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HEMA LEC 2 > HEMOGLOBINOPATHIES > Flashcards

HEMOGLOBINOPATHIES Flashcards

1
Q
  • Alpha and Zeta Globin genes
A

– Chromosome 16:

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2
Q

Beta, Gamma, Delta and Epsilon
Globin genes

A

– Chromosome 11

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3
Q
  • Referred as: Alpha-like genes
A

– Chromosome 16:

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4
Q

Referred as: Beta-like genes

A

Chromosome 11

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5
Q

– Synthesize the alpha-globin chains

A
  • Alpha globin gene (HBA1 & HBA2)
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6
Q

– Codes for Beta-globin chain

A
  • Beta globin gene (HBB)
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7
Q

– Codes for gamma- globin chain

A
  • Gamma globin genes (HBG1 and HBG2)
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8
Q

– Codes for delta-globin chain

A
  • Delta globin gene(HBD)
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9
Q

Hemoglobin
COMMON NAMES
– Morphology
*___________, _____________
– Location
* ____________, ___________
– Content
________________

A
  • HbS (sickle cell); HbC (Crystallization)
    Gun-Hill, Constant-Spring
  • HbM(Methemoglobin)
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10
Q

Hemoglobin
* SCIENTIFIC DESIGNATION
Nature of abnormality

A

– Substitution, Deletion,Addition, Fusion,
Elongation

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11
Q

____________ symptoms of the disease have been traced in one Ghanaian family

A

1670

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12
Q

Sickle cell anemia was 1st reported by a Chicago cardiologist, Herrick, in a West Indiana Student with severe anemia

A

1910

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13
Q

Emmel recorded that sickling occurred in non-anemic patients and in patients who
were severely anemic.

A

1917

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14
Q

In 1927 _____________ described the pathologic basis of the disorder and its relationship
to the hemoglobin molecule.

A

Hahn and Gillespie

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15
Q

Beet reported that malarial parasites were present less often in blood films from
patients with SCD that in individuals without SCD

A

1946

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16
Q

Pauling showed that when Hb S is subjected to electrophoresis, it migrates differently
than does Hb A

A

1949

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17
Q

more severe disease

A
  • Homozygotes (Hb SS)
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18
Q

Less severe disease

A

Heterozygotes Hb S (Hb SC or Hb S-Bthal)

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19
Q

Asymptomatic but may have mild
symptoms
– Military boot camp and High level athletics

A
  • Heterozygotes (Hb AS)
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20
Q

Glutamic acid(GAG) is replaced by Valine(GTG)

A
  • On the Beta chain at Position 6
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21
Q

Thymine replaces adenine

A

Mutation occurs in nucleotide 17

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22
Q

Quaternary structure of the molecule does
not produce a hydrophobic pocket for
valine

A
  • Hb S – fully oxygenated
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23
Q

– Creates a hydrophobic pocket (Phe 85 &
Leu 88)
Allows the valines from adjacent Hb S
molecules to BIND

A
  • Deoxygenation
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24
Q

Sickling Begins – oxygen saturation decreases
to less than 85%

A
  • Homozygotes
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25
Q

Sickling Begins – Oxygen saturation is reduced
to less than 40%

A
  • Heterozygotes
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26
Q

Reduction in pH
– Increase in 2,3 BPG

A
  • Decrease in oxygen tension
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27
Q
  • END RESULT: Occlusions of __________ and _________ and infarction of surrounding
    tissue.
A

capillaries and arterioles

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28
Q
  • 2 FORMS OF SICKLE CELL:
A
  1. Reversible Sickle Cell
  2. Irreversible Sickle Cell
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29
Q
  • Change shape in response to oxygen tension
  • Circulate as normal biconcave discs when fully
    oxygenated but undergo hemoglobin
    polymerization
A
  1. Reversible Sickle Cell
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30
Q
  • Seen in PBS – elongated sickle cells with a
    point at each end
  • Recognized as ABNORMAL by the spleen
A
  1. Irreversible Sickle Cell
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31
Q
  • Other Reason Affects the Sickling process:
    Microparticles, previously known as ________
A

“cellular dust”

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32
Q
  • More than _________ hemoglobin variants are known;
A

1200 hemoglobin

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33
Q

8 genotypes causes SEVERE DISEASES

A

– Hb SS,
Hb S-B0-thal,
severe Hb S-B1-thal,
Hb SD-Punjab,
Hb SO-Arab,
Hb SC-Harlem,
Hb CS-Antilles, and
Hb S-Quebec-CHORI.

