6. Clinical Presentation: Signs and Symptoms
General anemia pallor, fatigue, SOB on exertion
Acute chest syndrome cough, dyspnea, chest pain, fever
Infection malaise, cough and chest pain, diarrhea and/or vomiting
Painful crises persistent pain in skeleton, chest, and/or abdomen
Hand-foot syndrome swollen and painful hands and feet (by 2 years of age: 50% of Jamaican
and 25% of American children with sickle cell anemia have experienced
at least one episode of dactylitis)
Stroke (affects 10% of patients; 6-17% of children and young adults), sudden
neurologic deficits including motor, difficulty with language, writing,
and/or reading; seizures; sensory deficits; altered consciousness
Priapism penile erection not related to arousal
Delayed growth and
puberty
Patient more slender or small in size.
Jaundice Yellowing of skin and eyes
Other Some people remain asymptomatic into late childhood and are only
incidentally diagnosed
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/sca.shtml
8. • There are a range of
Treatments per extremes or
per symptoms
Clinical Presentation
9. Sickle Cell Anemia
A hereditary
genetic disorder
that results in
the production
of abnormal
hemoglobins
10. In Sickle Cell, the Beta chain is affected
by a point mutation…
Source: Robbins
11. One small point mutation leads to a major problem
when HbS is deoxygenated…
Deoxyhemoglobin A (HbA)
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml
Deoxyhemoglobin S (HbS)
12. A prolonged environment of low oxygen leads to
aggregation and polymerization of hemoglobins into long
chains of rod-like fibers, causing the RBC to form the
shape of a crescent or sickle.
http://www.humanillnesses.com/original/images/hdc_0001_0003_0_img0235.jpg
• Donut-shaped
• Soft and malleable
• Able to pass through
small spaces
• Lifespan ~120 days
• Sickle-shaped
• Hard and rod-like
• Gets stuck in narrow
spaces
• Lifespan ~20 days
13. Sickling of red blood cells leads to:
1. Vaso-occlusive
complications
2. Severe anemia
3. Chronic
hyperbilirubinemia
16. Severe Anemia and Chronic
Hyperbilirubinemia
1. Young RBCs with HbS can
alternate between the
sickled and normal
formation.
2. However, sickling causes
oxidative damage to the
RBCs cell membrane (and
to the cells around it).
3. Eventually, RBCs become
irreversibly sickled.
17. Severe Anemia and Chronic
Hyperbilirubinemia
• Irreversibly sickled cells
end up in the spleen.
• Hemolysis occurs at
the splenic cords.
• Decreased RBCs and
increased bilirubin
• Infarction and fibrosis
causes
autosplenectomy.
Source: Robbins
19. G6PD-Deficiency Distribution
• 12% of males of African descent (A type)
• 22% of Southeast Asian males (Mahedian
type)
• 50% of Kurdish males (Mediterranean type)
• Also, a significant prevalence in males of
Italian, Greek, Lebanese, Iraqi, and
Sephardic heritage (Mediterranean type)
22. G6PD-Deficiency – Pathology
• Genetic abnormalities (of which there are
several varieties) lead to deficient or
impaired enzyme function
• High levels of oxidants (from foods, drugs,
exercise, infections) may damage or
denature proteins within the erythrocyte
• RBCs may then be subject to intravascular
or extravascular hemolysis
23. G6PD Crisis Precipitation - Beans
• Broad beans (favism)
– Fava beans, bell beans, fever beans, hava
beans, pigeon beans, horse beans, tick
beans, silkworm beans, English dwarf beans
25. Other oxidants
– Henna – primarily infants and pregnant
women
– Naphthlene (moth balls) – regular exposure
26. Early Lab Tests – CBC
• RBC – Low
• Hct – Low
• Hb – Low
• MCV – Normal to High
• MCHC – Low to Normal
• MCH – Low to Normal
• So…initial CBC is only your starting point
27. Early Lab Tests – Urinalysis
• Hemoglobin
– Elevated post-crisis
• Bilirubin
– Elevated post-crisis
• Urobilinogen
– Elevated post-crisis
• May also see hematuria, proteinuria, LDH
• These account for dark color of urine following a
crisis, but are also non-specific for any given
type of hemolytic anemia
28. Early Lab Tests - Smear
• Often readily seen with initial CBC, or easily ordered
alongside
• If anemias are suspected, probably best to run a smear
in the early stages
• G6PD-Deficiency may show:
– Heinz bodies
• Denatured Hb bound to cell membrane
• May damage cell membrane, leading to intravascular hemolysis
– “Bite” cells
• Spleen removes portion of RBC that had Heinz body, preventing
intravascular hemolysis
– These aren’t typically present immediately following an acute
hemolytic crisis (problem cells have been destroyed)
29. Other Non-Specific Lab Tests
• Reticulocyte count
– May be elevated following acute crisis (6-8 weeks)
– May be normal in non-crisis situations
– May be reduced in aplastic crisis (could go to zero)
– Should be considered in conjunction with smear, other data
• Serum bilirubin
– Present in the unconjugated (prehepatic) form
– Elevated after an acute hemolytic crisis
• Serum haptoglobin
– Binds to Hb in the blood for removal by spleen (preventing Hb
from excretion in the urine, which could lead to renal failure)
– Decreased (depleted) after an acute hemolytic crisis
30. Screening for G6PD
• Cells from G6PD-deficient subjects can’t
convert the oxidized substrate to a
reduced state
• Different tests use different substrates
• Substrates can either be the enzyme’s
natural substrate (NADP) or substrates
from secondary reactions
31. Fluorescent Screening Test
• G6PD generates NADPH
• NADPH fluoresces under long-wave UV
light
• No G6PD? No fluorescence.
32. Fluorescent Screening Test
• Shortcomings:
– False Negative: young red blood cells have more
G6PD activity. During an acute hemolytic episode,
reticulocytosis results in a bigger population of young
red blood cells, so even in G6PD Deficiency, the
fluorescence may appear normal.
– False Positive: if the patient is anemic, very little
fluorescence may be seen because there are very
few red blood cells.
33. Methemoglobin Reduction Test
• Sodium nitrite converts Hb (hemoglobin)
to Hi (methemoglobin)
• Adding methylene blue should stimulate
the pentose phosphate pathway, reducing
methemoglobin
• In G6PD Deficiency, methemoglobin
persists
34. Methemoglobin Reduction Test
• Normal blood → clear red color
• Deficient blood → brown color
• Heterozygotes → intermediate color
35. Methemoglobin Reduction Test
- Takes longer than fluorescence
+ Extremely inexpensive
+ Requires only a water bath
• Test should be complemented by
cytochemical analysis
36. Cytochemical Analysis
• Only way to reliably detect deficiency in
heterozygous women
• More reliable than assay
• Good complement for other tests
37. Cytochemical Analysis
• Treat red cells to convert their oxyhemoglobin (HbO2) to
methemoglobin (Hi)
• In the presence of G6PD, Hi converts back to HbO2
• Add MTT, which will be reduced by HbO2 to an insoluble
form
• In G6PD Deficiency:
– Hi persists
– MTT is not reduced
– Ergo, cells are not stained
39. Cytochemical Analysis
• Interpretation:
– Normal G6PD activity: majority stained
– Hemizygous: majority unstained
– Heterozygotes:
• Most show mosaicism (40-60% unstained)
• Some have only 2-3% unstained (fortunate
lyonization)
40. G6PD Assay
• Tracks activity of enzyme by following rate
of production of NADPH over time
• NADPH has peak of UV light absorption at
340nm
• Note potentially misleading results in
following table
41. G6PD Assay
Male Gd+ (n orm al)
Gd-
(enti rely defici ent )
Fem a le Gd+/ Gd+ (norm al)
Gd-/ Gd-
(enti rely defici ent )
Gd+/ Gd-
(so me what
deficie nt)
In he a lth 7 -1 0 <2 2 -7
In increas e d
de mo lys is
unrelate d t o
G6P D
defi ci en c y
15 4 4 -9
Dur ing
rec o ve ry fro m
G6P D-re lat e d
an e mia
6.5 (appe ar s
norm al)
6 -1 0 (appe ars
norm al)
Values are examples only (Lewis 10e, p226)
42. G6PD Assay
• Interpretation:
– Red cells are likely to lyse from G6PD deficiency if
they have less than ~20% of normal enzyme activity
• Confounding factors:
– With reticulocytosis, the relatively large population of
reticulocytes yields a higher enzyme activity, covering
up deficiency
– Therefore, a low-normal enzyme activity assay during
reticulocytosis points towards G6PD deficiency
(without deficiency, values would be very high during
reticulocytosis)
– Re-evaluate after reticulocytosis slows
43. Choosing Appropriate Tests
• More than one test should be used
• Are they in the middle of a hemolytic crisis?
