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SICKLE CELL

ANEMIA

HAZEL ARVEE B. POSIS


Red Blood Cells
 small,biconcave disks that lack a nucleus
when mature. 4 to 6 million red blood cells
per mm3 of whole blood.
 Red blood cells transport oxygen, and
each contains about 200 million molecules
of hemoglobin, the respiratory pigment.
 Make ATP by anaerobic metabolism
HEMOGLOBIN

The cytoplasm of an RBC consists mainly of a


33%solution of hemoglobin (Hb), the red pigment
that gives the RBC its color and name.

lungs
 Hb + O2 HbO2
tissues
HEMOGLOBIN
 Hemoglobin consists of four protein
chains.
Each chain is
conjugated with a
β α nonprotein moiety
called the heme
group, which binds
oxygen to a ferrous
α β ion
(Fe2) at its center
Hypoxemia RBC PRODUCTION AND
(inadequate O2 transport REGULATION

Sensed by The kidneys release


liver and Increased increased
kidneys O2 transport amounts of
erythropoietin whenever
the oxygen capacity of
the blood is
reduced. Erythropoietin
stimulates the red bone
Increased marrow to speed up its
Secretion of
RBC count production of red blood
erythropoietin
cells, which carry
oxygen. Once the
oxygen-carrying
Accelerated capacity of the blood is
erythropoiesis sufficient to support
normal cellular activity,
the
kidneys cut back on their
Stimulation of production of
red bone marrow erythropoietin.
ANEMIA Impaired erythropoietin
production
Decreased
erythropoietin Impaired cellular response to
effect
erythropoietin (e.g. anemia of
chronic diseases)

↓ proliferation
By external agents, physical
or chemical (e.g. ionizing
radiation, marrow toxins
Marrow
damage Hereditary or acquired
or defect aplastic anemia

Intrinsic marrow replacement


(e.g. myelofibrosis
ANEMIA
Megaloblastic Vit B12 deficiency

macrocytic Folate deficiency

Maturation
defect
Iron deficiency and the
anemia of chronic disease
Microcytic
Impaired globin chain
(hypochromic synthesis
(thalassemias)
Impaired porphyrin
synthesis
ANEMIA Membrane defects (e.g.
hereditary
Phagocytosis by spherocytosis)
reticuloendothelial
cells Heinz body associate
(e.g. G6PD deficiency)
Hemoglobin discorders
(e.g. sickle cell)
Accelerated Red cell
fragmentation DIC
Hemolysis
syndromes Vasculitis
syndromes
Sickle cell

Intravascular Osmotic and


hemolysis physical injury
ANEMIAS
Type Morphologic Causes Underlying
characteristics Pathophysiology
Microcytic: Microcytic; Inadequate Insufficient iron stores lead to
Iron hypochromic diet a depleted RBC mass with
deficiency; Blood loss, subnormal hgb conc, and in
chronic blood chronic turn, subnormal O2 carrying
loss capacity of the blood

Macrocytic or Macrocytic with Inadequate Vit B12 deficiency Inhibits


megaloblastic; variation in size, diet, lack of cell growth; deformed RBCs
pernicious or shape of RBCs intrinsic with poor O2 carrying capacity
folic acid factor for Neuro damage occurs bec
pernicious VB12 impairs myelin formation
anemia, Deficiency of folic acid results
impaired in inhibits cell growth, which
absorption have shortened life span
ANEMIAS
Type Morphologic Causes Underlying
Characteristics Pathophysiology

Aplastic Normocytic, drug toxicity, Damage of


normochromic RBCs, genetic failure, destroyed stem cells
depletion of radiation, inhibit blood cell
leukocytes and chemicals, production
platelets infections
Hemolytic Normocytic, Mechanical injury, Reduced RBC
normochromic, inc RBC antigen- survival
number of antibody reaction,
reticulocytes chemical reactions

Post Normocytic, Internal or external Reduced circulating


hemorrhagic; normochromic, inc hemorrhage blood volume
acute number of
hemorrhage reticulocytes within
48-72 h
POLYCYTHEMIA VERA
 Uncontrolled and rapid cellular
reproduction and maturation cause
proliferation or hyperplasia of all bone
marrow cells (panmyelosis)
 ↑ RBC mass, ↑ blood viscosity, inhibits
blood flow to microcirculation
 ↓ blood flow and thrombocytosis set the
stage for intravascular thrombosis
OVERVIEW
 Sickle-celldisease is a general term for a
group of genetic disorders caused by
sickle hemoglobin (Hgb S or Hb S).
 Erythrocytes become elongated and
crescent shaped (sickled)
 removed from the circulation and destroyed at
increased rates, leading to anemia.
Figure A shows normal red blood
cells flowing freely in a blood vessel.
The inset image shows a cross-
section of a normal red blood cell
with normal hemoglobin.