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34
Q

3 genotypes cause MODERATE DISEASES

A

Hb SC, moderate
Hb S-B1-thal,
and Hb AS-Oman

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35
Q

3 genotypes cause MILD DISEASE

A

– mild Hb S-B silent-thal,
Hb SE, and
Hb SA-Jamaica Plain

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36
Q
  • 2 produce very mild disease:
A

– Hb S-HPFH
and Hb S with
a variety of mild variants.

37
Q
  1. VASOOCCLUSIVE CRISIS
    * Frequency of painful episodes varies from
    none to ___________
    – Average: episodes persists for _______ or may
    last for weeks
A

six years
4-5 years

38
Q

2nd most common cause of hospitalization

A
  1. Acute Chest Syndrome (ACS)
39
Q

– 3rd most common cause of death among adults with SCD
– Most common inciting factors: Pulmonary infection, fat embolism, pulmonary infarction à decrease oxygen

A
  1. Acute Chest Syndrome (ACS)
40
Q

_________ is administered to maintain saturation at greater than or equal to95% and intravenous fluids to
prevent dehydration

A

Oxygen

41
Q

FES secondary to BMN is a rare but often fatal sequalae of SCD.
– It occurs more often in often in Hb SC (43%) and at similar frequency in Hb S-b1-thal (17%) and Hb SS
(19%)

A
  1. Fat Embolism syndrome(FES) and Bone marrow necrosis(BMN)
42
Q

Is a serious and potentially fatal sequela of SCD
– An association has been documented between the development of PHT and the nitrous oxide (NO)
pathway,
– Patients with SCD have decrease in NO, and leads to vasoconstriction and hypertension.

A
  1. Pulmonary Hypertension (PHT)
43
Q

– Pose a major problem for SCD patients
Increased susceptibility to life threatening infections from _________, ________, __________
– Common cause of death, especially in the first __________
– __________ are exacerbated by the autosplenectomy effect
* Gradually loses its ability to function
* Not effectively clear organism from the blood

A

Staphylococcus aureus, Streptococcus
pneumoniae, and Haemophilus influenzae.
3 years of life
Septicemia

44
Q

Shortened RBC survival (between 16-20 days)

A
  1. Chronic Hemolysis
45
Q

Continuous screening and removal of sickle cells by the spleen perpetuate the chronic hemolytic
anemia and autosplenectomy effect
* RBC hemolysis releases free hemoglobin, which disrupts the argnine-NO pathway, resulting in the
sequestration and lowering of NO à Pulmonary hypertension
– Another major sequelae of hemolysis is renal hyper-filtration and dysfunction
* which can be detected early by an increased glomerular filtration rate

A
  1. Chronic Hemolysis
46
Q

Result from the sudden arrest of erythropoiesis caused by folate depletion
– Folic acid deficiency as a cause of exaggerated anemia in SCD
– Prescribe prophylactic folic acid for patients with SCD

A
  1. Megaloblastic Episodes
47
Q

Most common life-threatening hematologic complications and usually associated with infection
(Parvovirus)
– Are short lived , Require no therapy
– Sickle cell patients usually can compensate for the decrease in RBC survival by increasing bone
marrow output

A
  1. Aplastic Episode(Bone marrow failure)
48
Q

In patients with severe anemia, cardiomegaly can develop as the heart works harder to maintain adequate blood flow and
tissue oxygenation

A
  1. Cardiac Abnormalities
49
Q

Impaired blood supply to the head of the femur and humerus results in a condition called avascular necrosis (AVN)
– 50% of patients with SCD developed AVN by age 35 years

A
  1. Bone and skin abnormalities
50
Q

occurs in approximately 11% of children with SCD before age 20 years.

A

Hemorrhagic or ischemic stroke

51
Q

Due to retinal ischemia and neovascularization
– Begins at 10 years of age
– Retinopathy occurs at a rate of 45% in patients with
Hb SC, 11% with
Hb SS, and 17%
with Hb S-B-thal by early adulthood

A

Retinopathy

52
Q

Incidence with Malaria

Greatest frequency in_________, _______, _______, _________

A

Central Africa, the
Near East, the Mediterranean region, and
parts of India.

