Term
| What is sickle cell disease? |
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Definition
A blood disorder affecting hemoglobin in red blood cells
Cells look a sickle
It affects about 1 in 400 people of African descent |
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Term
| What is the genetic defect that causes sickle cell? |
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Definition
A single DNA base substitution causes sickle cell disease
beta-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 (polar) to valine (non-polar) |
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Term
| What is a driving force behind the epidemiology of sickle cell? |
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Definition
Hemoglobin and red cell enzyme mutations may have arisen as an adaptive response to malaria
Sickle cell trait (Hb AS) improves survival against malaria
RBCs with some sickle hemoglobin have reduced lifespan after parasite infection: cleared more quickly by macrophages |
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Term
| What are the basics of the sickle cell trait? |
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Definition
A person with sickle cell trait (Hb AS) is called a heterozygous “carrier.”
Carriers are usually asymptomatic
Approximately 1 in 12 African Americans have Hb AS
In some areas of Africa, the gene frequency is over 90% (20-30% on average) |
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Term
| What is the inheritance of sickle cell? |
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Definition
It is an autosomal recessive disease
If both parents are carriers (AS) then there is a 1 in 4 chance the offspring will have the disease (SS) |
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Term
| What are the other types of sickle cell mutations besides Hb S? |
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Definition
In combination with Hb S, there are other compound heterozygous conditions
Hemoglobin SC - 2nd most common type
Hemoglobin S-beta thalassemia
There are many other combinations, but they are less common: SD, S-O Arab, SG, etc. |
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Term
| Can sickle cell disease be found in other races besides blacks? |
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Definition
YES
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, Latin America
“White” people can have sickle cell disease
Everyone should be screened for sickle cell disease |
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Term
| How does the sickle cell mutation affect hemoglobin? |
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Definition
Sickle hemoglobin can polymerize or stick together to form long, rigid rods
This happens because of increased hydrophobic interactions caused by the mutation of glutamine to valine (hydrophobic)
The polymerization causes sickle hemoglobin to have a lower oxygen affinity than normal hemoglobin |
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Term
| What are the different conditions that can cause polymerization in sickle hemoglobin? |
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Definition
High temperature - fever
low oxygen -strenuous exercise
acidic pH - strenuous exercise
high concentration of sickle hemoglobin
- when they are packed close together
- when the cell loses water |
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Term
| What are the different cellular pathologies that sickle cell causes? |
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Definition
Abnormal shape, rigidity
Oxidative membrane damage
Cation loss
Adhesion to endothelial cells
Other cell-cell interactions |
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Term
| What is the effect of abnormal shape and rigidity of RBC's in sicke cell? |
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Definition
| Abnormal shape and loss of flexibility reduces blood flow |
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Term
| What does oxidative membrane damage of sickle cells lead to? |
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Definition
The lipids in the membrane of the RBC can be damaged by oxidation which leads to increase clearing by macrophages
This causes the lifespan of sickle cells to be ~2-4 weeks as opposed to 120 days in normal RBC's |
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Term
| What effect does increased K+ loss have on sickle cells? |
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Definition
Water follows the ions out of the cell and this dehydrates the cell
This loss of water leads to increased hemoglobin polymerization |
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Term
| What type of cell-to-cell interactions can the sickle mutation cause? |
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Definition
Adhesion to vascular endothelial cells which leads to vessel obstruction
Adhesion or activation of white blood cells which leads to production of inflammatory cytokines
Activation of platelets which leads to thrombosis (clotting) |
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Term
| What are some basic clinical manifestations of sickle cell? |
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Definition
Hemolytic anemia
Vaso-occlusion
-Painful episodes
-Chronic organ damage
Reduced life expectancy |
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Term
| What are beta-globin haplotypes? |
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Definition
Unique gene sequences outside of the beta-globin gene that are associated with different geographic origins in Africa and Asia
The severity of the disease appears to be related to haplotype |
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Term
| How does the slave trade relate to sickle cell? |
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Definition
Sickle cell haplotypes reflect the patterns of slave trade
Cape Verde: 100% Senegal (SEN) haplotype
Jamaica: 72% have Central African Republic (CAR) haplotype: Less severe
Virginia, USA: >50% CAR haplotype
South Carolina and “Deep South”: SEN and Bantu haplotypes are more common |
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Term
| What are the symptoms of hemolytic anemia? |
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Definition
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 - breakdown product of hemoglobin) |
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Term
| What are the basics behind vaso-occlusion? |
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Definition
Definition:
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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Term
| What changes in blood vessels does sickle cell cause? |
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Definition
Arteries of many organs may develop chronic intimal thickening, leading to stenosis and occlusion
Brain: stroke
Lungs: pulmonary hypertension |
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Term
| What are the primary organs that vaso-occlusion can cause damage to? |
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Definition
Brain (stroke)
Lung
Bone or bone marrow
Spleen
Eyes
Kidney |
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Term
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Definition
| Tissue damage due to lack of oxygen and circulation |
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Term
| How has life expectancy w/ sickle cell changed over time? |
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Definition
In the past sickle cell was one of the diseases that children did not survive.