Figure B shows abnormal, sickled


red blood cells clumping and
blocking blood flow in a blood vessel.
(Other cells also may play a role in
this clumping process.) The inset
image shows a cross-section of a
sickle cell with abnormal hemoglobin.
OVERVIEW
 An autosomal
recessive inherited
defect
 The disease is
chronic and lifelong.
 Lifespan is often
shortened with
sufferers living to an
average of 40 years.
OVERVIEW
 The polymerization of deoxygenated HbS is the
primary indispensable event in the molecular
pathogenesis of sickle cell disease
 HbS polymerization is associated with increased
red cell density (dense erythrocytes) as well as
red cell membrane damage favoring the
generation of distorted rigid sickle cells and
contributing to vaso-occlusion and premature
red cell destruction (hemolytic anemia).
OVERVIEW
 The gene defect is a known mutation of a
single nucleotide polymorphism (SNP) (A
to T) of the β-globin gene, which results in
glutamic acid to be substituted by valine at
position 6.
 GAG to GUG codon mutation = LEADING
TO HbS FORMATION
OVERVIEW
 Fetalhemoglobin contains a gamma, not
a beta chain, the disease usually will not
result in clinical symptoms until the child’s
hemoglobin changes from the fetal to the
adult form at approximately 6 months.
2 most common forms of SCD:
 SICKLE CELL TRAIT – heterozygous form
of disease in w/c the affected individual
has both normal (Hb A) & sickle (Hb S)
hemoglobin.
 SICKLE CELL ANEMIA- also known as
hemoglobin SS disease, is the
homozygous form in which the affected
individual has predominantly sickle
hemoglobin (Hb SS).
A A S A

NORMAL SC TRAIT

A S A A A S A A

SC TRAIT NORMAL SC TRAIT NORMAL

When 1 parent has SC trait (Hb Sa), 50%


probability (2/4) exists that a child will have
sickle cell trait.
A S S A
SC TRAIT SC TRAIT

A S A A S S S A

SC TRAIT NORMAL SC DISEASE SC TRAIT

When both parents have sickle cell disease


and a 25% probability (1/4) that a child will
have sickle cell disease and 50% probability
of sickle cell trait.
Characteristics of Sickled Cells
Normal RBC Sickled
Cells
120-day life span 30- to 40- day
life span

Hgb has normal Hb has


O2 carrying decreased O2
capacity carrying
capacity
12 to 14 g/ml of 6 to 9 g/ml of Hb
Hb

RBC destroyed at RBCs destroyed at


accelerated rate
Signs and symptoms of sickle cell anemia usually
show up after an infant is 4 months old and may
include:
 Anemia. Sickle cells are fragile. They break apart easily and die, leaving
you chronically short on red blood cells. Red blood cells usually live for
about 120 days before they die and need to be replaced. However, sickle
cells die after only 10 to 20 days. The result is a chronic shortage of red
blood cells, known as anemia. Without enough red blood cells in circulation,
your body can't get the oxygen it needs to feel energized. That's why
anemia causes fatigue.
 Episodes of pain. (Vaso-occlusive) Periodic episodes of pain, called crises,
are a major symptom of sickle cell anemia. Pain develops when sickle-
shaped red blood cells block blood flow through tiny blood vessels to your
chest, abdomen and joints. Pain can also occur in your bones. The pain
may vary in intensity and can last for a few hours to a few weeks. Some
people experience only a few episodes of pain. Others experience a dozen
or more crises a year. If a crisis is severe enough, you may need
hospitalization so that pain medication can be injected into your veins
(intravenously).
 Hand-foot syndrome. Swollen hands and feet may be the first signs of
sickle cell anemia in babies. The swelling is caused by sickle-shaped red
blood cells blocking blood flow out of their hands and feet.
 Jaundice. Jaundice is a yellowing of the skin and eyes that occurs because
of liver damage or dysfunction. Occasionally, people who have sickle cell
anemia have some degree of jaundice because the liver, which filters
harmful substances from the blood, is overwhelmed by the rapid breakdown
of red blood cells. In people with dark skin, jaundice is visible mostly as
yellowing of the whites of the eyes.
 Frequent infections. Sickle cells can damage your spleen, an organ that
fights infection. This may make you more vulnerable to infections. Doctors
commonly give infants and children with sickle cell anemia antibiotics to
prevent potentially life-threatening infections, such as pneumonia.
 Acute splenic sequestration or pooling of blood
The spleen is an organ in the abdomen that filters out abnormal red blood
cells and helps fight infection. Sometimes, the spleen traps many cells that
should be in the bloodstream and it grows large. This causes anemia. Blood
transfusions may be needed until the body can make more cells and
recover. If the spleen becomes too clogged with sickle cells, it can’t work
normally. It begins to shrink and stop working.
 Delayed growth. Red blood cells provide your body with the
oxygen and nutrients you need for growth. A shortage of healthy red
blood cells can slow growth in infants and children and delay
puberty in teenagers.
 Vision problems. Some people with sickle cell anemia experience
vision problems. Tiny blood vessels that supply your eyes may
become plugged with sickle cells. This can damage the retina — the
portion of the eye that processes visual images.
 Cerebrovascular accident. blockage of major blood vessels-
Sickle-shaped red blood cells may stick to the walls of the tiny blood
vessels in the brain. This can cause a stroke. This type of stroke
occurs mainly in children. The stroke can cause learning disabilities
or more severe problems.
 Acute Chest syndrome. similar to pneumonia-Acute chest
syndrome is a life-threatening condition linked to sickle cell anemia.
It's similar to pneumonia and is caused by an infection or by sickle
cells trapped in the lungs. People with this condition usually have
chest pain, fever, and an abnormal chest x ray. Over time, lung
damage may lead to pulmonary arterial hypertension
• Priapism. Males with sickle cell anemia may have painful and unwanted
erections called priapism (PRI-a-pizm). This happens because the sickle
cells stop blood flow out of an erect penis. Over time, priapism can
damage the penis and lead to impotence.

