Term
A blood disorder affecting hemoglobin in the red blood cells
Cells look a sickle
It affects about 1 in 400 people of African descent |
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Definition
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Term
A single DNA base substitution causes sickle cell disease
b-globin is encoded on chromosome 11
Instead of “A” for adenine, there is a “T” for
thymine where the DNA encodes the 6th amino acid in b-globin
This amino acid is changed from glutamic acid to valine |
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Definition
| Genetic Defect leading to Sickle Cell Disease |
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Term
| Why is sickle cell disease more common among people of African descent? |
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Definition
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Term
Mosquito-borne parasitic disease which infects red blood cells
Endemic to Africa and other equatorial areas
Causes fevers, severe anemia, can cause brain damage, death
What disease has these traits? |
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Definition
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Term
Hemoglobin and red cell enzyme mutations may have arisen as an adaptive response to ???
Sickle cell trait (Hb AS) improves survival against malaria (heterozygous carrier)
RBCs with some sickle hemoglobin have reduced lifespan after parasite infection: cleared by macrophages |
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Definition
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Term
A person with sickle cell trait (Hb AS) is called a ???
Carriers are usually asymptomatic
Approximately 1 in 10 African Americans have Hb AS
In some areas of Africa, the gene frequency is over 90% (20-30% on average) |
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Definition
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Term
| People with sickle cell trait have a 50% chance of passing the sickle cell gene to each offspring. This is known as ??? |
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Definition
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| True or False: If both parents have sickle cell trait, there is a 25% chance that a child will have sickle cell disease. |
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Definition
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| Sickle cell disease inheritance follows an ??? pattern |
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Definition
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Term
Other types of Sickle Cell Disease
People may carry genes for other hemoglobin mutations. In combination with Hb S, there are other compound heterozygous conditions
- Hemoglobin SC
- Hemoglobin S-b thalassemia
- There are many other combinations, but they are less common:
- SD, S-O Arab, SG, etc. |
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Definition
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Sickle Cell Disease and race
While sickle cell disease is more common in African people of African descent, it does not only affect African Americans
- The sickle gene mutation is found in the Middle East, Mediterranean countries, India, Turkey, Afghanistan
“White” people can have sickle cell disease
Everyone should be screened for sickle cell disease |
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Definition
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Term
Made of:
4 globin chains
2 alpha (a)
2 beta (b)
4 heme molecules
- Carries oxygen |
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Definition
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Term
| True or False: Sickle hemoglobin can polymerize - stick together to form long, rigid rods |
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Definition
| True (Valine has interaction with other valines in other hemoglobin) |
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Term
Sickle hemoglobin will ??? under certain conditions
- High temperature
- low oxygen
- acidic pH
- high concentration
- when they are packed close together
- when the cell loses water |
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Definition
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Term
| True or False: Hemoglobin SS disease whole blood has a lower affinity than HbS (or HbA) in solution at the same partial pressure. |
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Definition
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Cellular Physiology
Abnormal shape, rigidity
Oxidative membrane damage
Cation loss
Adhesion to endothelial cells
Other cell-cell interactions |
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Definition
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Term
Abnormal Shape, rigidity of Hb
Hb S polymerization leads to abnormal shape, loss of flexibility, and reduced flow within blood vessels. |
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Definition
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Term
| Red cell membrane lipids can become damaged by oxidation (hydrogen peroxide, superoxides, hydroxy radicals, oxygen) --> increased clearance by macrophages |
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Definition
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Term
| Excessive loss of ions and water through the membrane --> cell dehydration, increased hemoglobin polymerization (leads to a "shrinked" cell) |
