIONS
 Neurologic complications associated with sickle cell
anemia are varied and complex, ranging from acute
ischemic stroke with focal neurologic deficit to
clinically silent abnormalities found on radiologic
imaging.
 A functional definition of overt stroke is the presence
of a focal neurologic deficit lasting for >24 hr and/or
abnormal neuroimaging of the brain indicating a
cerebral infarct on magneticresonance imaging (MRI)
corresponding to the focal neurologic deficit.

 Silent cerebral infarct; lacks focal neurologic
findings lasting >24 hr and is diagnosed by
abnormal imaging on MRI.
 For patients presenting with acute focal
neurologic deficit, a prompt pediatric neurologic
evaluation is recommended, as well as
consultation with a pediatric hematologist.

 In addition, oxygen administration to keep oxygen
saturations >96% and simple blood transfusion
within 1 hr of presentation with a goal of increasing
the hemoglobin to a maximum of 10 g/dL is
warranted.
 A timely simple blood transfusionis important
because this is the most efficient strategy to
dramatically increase oxygen content of the blood,
 Subsequently, prompt treatment with an exchange
transfusion should be considered, either manually or
with automated erythrocytapheresis, to reduce the
HbS percentage to at least <50%, and ideally to <30%.

 Exchange transfusionat the time of acute stroke is
associated with a decreased risk of second stroke
when compared to simple transfusion alone.
 In children and adults who have had a stroke,
initiate a program of monthly simple or exchange
transfusions.
 In children and adults who have had a stroke, if it
is not possible to implement a transfusion
program, initiate hydroxyurea therapy.

Transcranial Doppler Ultrasonography
 Primary prevention of overt stroke can be
accomplished using transcranial Doppler
ultrasonography (TCD) assessment of the blood
velocity in the terminal portion of the internal
carotid and the proximal portion of the middle
cerebral artery.
 Children with sickle cell anemia with an elevated
time-averaged mean maximum (TAMM) blood-
flow velocity >200 cm/sec are at increased risk for
a cerebrovascularevent.
 A TAMM measurement of <200 cm/sec but ≥180
cm/sec represents a conditional threshold.

 The primary approach for prevention of recurrent
overt stroke is blood transfusion therapy aimed at
keeping the maximum HbS concentration <30%.
 Children with TCD values above defined
thresholds should begin chronic blood transfusion
therapy to maintain HbS levels <30% to decrease
the risk of first stroke. This strategy results in an
85% reduction in the rate of overt strokes

PRIAPISM
 Priapism is defined as an unwanted painful
erection of the penis.
 The mean age of first episode is 15 yr, although
priapism has been reported in children as young as
3 yr.
 occurs in 2 patterns: prolonged, lasting more than
4 hr, or stuttering, with brief episodes that resolve
spontaneously but may occur in clusters and
herald a prolonged event.

 Both types occur from early childhood to
adulthood.
 a low flow state caused by venous stasis from
sickling of red blood cells in the corpora
cavernosa.
 The optimal treatment for acute priapism is
unknown.
 Acutely, supportive therapy, such as a hot
shower, short aerobic exercise, or pain medication,
is commonly used by patients at home.
.

 A prolonged episode lasting >4 hr should be
treated by aspiration of blood from the corpora
cavernosa followed by irrigation with dilute
epinephrine to produce immediate and
sustained detumescence.

LEG ULCERS
 Uncommon in children
 All ulcers develop in ankle region near the
malleolus and often exist bilaterally.
 Pathogenesis of this condition is uncertain,but
is likely to develop from poor microvascular
blood flow of abnormal red cells

PHARMACOTHERAPY
HYDROXYUREA
 Hydroxyurea, a ribonucleotide reductase
inhibitor, was identified as a promising drug
candidate to increase HbF levels in people with
SCD.
 Myelosuppresive agent
 Additional mechanisms of action and benefits
exist.
 For example, hydroxyurea lowers the number
of circulating leukocytes and reticulocytes and
alters the expression of adhesion molecules.
 Also improves hemoglobin levels

Hydroxyurea Treatment Recommendations
 In adults with SCA who have three or more sickle
cell-associated moderate to severe pain crises in a
12-month period, treat with hydroxyurea.
 In adults with SCA who have sickle cell-associated
pain that interferes with daily activities and quality
of life, treat with hydroxyurea.
 In adults with SCA who have a history of severe
and/or recurrent ACS, treat with hydroxyurea.

 In infants 9 months of age and older, children,
and adolescents with SCA, offer treatment with
hydroxyurea regardless of clinical severity to
reduce SCD-related complications (e.g., pain,
dactylitis, ACS, anemia).
 In adults and children with SCD who have
chronic kidney disease and are taking
erythropoietin, hydroxyurea therapy can be
added to improve anemia.
 In females who are pregnant or breastfeeding,
discontinue hydroxyurea therapy.