• Ulcers on the Legs. Sickle cell ulcers (sores) usually begin as small,
raised, crusted sores on the lower third of the leg. Leg sores occur more
often in males than in females and usually appear between the ages of
10 and 50. The cause of leg ulcers is not clear. The number of ulcers can
vary from one to many. Some heal rapidly, but others persist for years or
come back after healing.

• Multiple Organ Failure. Multiple organ failure is rare, but serious. It


happens when a person has a sickle cell crisis that causes two out of
three major organs (lungs, liver, or kidney) to fail. Symptoms linked to this
complication are a fever and changes in mental status such as sudden
tiredness and loss of interest in your surroundings
Change in one base-pair in DNA molecule

Valine produced instead of glutamic


acid at position, 6 in β-chain

Desctruction Abnormal hemoglobin molecule Concentration


of many of sickle-
sickle cells shaped cells in
Sickling of RBC the spleen

Clumping of sickle shaped cells


Enlargement
Anemia interferes with circulation
of spleen

Proliferation Impaired blood supply to


of bone Enlargement various organs Fibrosis of
marrow of heart spleen

Weakness Slowed
and physical Damage Damge Damage Brain Damage
lassitude development to heart to lungs to damage to abd Kidney
muscle muscles organs damage
Impaired and
mental joints
function
Heart pneumonia paralysis Kidney
Abd
Failure Rheumatism pain failure

DEATH
Who Is At Risk for Sickle Cell Anemia?

 mostcommon in people whose families


come from Africa, South or Central America
(especially Panama), Caribbean islands,
Mediterranean countries (such as Turkey,
Greece, and Italy), India, and Saudi Arabia.
Diagnostic Tests
 Can be diagnose prenatally by chorionic
villi sampling or from cord blood during
amniocentesis
 Routine SCA screening of newborns
 Abnormal hemoglobin forms are detected
on hemoglobin electrophoresis, a form
of gel electrophoresis on which the various
types of hemoglobin move at varying
speed
Treatments and drugs