– Anemia + Reticulocytosis = Misleading results
• For females, cytochemical analysis should be
used
• Normal and deficient control blood should
always be used for comparison
– Sheep are naturally deficient, bah!
Editor's Notes
In sickle cell trait, about half the Hemoglobin in the RBC is sickle and will exhibit sickling when under severe conditions of low oxygenation.
Who is affected by sickle cell disease?
Sickle cell disease is estimated to affect more than 50,000 Americans and has been identified in persons from several different racial backgrounds. The estimated prevalence of the common sickle cell disease variants in African-American live births is approximately 1 in 375 for sickle cell disease, 1 in 835 for Hb SC disease. While sickle cell disease is most commonly found in persons of African ancestry, it also affects persons of Mediterranean, Caribbean, South and Central American, Arabian, and East Indian ancestry
Is Sickle Cell only in African Americans?
Sickle cell is in many nationalities including African Americans, Arabs, Greeks, Italians, Latin Americans and people from India. All races should be screened for this hemoglobin at birth. In the US, 1 out of 10 African Americans have sickle cell trait and 1 out of 625 newborns have the disease
Although sickle cell disease is present at birth, symptoms usually don&apos;t occur until after 4 months of age.
Severe anemia, vaso-occlusive complications, and chronic hyperbilirubinemia are the main causes of SCDisease symptoms.
A vasoocclusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied. Pain is the most frequent complaint during these episodes, and it is ischemic in origin. Recurrent episodes may cause irreversible organ damage.
Hematologic crises are sudden exacerbations of anemia, with a corresponding drop in the hemoglobin level. This can happen when sickled cells block splenic outflow, leading to the pooling of peripheral blood in the engorged spleen (seen in young patients with functioning spleens). Less commonly, it is due to hepatic sequestration.
Hematologic crises can also be caused by aplasia, in which the bone marrow stops producing new RBCs (aplastic crisis). This is most commonly seen in patients with Parvovirus B19 infection or folic acid deficiency.
Infectious crises are due to underlying functional asplenia in most adults with sickle cell anemia, leading to defective immunity against encapsulated organisms (eg, Haemophilus influenzae, Streptococcus pneumoniae).
Individuals with infectious crisis also have lower serum immunoglobulin M (IgM) levels, impaired opsonization, and sluggish alternative complement pathway activation. Accordingly, persons with sickle cell anemia also exhibit increased susceptibility to other common infectious agents, including Mycoplasma pneumoniae, Salmonella typhimurium, Staphylococcus aureus, and Escherichia coli.
General Anemia: (same) – Due to the shortage of RBCs
Acute chest syndrome: (cough, dyspnea, tachypnea, hypoxemia, sickling of cells in pulmonary vesselscan be indistinguishable from pneumonia) this life-threatening complication is caused by infection or trapped sickled cells in the lung.
Infection: (oral temperature &gt;38.5ºC (101.3ºF), cough, watery stools, tender abdomen) In general, both children and adults with sickle cell anemia are more vulnerable to infections and have a harder time fighting them off. This is the result of spleen damage from sickled red cells, thus preventing the spleen from destroying bacteria in the blood. Infants and young children, especially, are susceptible to bacterial infections that can kill them in as little as 9 hours from onset of fever. Pneumococcal infections used to be the principal cause of death in children with sickle cell anemia until physicians began routinely giving penicillin on a preventive basis to those who are diagnosed at birth or in early infancy.