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Definition
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Term
Cell to Cell Interactions
Interactions with other cells
Adhesion to vascular endothelial cells --> vessel obstruction
Adhesion or activation of white blood cells --> production of inflammatory cytokines
Activation of platelets --> thrombosis (clotting) |
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Definition
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Clinical Manifestions
Hemolytic (RBC breakdown) anemia
Vaso-occlusion (vessel blockage)
- Painful episodes
- Chronic organ damage
Reduced life expectancy |
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Definition
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Term
Severity and b-globin haplotypes
The sickle cell mutation probably arose in several areas of Africa. Each geographic origin is associated with unique gene sequences outside of the b-globin gene
These gene sequences are called b-globin haplotypes
Disease severity appears to be related to the haplotype |
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Definition
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Term
Slave trade and Sickle Cell Disease
Sickle cell haplotypes reflect the patterns of slave trade
- Cape Verde: 100% Senegal (SEN) haplotype
- Jamaica: 72% have Central African Republic (CAR) haplotype
- Virginia, USA: >50% CAR haplotype
- South Carolina and “Deep South”: SEN and Bantu haplotypes are more common |
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Definition
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Term
Anemia: low red blood cell count
- Normal adult: Hemoglobin level 13-15 gm/dl
- Person with Hb SS: 6-8 gm/dl
Hemolysis
- Hemo: blood
- Lysis: breakage
- Blood cells are fragile and break more easily, leading to anemia and jaundice (high bilirubin, yellow) |
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Definition
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Term
Blockage of blood vessels by sickle cells
Mechanisms:
Decreased flexibility of sickled cells
Increased adherence of red cells to vascular endothelium |
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Definition
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Term
In the brain and other organs, the arteries may show:
Intimal proliferation
Smooth muscle cell hyperplasia
Proliferation of fibrous tissue
Mural thrombosis
Fragmentation and/or duplication of the internal elastic lamina
Arteries of many organs may develop chronic intimal thickening, leading to stenosis and occlusion
- Brain Stroke
- Lungs: pulmonary hypertension |
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Definition
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Term
Vaso-occlusion can cause damage to:
Brain (stroke)
Lung
Bone or bone marrow
Spleen
Eyes
Kidney
??? is tissue damage due to lack of oxygen and circulation |
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Definition
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Life Expectancy of Sickle Cell Disease
Sickle cell was one of the diseases that children did not survive.
Today, the average life expectancy for adults with sickle cell disease is about 50 years for people with Hb SS, and 60’s for Hb SC |
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Definition
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Life-threatening Conditions of Sickle Cell Disease
- Sepsis, especially Streptococcus pneumoniae
- Splenic sequestration
- Aplastic anemia
- Acute chest syndrome
- Cerebro-vascular accident (stroke) |
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Definition
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Term
Education of Families
Early identification of a problem by family members can allow early treatment
This can often prevent a problem from becoming life-threatening or fatal.
Education is as important as medical treatment. |
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Definition
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Bacterial Sepsis
Children with sickle cell disease have an increased risk of bacterial blood infections due to splenic dysfunction
The spleen may be completed infarcted by 4-5 years but is dysfunctional very early in life
Pneumococcal sepsis was the leading cause of death in children < 5 years before penicillin prophylaxis was routinely prescribed |
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Definition
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Sepsis, especially Streptococcus pneumoniae
Sepsis = life threatening infection from bacteria.
- Strep pneumococcal is the most common. Causes you to go into shock and organ function is impaired
Children with sickle cell have an increased risk of bacterial blood infections due to splenic dysfunction (will have trouble fighting bacterial infections)
- Abnormal spleen function due to abnormal shape of cells. Spleen is constantly dying. By 5 years old, spleen has shrunken down.
The spleen may be completed infarcted by 4-5 years but is dysfunctional very early in life
Pneumococcal sepsis was the leading cause of death in children < 5 years before penicillin prophylaxis was routinely prescribed
o Daily penicillin prevents death |
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Definition
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Term
Splenic Sequestration
Spleen becomes significantly enlarged (compared to baseline) - vessels are engorged with blood
Hemoglobin drops rapidly
Often associated with viral illness
