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Sickle Cell Anemia (Hemoglobinopathies). By: Jessica Hebert, Rob McElroy, Beth McQuinn, Yuway Tsing, Elias Kass, Bill Walter, Amelia Kramer. What are hemolytic anemias?. Decreased life-span of erythrocytes Removal of RBCs may be: Intravascular (within the blood)

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Sickle Cell Anemia (Hemoglobinopathies)

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sickle cell anemia hemoglobinopathies

Sickle Cell Anemia (Hemoglobinopathies)

By: Jessica Hebert, Rob McElroy, Beth McQuinn, Yuway Tsing, Elias Kass, Bill Walter, Amelia Kramer

what are hemolytic anemias
What are hemolytic anemias?
  • Decreased life-span of erythrocytes
  • Removal of RBCs may be:
    • Intravascular (within the blood)
    • Extravascular (within the spleen)
  • Associated with:
    • Increased erythropoiesis
    • Increased hemoglobin catabolism byproducts
  • Many types of hemolytic anemias:
    • G6PD-Deficiency
    • Hemoglobinopathies
      • Sickle Cell Disease
      • Hereditary Spherocytosis
      • Thalassemias
    • Immunohemolysis
    • Others…

Background:Prevalence in Populations

clinical presentation signs and symptoms
Clinical Presentation: Signs and Symptoms


Clinical Presentation

  • There are a range of Treatments per extremes or per symptoms
sickle cell anemia

Sickle Cell Anemia

A hereditary genetic disorder that results in the production of abnormal hemoglobins

one small point mutation leads to a major problem when hbs is deoxygenated
One small point mutation leads to a major problem when HbS is deoxygenated…

Deoxyhemoglobin A (HbA)

Deoxyhemoglobin S (HbS)

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.
  • 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

sickling of red blood cells leads to
Sickling of red blood cells leads to:
  • Vaso-occlusive complications
  • Severe anemia
  • Chronic hyperbilirubinemia
vaso occlusive complications
Vaso-occlusive complications
  • Occur in areas with:
    • Prolonged, low oxygen tension
    • Decreased pH
    • Inflammation
    • Low blood flow

Source: Robbins

severe anemia and chronic hyperbilirubinemia
Severe Anemia and Chronic Hyperbilirubinemia
  • Young RBCs with HbS can alternate between the sickled and normal formation.
  • However, sickling causes oxidative damage to the RBCs cell membrane (and to the cells around it).
  • Eventually, RBCs become irreversibly sickled.
severe anemia and chronic hyperbilirubinemia17
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

g6pd deficiency distribution19
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)

G6PD-Deficiency Distribution
g6pd deficiency presenting symptoms
G6PD-DeficiencyPresenting Symptoms
  • Fatigue or muscle weakness
  • Jaundice or pallor
  • Dyspnea
  • Dark urine
  • Pain (especially abdominal)
  • Splenomegaly
g6pd deficiency pathology
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
g6pd crisis precipitation beans
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
g6pd crisis precipitation oxidizing drugs
G6PD Crisis Precipitation - Oxidizing Drugs
  • Antimalarials (primaquine, quinine, quinidine)
  • NSAIDs (aspirin, ibuprofen)
  • Antibiotics (sulfonamides)
  • Nitrofurantoin
  • TCM herbs (rhizoma coptidis, margarita, calculus bovis)
other oxidants
Other oxidants
  • Henna – primarily infants and pregnant women
  • Naphthlene (moth balls) – regular exposure
early lab tests cbc
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
early lab tests urinalysis
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
early lab tests smear
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)
other non specific lab tests
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
screening for g6pd
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
fluorescent screening test
Fluorescent Screening Test
  • G6PD generates NADPH
  • NADPH fluoresces under long-wave UV light
  • No G6PD? No fluorescence.
fluorescent screening test32
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.
methemoglobin reduction test
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
methemoglobin reduction test34
Methemoglobin Reduction Test
  • Normal blood → clear red color
  • Deficient blood → brown color
  • Heterozygotes → intermediate color
methemoglobin reduction test35
Methemoglobin Reduction Test

- Takes longer than fluorescence

+ Extremely inexpensive

+ Requires only a water bath

  • Test should be complemented by cytochemical analysis
cytochemical analysis
Cytochemical Analysis
  • Only way to reliably detect deficiency in heterozygous women
  • More reliable than assay
  • Good complement for other tests
cytochemical analysis37
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
cytochemical analysis39
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)
g6pd assay
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
g6pd assay41
G6PD Assay

Values are examples only (Lewis 10e, p226)

g6pd assay42
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
choosing appropriate tests
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!