Initiating and Monitoring Therapy
 Both males and females of reproductive age
should be counseled regarding the need for
contraception while taking hydroxyurea.
 Starting dosage for adults (500 mg capsules): 15
mg/kg/day (round up to the nearest 500 mg); 5–
10 mg/kg/day if patient has chronic kidney
disease
 Starting dosage for infants and children: 20
mg/kg/day
 Monitor CBC with WBC differential and
reticulocyte count at least every 4 weeks when
adjusting dosage.

 Hydroxyurea should be temporarily discontinued
and dose adjusted if the absolute neutrophil
count falls below 2,000/μL or platelets fall below
80,000/μL.

potential toxicities of hydroxyurea therapy .
Very rare (≪ 1%) Rare (< 1%) Occasional
(1–10%)
Common (> 10%)
Allergic reaction Diarrhea Anemia
(mild, dose-
dependent)
Leukopenia (mild, dose-
dependent)
Increased ALT Gastritis Anorexia Nail/Skin
hyperpigmentation
Increased Creatinine Hyperspleni
sm
Hair
thinning
Neutropenia (mild, dose-
dependent)
Malignancy Pancytopeni
a
Nausea Reticulocytopenia (mild,
dose-dependent)
Skin ulcers Rash
Vomiting
Thrombocyt
openia

RED BLOOD CELL TRANSFUSIONS
 Red blood cell transfusions are frequently used
in the management of children with sickle cell
anemia, both in the treatment of acute
complications such as ACS, aplastic crisis, splenic
sequestration, and acute stroke
 and to prevent surgery-related ACS and
 first stroke in patients with abnormal TCD or
MRI findings (silent stroke).

 Donor erythrocytes may be administered as a
simple transfusion or as an exchange transfusion.
 Simple transfusion is the infusion of donor
erythrocytes without removal of recipient blood,
 Exchange transfusion involves removal of
recipient blood before and/or during donor
erythrocyte infusion.
 Exchange transfusion can be accomplished by
manual or automated (erythrocytapheresis)
methods.
 Simple transfusion therapy results in the highest
net-positive iron balance after the procedure

Three benefits of exchange transfusion, include
 (1) increasing the percent of normal (donor)
hemoglobin (HbA)-containing erythrocytes
remaining after transfusion.
 (2) permitting transfusion of increased volumes of
donor blood without increasing the hematocrit to
levels that excessively increase blood viscosity.
 (3) reducing the net transfused volume, which
reduces iron overload.

 potential risks of exchange transfusion include
(1) increased donor unit exposure and
subsequent alloimmunization
 (2) higher costs
 (3) the need for specialized equipment
 (4) the frequent need for permanent venous
access.

Preparation for surgery
 In adults and children with SCA, transfuse RBCs
to bring the hemoglobin level to 10 1. g/dL prior
to undergoing a surgical procedure involving
general anesthesia.

 EXCESSIVE IRON STORES
 The primary toxic effect of blood transfusion
therapy relates to excessive iron stores, which can
result in organ damage and premature death.
 Excessive iron stores develop after 100 mL/kg of
red cell transfusion or about 10 transfusions.
 The primary treatment of excessive iron stores
resulting from red blood cell transfusion requires
iron chelation using medical therapy.

 3 chelating agents are commercially available
and approved for use in transfusional iron
overload.
 Deferoxamine is administered subcutaneously 5
of 7 nights/wk for 10 hr a night
 Deferasirox is an effervescent tablet that is
dissolved in liquid and taken by mouth daily.
 Deferiprone is available in tablets taken orally
twice a day.

Hematopoietic Stem Cell Transplantation
 The only cure for sickle cell anemia is
transplantation with human leukocyte antigen
(HLA)–matched hematopoietic stem cells
from a sibling or unrelated donor.
 The most common indications for transplant
are recurrent ACS, stroke and abnormal TCD.

Preventive Pharmacotherapeutic Agents
 Penicillin
 Streptococcus pneumonia is a common pathogen
that causes bacteremia in children with sickle
cell disease
 Prophylatic penicillin
 Folate
 when there are cases of malnutrition or
undernutrition, folate supplementation may
need to be considered in patients with sickle
cell disease.

Vaccines
 In addition to penicillin prophylaxis, routine
childhood immunizations, as well as the
annual administration of influenza vaccine,
arehighly recommended.
 Children with sickle cell anemia develop
functional asplenia and also require
immunizations to protect against encapsulated
organisms including additional pneumococcal
and meningococcal vaccinations.

SUMMARY
 Sickle cell disease (SCD) is a potentially
devastating condition that is caused by an
autosomal recessive inherited hemoglobinopathy
which results in the vaso-occlusive phenomena
and hemolysis.
 The severity of the complications that occur with
this disorder are widely variable.
 Painful vaso-occlusive events are the most
common complication experienced by both
children and adults with sickle cell disease

Sickle cell disease

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