Can be rapidly fatal |
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Definition
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Term
Splenic sequestration
•Splenic sequestration = spleen sucks up blood
•Spleen becomes significantly enlarged (compared to baseline)
- vessels are engorged with blood
•Hemoglobin drops rapidly
- Sickle cell blood can get stuck in the sinuses. Blood is stuck there & this causes drop in hemoglobin in body
•Often associated with viral illness
•Can be rapidly fatal |
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Definition
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Term
Early recognition of severe anemia
Educate family about spleen palpation and inform them of their child’s spleen size
- Either not palpable or if palpable, give spleen stick
Educate about signs and symptoms of anemia
Paleness (pallor - more white than pink), lethargy, poor feeding, fainting |
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Definition
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Term
Aplastic anemia
•Aplastic anemia = no growth of cells
•Educate family about spleen palpation and inform them of child’s spleen size
o Either not palpable or if palpable, give spleen stick
•Educate about signs and symptoms of anemia
o Paleness, lethargy, poor feeding, fainting
•Aplastic anemia can be due to a virus. It stops rbc production for a month (in bone marrow) until body fights it off. Normal half life of blood is 3 months, but if not producing blood then hemoglobin starts dropping. SS patients already start with low hemoglobin and therfore aplastic anemia is more sever. Will need give transfusion to the pateint. |
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Definition
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Term
Acute Chest Syndrome (ACS)
Hypoxia (low oxygen) can KILL
- Hypoxia can cause a progressive cycle of sickling in the lung, further hypoxia, and possibly lead to death
Acute chest syndrome (ACS)
- Definition: abnormal area on a chest x-ray
- Often associated with fever, cough, difficulty breathing, chest, abdominal or back pain, worsened anemia |
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Definition
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Term
Acute chest syndrome = lung problem
• Hypoxia (low oxygen) can KILL
o Hypoxia can cause a progressive cycle of sickling in the lung, further hypoxia, and possibly lead to death
• Acute chest syndrome (ACS)
o Definition: abnormal area on a chest x-ray
o Often associated with fever, cough, difficulty breathing, chest, abdominal or back pain, worsened anemia
• Causes of ACS
o Children: usually infection, bacterial or viral
o Sickling or infarction
o Adolescents and adults: bone marrow embolus
- pieces of bone marrow travels to lungs and lodges there (very very bad)
•Treatments
o Treat asthma if present
o Antibiotics
o Oxygen
o Sometimes blood tranfusions are needed |
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Definition
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Term
Cerebro-vascular accident (stroke)
• Stroke (cerebral infarction) results from insufficient blood flow and oxygen
o Can occur in children as young as 2 -3 years
o Young children (<15 years): ischemic (= restriction of blood supply)
o Adolescents and adults: hemorrhagic (= severe bleeding)
• Symptoms
o Severe headache, visual problems, weakness, slurred speech, behaviorial changes, seizures
• Stroke can cause long-term disability, difficulty learning, & changes in personality
o Children may improve very rapidly and regain strength completely (plasticity)
o Learning ability may not always return to normal
• Longterm transfusions help prevent more strokes from occurring and can prevent the occurrence of first stroke in high risk individuals
Note: In cerebral infarctions, the neurons shrink (neuronal cells cant be regenerated) |
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Definition
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Pain episodes (Crises) are the most common complication of sickle cell disease
- 1/3 of all people with sickle cell disease have pain once a year or less
- 1/3 have a few episodes a year
- The remaining 1/3 have frequent pain
Pain occurs because areas of vaso-occlusion: insufficient blood flow and oxygen to different parts of the body
This causes tissue damage which is very painful
Pain episodes are not life-threatening, but may be associated with other complications
Can occur anywhere in the body, but most often in bones and muscles
In babies,
Excessive crying
Hand or foot swelling (dactylitis)
Not using extremity |
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Definition
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Late complications of Sickle Cell Disease
Growth or pubertal delay
Retinopathy: abnormal growth of blood vessels
Priapism: painful, sustained erections
Renal disease: may lead to renal failure and dialysis
Gallstones: from hemoglobin breakdown
Avascular necrosis: bone damage (hips & shoulders)
Leg ulcers
Hemorrhagic stroke
Pregnancy complications |
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Definition
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Term
Symptoms and complications of sickle cell are treated when they occur:
o antibiotics
o oxygen
o pain medications
o Red blood cell transfusions
- Red blood cell transfusions are used when a person’s hemoglobin level is well below their usual (baseline) level.
- This is one of the most important treatments for sickle cell disease.
