Sickle Cell Anemia

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.

β

α

α

β

Each chain is conjugated with a nonprotein moiety called the heme group, which binds oxygen to a ferrous ion (Fe2) at its center

Hypoxemia (inadequate O2 transport Sensed by liver and kidneys

RBC PRODUCTION AND REGULATION

Increased O2 transport

Secretion of erythropoietin

Increased RBC count

Accelerated erythropoiesis

Stimulation of red bone marrow

The kidneys release increased amounts of erythropoietin whenever the oxygen capacity of the blood is reduced. Erythropoietin stimulates the red bone marrow to speed up its production of red blood cells, which carry oxygen. Once the oxygen-carrying capacity of the blood is sufficient to support normal cellular activity, the kidneys cut back on their production of erythropoietin.

ANEMIA Decreased erythropoietin effect

↓ proliferation

Impaired erythropoietin production Impaired cellular response to erythropoietin (e.g. anemia of chronic diseases)

By external agents, physical or chemical (e.g. ionizing radiation, marrow toxins Marrow damage or defect

Hereditary or acquired 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 (hypochromic

Impaired globin chain synthesis (thalassemias) Impaired porphyrin synthesis

ANEMIA Phagocytosis by reticuloendothelial cells

Membrane defects (e.g. hereditary spherocytosis) Heinz body associate (e.g. G6PD deficiency) Hemoglobin discorders (e.g. sickle cell)

Accelerated Hemolysis

Red cell fragmentation syndromes

DIC Vasculitis syndromes Sickle cell

Intravascular hemolysis

Osmotic and physical injury

ANEMIAS Type

Morphologic Causes characteristics

Microcytic: Iron deficiency; chronic blood loss

Microcytic; hypochromic

Macrocytic or Macrocytic with megaloblastic; variation in size, pernicious or shape of RBCs folic acid

Underlying Pathophysiology

Inadequate diet Blood loss, chronic

Insufficient

iron stores lead to a depleted RBC mass with subnormal hgb conc, and in turn, subnormal O2 carrying capacity of the blood

Inadequate diet, lack of intrinsic factor for pernicious anemia, impaired absorption

Vit

B12 deficiency Inhibits cell growth; deformed RBCs with poor O2 carrying capacity Neuro damage occurs bec VB12 impairs myelin formation Deficiency of folic acid results in inhibits cell growth, which have shortened life span

ANEMIAS Type

Morphologic Causes Characteristics

Underlying Pathophysiology

Aplastic

Normocytic, normochromic RBCs, depletion of leukocytes and platelets

drug toxicity, genetic failure, radiation, chemicals, infections

Damage of destroyed stem cells inhibit blood cell production

Hemolytic

Normocytic, normochromic, inc number of reticulocytes

Mechanical injury, RBC antigenantibody reaction, chemical reactions

Reduced RBC survival

Post hemorrhagic; acute hemorrhage

Normocytic, normochromic, inc number of reticulocytes within 48-72 h

Internal or external hemorrhage

Reduced circulating blood volume

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-cell

disease 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 crosssection 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  Fetal

hemoglobin 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

NORMAL

A

S

SC TRAIT

A

A

SC TRAIT

A

NORMAL

A

S

SC TRAIT

A

A

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

SC TRAIT

A

S

SC TRAIT

A

SC TRAIT

A

A

NORMAL

S

S

SC DISEASE

S

A

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 sickleshaped 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. 

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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 vesselsSickle-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

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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.

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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.

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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 Abnormal hemoglobin molecule

Desctruction of many sickle cells

Sickling of RBC Clumping of sickle shaped cells interferes with circulation

Anemia

Proliferation of bone marrow

Slowed physical development

Impaired mental function Heart Failure

Enlargement of spleen

Impaired blood supply to various organs

Enlargement of heart

Weakness and lassitude

Concentration of sickleshaped cells in the spleen

Damage to heart muscle

Damge to lungs

Damage to muscles and joints

Brain damage

paralysis

pneumonia Rheumatism

DEATH

Fibrosis of spleen

Damage to abd organs

Abd pain

Kidney damage

Kidney failure

Who Is At Risk for Sickle Cell Anemia?  most

common 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. 

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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 

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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 highaltitude 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