 Bone marrow transplant offers


the only potential cure for sickle
cell anemia. But, finding a donor is
difficult and the procedure has
serious risks associated with it,
including death.
 Bone marrow transplantation
(BMT) is a special therapy for
patients with cancer or other
diseases which affect the bone
marrow. A bone marrow transplant
involves taking cells that are
normally found in the bone marrow
(stem cells), filtering those cells,
and giving them back either to the
patient or to another person. The
goal of BMT is to transfuse healthy
bone marrow cells into a person
after their own unhealthy bone
marrow has been eliminated.
Medications
 Treatment for sickle cell anemia is usually aimed at avoiding crises, relieving
symptoms and preventing complications :
 Antibiotics. Children with sickle cell anemia usually begin taking the
antibiotic penicillin when they're about 2 months of age and continue taking
it until they're 5 years old. Doing so helps prevent infections, such as
pneumonia, which can be life-threatening to an infant or child with sickle cell
anemia. Antibiotics may also help adults with sickle cell anemia fight certain
infections.
 Pain-relieving medications. To relieve pain during a sickle crisis, your
doctor may advise over-the-counter pain relievers and application of heat to
the affected area. You may also need stronger prescription pain medication.
 Blood transfusions. Blood transfusions carry some risk. Blood contains
iron. Regular blood transfusions cause an excess amount of iron to build up
in your body. Because excess iron can damage your heart, liver and other
organs, people who undergo regular transfusions must often receive
treatment to reduce iron levels. Deferasirox (Exjade) is an oral medication
that can reduce excess iron levels. It can be used in people older than 2.
 Supplemental oxygen
Breathing supplemental oxygen through a breathing mask adds oxygen to
your blood and helps you breathe easier. It may be helpful if you have acute
chest syndrome or a sickle cell crisis.
 Hydroxyurea (Droxia, Hydrea). This prescription drug, normally
used to treat cancer, may be helpful for adults with severe disease.
When taken daily, it reduces the frequency of painful crises and may
reduce the need for blood transfusions. It seems to work by
stimulating production of fetal hemoglobin — a type of hemoglobin
found in newborns that helps prevent the formation of sickle cells.
There is some concern about the possibility that long-term use of
this drug may cause tumors or leukemia in certain people.
Experimental treatments
 Gene therapy. Because sickle cell anemia is caused by a defective gene,
researchers are exploring whether inserting a normal gene into the bone
marrow of people with sickle cell anemia will result in the production of
normal hemoglobin. Scientists are also exploring the possibility of turning off
the defective gene while reactivating another gene responsible for the
production of fetal hemoglobin — a type of hemoglobin found in newborns
that prevents sickle cells from forming.
 Butyric acid. Normally used as a food additive, butyric acid may increase
the amount of fetal hemoglobin in the blood.
 Clotrimazole. This over-the-counter antifungal medication helps prevent a
loss of water from red blood cells, which may reduce the number of sickle
cells that form.
 Nitric oxide. Sickle cell anemia causes low levels of nitric oxide, a gas that
helps keep blood vessels open and reduces the stickiness of red blood
cells. Treatment with nitric oxide may prevent sickle cells from clumping
together.
 Nicosan. This is an herbal treatment in early trials in the U.S. Nicosan has
been used to prevent sickle crises in Nigeria.
 Decitadine. This medicine increases hemoglobin F levels (this type of
hemoglobin carries more oxygen). It may be a good choice instead of
hydroxyurea.
Lifestyle and home remedies

 Take folic acid supplements daily, and eat a


balanced diet. Bone marrow needs folic acid
and other vitamins to make new red blood cells.
 Drink plenty of water. Staying hydrated helps
keep your blood diluted, which reduces the
chance that sickle cells will form.
 Avoid temperature extremes. Exposure to
extreme heat or cold can trigger the formation of
sickle cells.
Lifestyle and home remedies

 Reduce stress. A sickle crisis can occur as a


result of stress.
 Exercise regularly, but don't overdo it. Talk
with your doctor about how much exercise is
right for you.
 Use over-the-counter medications with
caution. Some medications, such as the
decongestant pseudoephedrine, can constrict
your blood vessels and make it harder for the
sickle cells to move through freely.
Lifestyle and home remedies

 Fly on airplanes with pressurized cabins.


Unpressurized aircraft cabins may not provide
enough oxygen. Low oxygen levels can trigger a
sickle crisis. Additionally, be sure to drink extra
water when traveling by air, as pressurized
cabins can be dehydrating.
 Avoid high-altitude areas. Traveling to a high-
altitude area may also trigger a crisis because of
lower oxygen levels.
References
 Andreoli & Bennett etal; Cecil Essential of Medicine, 4th Edition,
1997, WB Saunders Co
 Bullock: Pathophysiolgy: Adaptations and Alterations in Function, 4th
Edition; 1996, Lippincott
 Fauci et al: Harrison’s Principle of Internal Medicine, 17th Edition:
McGraw Hill Companies, Inc
 Mader: Understanding Human Anatomy Physiology, Fifth Edition,
The McGraw−Hill Companies, 2004
 Marieb: Essentials of Human Anatomy and Physiology, 6th Edition,
2002, Pearson Education Asia Pte, Ltd
 McPhee at al: Pathophysiology: An Introduction to Clinical Medicine,
2nd Edition, 1997, Prentice Hall, ltd
 Rifknd et al: Fundamentals of Hematology, 2nd Edition; 1980; Year
Book Medical Publishers, Inc
 Straight A’s in Pathophysiology: A Review Series; Lippincott
Williams & Wilkins