- Blood from a donor with normal hemoglobin will flow better and carry more oxygen
- Problems with Blood Transfusions
• Development of antibodies due to minor antigen mismatch (ethnic differences)
• Infections
o Rates of HIV and Hepatitis C are much lower now, but were quite high in the past
• Iron overload
o Damages the heart, liver, and endocrine organs
• Goal: to reduce sickling of the red blood cells and vaso-occlusion |
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Definition
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Treatment of Pain
Increased fluids: helps improve blood flow and reduces sickling within the red blood cells
Rest
Local warmth or massage
Pain medicines
- Anti-inflammatory medications: like Motrin
- Opioid analgesics: Codeine or morphine
Prejudice and pain treatment
- Many health care providers view people with sickle cell disease as “drug-seeking” or drug addicts
- African American race
- Site of pain is not visible
- Pain can be frequent and requires strong medications (opioid analgesics)
The most important thing is to believe the patient |
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Definition
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Vaso-occlusion
Factors which promote sickle hemoglobin polymerization
- High temperature
- Intracellular dehydration
- Increased concentration of intracellular Hb S
- Hypoxia
Other factors that may worsen vaso-occlusion
- Vaso-constriction (cold, drugs)
- Adhesion of red cells to activated endothelium: due to inflammation |
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Definition
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Prevention of Vaso-occlusion
Avoid temperature extremes
Drink lots of fluids
Treat respiratory symptoms and infections IMMEDIATELY
Use anti-inflammatory drugs to treat pain
Get lots of rest and avoid over-exertion
Avoid drugs: cocaine vaso-constricts, tobacco contains CO which displaces O2 on hemoglobin, alcohol and caffeine dehydrate |
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Definition
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Treatment Design
Reduce sickle hemoglobin polymerization
- reduce Hb S concentration
- reduce contact between sickle Hb molecules
Reduce vaso-occlusion
- interrupt cell-cell interactions
- dilate blood vessels
Protect organs from damage
Get rid of sickle cells completely |
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Definition
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Anti-Sickling Therapy
Hydroxyyurea
Originally uses as anti-cancer drug
Increases fetal Hb
Fetal Hb interferes with sickle Hb polymer formation
Reduces pain episodes, acute chest syndrome, need for transfusions
Not known if it is effective for stroke prevention |
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Definition
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Possible Treatment Strategies
o Agents which increase fetal hemoglobin production
- Hydroxyurea, butyrates
o Agents which inhibit cell dehydration
- Clotrimazole, magnesium |
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Definition
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Cure of Sickle Cell Disease
o Bone marrow or stem cell transplantation
o More than 50 people in the USA have had BMT/SCT to cure sickle cell disease
o Replace a person’s blood producing cells with those from another without sickle cell disease (sickle cell trait is OK)
o Donated bone marrow must match sufficiently
- Major histocompatibility complex (HLA-type)
- Best donor is a full sibling (1 in 4 chance)
Stem Cell Transplantation
The existing bone marrow needs to be destroyed by using strong medications (chemotherapy)
Stem cells are removed from the donor
Stem cells are given to the recipient
Wait for new stem cells to “grow up” and produce blood cells
It may take 4-6 weeks for the bone marrow to grow
During that time, the recipient will have very low blood cell counts and need transfusions of red blood cells and platelets
Graft versus host disease may develop
About 10-15% of patients with sickle cell disease who had SCT rejected their new marrow
Alternative stem cell sources:
• Umbilical cord blood from one’s siblings
• Umbilical cord blood - unrelated
• Bone marrow - unrelated donor: excessively high rate of graft versus host disease |
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Definition
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Gene Therapy – THE HOLY GRAIL
Remove a person’s stem cells
Insert correct gene or a gene which would block the effects of sickle hemoglobin
Return corrected stem cells to host
Challenges
• Proper expression of normal b-globin gene
• Low number of stem cells
• High level introduction of new gene into human stem cells
• Longterm proliferation of the corrected stem cells |
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Definition
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Family Planning
o Sickle cell testing and genetic counseling for expectant couples
o Prenatal diagnosis
- Amniocentesis
- Chorionic villus sampling
o DNA analysis of fetal cells for sickle cell gene mutation
o Therapeutic abortion, if acceptable to the couple
o In vitro fertilization and selection of unaffected embryos |
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Definition
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Community
What can regular people do?
Blood donations from people of similar ethnic background provides a greater pool of antigenically similar blood
Bone marrow donor drives
Become educated about sickle cell disease and trait and reduce social stigma
Know your own sickle cell status and make informed decisions about having children |
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Definition
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Genetic Take-Home Points
Hemoglobin mutations probably arose in response to malaria.
Sickle cell trait provides a survival advantage against malaria
People with sickle cell trait are generally asymptomatic
Inheritance of Hb SS is autosomal recessive
Sickle cell disease does not only affect Black people |
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Definition
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Cell Biology Take Home Points
Sickle cell anemia (Hb SS) arises from a single DNA point mutation
This leads to a single amino acid substitution
Sickle hemoglobin polymerizes and causes the abnormal shape of the cell
Hemoglobin is not the only problem:
- Membrane, ion flux, interactions with many cell types, chronic blood vessel changes
A full understanding of the cellular pathophysiology of any disease is important for rational approaches to treatments and cures |
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Definition
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Clinical Take Home Points
Penicillin SAVES LIVES
Hypoxia KILLS
Prevent sickling
- Temperature control
- Fluids
- Lots of rest, avoid over-exertion
- Anti-inflammatory medications
Believe the patient who is in pain
Sickle cell disease can affect almost every organ
Not everyone has every problem
Some complications are preventable, others can be treated in the early stages to prevent long-term disability or death
Educate patients and families to recognize problems |
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Definition
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