Painful crisis: A patient may experience pain wherever sickled blood cells block oxygen flow to tissues. The frequency and amount of pain vary. Some patients have painful episodes (also called crises) less than once a year, and some have as many as 15 or more episodes in a year. Sometimes pain lasts only a few hours; sometimes; several weeks. Pain is the principal symptom of sickle cell anemia in both children and adults.
Hand-Foot syndrome: When small blood vessels in hands or feet are blocked, pain and swelling can result, along with fever. This may be the first symptom of sickle cell anemia in infants. (swollen dorsa of hands and feet (dactylitis) which can be presenting symptom in young infants and children )
Stroke: (mental status changes, neurologic deficits) Defective hemoglobin damages the walls of red blood cells, causing them to stick to blood vessel walls. The resulting narrowed or blocked small blood vessels in the brain can lead to serious, life-threatening strokes, primarily in children.
Priapism: (sustained and painful penile erection (occurs in 50% of all male patients))
Yellowing of skin and eyes: These are signs of jaundice, resulting from rapid breakdown of red blood cells.
Delayed growth and puberty: in children and often a slight build in adults. The slow rate of growth is caused by a shortage of red blood cell
When both parents have sickle cell trait, for each pregnancy, the chances are:
1 in 4 that the baby will have only normal hemoglobin.
2 in 4 that the baby will have both normal and sickle hemoglobin (sickle cell trait).
1 in 4 that the baby will have only sickle hemoglobin (sickle cell anemia).
Data from Quinn et al (2004) suggest improvement in mortality rates for patients with sickle cell disease over the past 30 years. Recent information suggests 85% survival to age 18 years. This study tracked 700 children for 18 years.
Earlier data reported that among patients with sickle cell disease, approximately 50% do not survive beyond age 20 years, and most do not survive to age 50 years.
People with sickle cell disease make abnormal Hb, HbS. The red blood cells of a person with sickle cell disease do not last as long as “normal
red blood cells. The result is chronic anemia. Also, these RBCs lose their normal disk shape. They become rigid and deformed and take on a “sickle” or crescent shape. These oddly shaped cells are not flexible enough to squeeze through small blood vessels. This may result in blood vessels being blocked. The areas of the body served by those blood vessels will then be deprived of their blood circulation, damaging tissues and organs. The homozygous state of HbS disease is associated with considerable morbidity and mortality. The heterozygous state presents little mortality.
Sickle cell anemia can be cured by a bone marrow transplant, which replaces the defective red blood cells with healthy cells from a donor. But a transplant isn’t a realistic option for most people with sickle cell anemia because of a shortage of compatible donors and because of the risks presented by the drug regimen that is required to prepare a patient for a transplant. (Bonds)
&quot;First you give drugs to kill off the patient&apos;s marrow, then you do the transplant to replace the marrow.&quot; But the powerful drugs given to kill the patient&apos;s bone marrow can be dangerous for someone who has had a stroke or is at risk for stroke, she said.
Because There is no cure for sickle cell anemia, and it is possible for some people to die from the disease (although when discovered at a young age, people with sickle cell anemia don&apos;t die).
Folic acid, helps the body produce new red blood cells.
Pain medications help relieve the symptoms of crises.
People with sickle cell disease are often prescribed Prophylactic penicillin or other antibiotics to help fight infections.
Some crises can be managed at home with pain medicines, rest, and extra fluids. But if a crisis is especially intense, the pt may need to go to the hospital for intravenous (IV) fluids and stronger pain meds. also using oxygen to help ease symptoms during a crisis or an episode of acute chest syndrome.
Pts with sickle cell anemia may need to get transfusions of healthy red blood cells to help carry oxygen to the tissues of their bodies more effectively.
Donut-shaped
Soft and malleable
Able to pass through small spaces
Lifespan ~120 days