More recently, 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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Term
| What are some conditions that are life threatening to people with sickle cell? |
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Definition
Sepsis (bacterial blood infection) especially Streptococcus pneumoniae
Splenic sequestration
Aplastic crisis
Acute chest syndrome
Cerebro-vascular accident (stroke |
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Term
| How does bacterial sepsis relate to sickle cell? |
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Definition
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 under 5 years before penicillin prophylaxis was routinely prescribed |
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Term
| How can some types of bacterial sepsis be prevented? |
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Definition
Penicillin prophylaxis SAVES LIVES - Begin ASAP and continue until at least age 5 years.
Conjugated pneumococcal vaccine (Prevnar, 7-valent): at 2, 4, 6, and 12 months of age
23-valent pneumococcal vaccine (Pneumovax):2, 5, 18 years |
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Term
| What is splenic sequestration? |
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Definition
Spleen becomes significantly enlarged (compared to baseline) - vessels are engorged with blood
Hemoglobin drops rapidly
Often associated with viral illness
Can be rapidly fatal
Is common during infancy |
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Term
| How can severe anemia be recognized early? |
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Definition
changes in spleen size is a good indicator
other symptoms - pallor, lethargy, poor feeding, fainting |
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Term
| What is acute chest syndrome? |
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Definition
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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Term
| Why is hypoxia so dangerous in people with sickle cell? |
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Definition
| Hypoxia can cause a progressive cycle of sickling (thus increasing Hb polymerization) in the lung, further hypoxia, and possibly lead to death |
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Term
| What are the causes of acute chest syndrome? |
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Definition
Children: usually infection, bacterial or viral
Sickling or infarction
Adolescents and adults: bone marrow embolus (fat cells released in lung) |
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Term
| What are the treatments of acute chest syndrome? |
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Definition
Treat asthma if present
Antibiotics
Oxygen
Sometimes blood tranfusions are needed |
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Term
| What is the basic information on strokes in people with sickle cell? |
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Definition
Stroke (cerebral infarction) results from insufficient blood flow and oxygen
Can occur in children as young as 2 years
Young children (<15 years): ischemic - blocked blood flow
Adolescents and adults: hemorrhagic - ruptured artery
Symptoms
Severe headache, visual problems, weakness, slurred speech, behaviorial changes, seizures |
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Term
| What are some long-term effects of a stroke? |
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Definition
Stroke can cause long-term disability, difficulty learning, changes in personality
Children may improve very rapidly and regain strength completely
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 |
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Term
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Definition
Pain episodes (formerly known as 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 |
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Term
| What are some characteristics of pain episodes? |
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Definition
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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Term
| What are some late complications of sickle cell disease? |
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Definition
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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Term
| What are some factors that can worsen vaso-occlusion? |
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Definition
Vaso-constriction (cold temperature, drugs)
Adhesion of red cells to activated endothelium: due to inflammation |
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Term
| How can vaso-occlusion be prevented? |
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Definition
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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Term
| How is pain from sickle cell treated? |
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Definition
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 |
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Term
| What obstacles can people with sickle cell face in obtaining treatment? |
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Definition
Many health care providers view people with sickle cell disease as “drug-seeking” or drug addicts b/c of:
-African American race
-Site of pain is not visible
-Pain can be frequent and requires strong medications (opioid analgesics) |
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Term
| What is the role of blood transfusions in treating sickle cell? |
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Definition
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 with normal hemoglobin will flow better and carry more oxygen |
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Term
| What are some potential problems associated with blood transfusions? |
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Definition
Development of antibodies due to minor antigen mismatch (ethnic differences)
Infections
Rates of HIV and Hepatitis C are much lower now, but were quite high in the past
Iron overload
Damages the heart, liver, and endocrine organs
Develops after 2 years of chronic RBC transfusions |
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Term
| What is the current "cure" for sickle cell? |
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Definition
Bone marrow or stem cell transplantation
More than 50 people in the USA have had BMT/SCT to cure sickle cell disease
>20 in Atlanta (Emory University)
Replace a person’s blood producing cells with those from another without sickle cell disease (sickle cell trait is OK)
Donated bone marrow must match sufficiently
Major histocompatibility complex (HLA-type)
Best donor is a full sibling (1 in 4 chance) |
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Term
| How does family planning relate to sickle cell disease? |
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Definition
Sickle cell testing and genetic counseling for expectant couples
Prenatal diagnosis
Amniocentesis
Chorionic villus sampling
DNA analysis of fetal cells for sickle cell gene mutation
Therapeutic abortion, if acceptable to the couple
In vitro fertilization and selection of unaffected embryos |
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Term
| How could the general community help in fighting sickle cell disease? |
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Definition
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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