53
Q

____________ - offer some protection
against cerebral falciparum malaria in
young patients

A

Sickle gene

54
Q

__________ used oxygen in the cell
– Causes the cells to sickle

A

Malaria

55
Q

Laboratory Diagnosis

  • Observed on a wright-stained PBS
    Normocytic, Normochromic
    – Long, curved cell with a pointed at each
    end (sickle cell) – HALLMARK OF SCD
    – Moderate to marked polychromasia
  • 10% & 25% reticulocyte count
    – Increased RDW
    – Moderate leukocytosis with neutrophilia
    and a mild shift to ward immature
    granulocytes
A

Sickle cell disease malaria

56
Q

________________
______ – not elevated
* ____________ – Present
_____________– Elevated in all forms
of SCD
*______________ – normal in young patients
but tend to be elevated later in life
* __________________
– Elevated levels of indirect and total bilirubin
with accompanying jaundice

A

LAP
Thrombocytosis
Immunoglobulin A
Serum ferritin
Chronic hemolysis

57
Q
  • DIAGNOSIS is a 2-STEP POCESS
A

– 1. demonstrate the insolubility of
deoxygenated Hb S in solution
– 2. confirmation of its presence using:
* hemoglobin electrophoresis
* high-performance liquid chromatography
(HPLC)
* Capillary electrophoresis

58
Q
  • Older screening test:
A

– Detects Hb S insolubility by inducing sickle
cell formation on a glass slide
* On a slide: drop of blood + a drop of 2% Na
metabisulfite
* Sealed under a coverslip
* Hgb in RBCs is reduced to deoxygenated
form à polymerization à sickling of cell
(microscopically)
* Slow and hassle to perform

59
Q

Laboratory Diagnosis: Hemoglobin Solubility test

A
  • Most commons screening test
  • Capitalizes on the decreased solubility of
    deoxygenated Hb S in solution, producing
    TURBIDITY
  • BLOOD + Buffered salt Solution containing reducing
    agent (sodium hydrosulfite (dithionite)) + a
    detergent-based lysing agent (Saponin)
  • Saponin: dissolves membrane lipids à release HGB
  • Dithionite: reduces ferrous to ferric (does not bind
    oxygen) à deoxygenated Hb S polymerizes
  • TURBID -Deoxygenated Hb S
  • CLEAR– Non sickling hemoglobins
60
Q

*Laboratory Diagnosis: Hemoglobin Solubility test

False-Positive
– _______________
- _______________
- ________________
* False-Negative
- ______________
- ______________

A
  • Hyperlipidemia
    – Few rare hemoglobinopathies
    – Too much blood added

– Infants younger than 6 months
– Low hematocrit

61
Q

– common 1st step in confirmation of hemoglobinopathies

A
  • Alkaline Hemoglobin electrophoresis
62
Q

some hemoglobin assume a positive charge migrate toward the cathode (negative pole)

A

Acid pH

63
Q

– Separates hgb types in a cation exchnage
column and usually requires only one
sample injection

A

HPLC

64
Q

Can identify and quantify low levels of Hb
A2 and Hb F, but comigration of Hb A2 and
Hb E occurs

A
  • HPLC
65
Q

– It is BEST use for thalassemias

A
  • HPLC
66
Q

CONFIRMATORY TECHNIQUE that is expensive and complex
Requires well trained and experienced laboratory personnel
* Uses electric current to push the hgb molecules across a pH gradient

– They migrate through the pH gradient until the hgb reaches its isoelectric point (net
charge of zero)

– The migration stops and the hgb molecules accumulate at their isoelectric position

– Isoelectric point differences of as little as 0.02 pH units can be effectively separated

A
  • Isoelectric Focusing (IEF)
67
Q

Requires a more sophisticated approach

A
  • Neonatal Screening
68
Q
  • Using 3 techniques: _____________, ____________, _____________
A

adapted IEF,
HPLC
& Reversed-phase HPLC

69
Q
  • Some reference laboratories may use:
A

mass spectroscopy, matrix-assisted laser desorption- ionization time-of-flight (MALDI-TOF) mass
spectrometry, or IEF to separate hemoglobin types, or nucleic acid identification of the genetic
mutation.

70
Q
  • Common indicators of inflammation

___________ – good predictor of sickle cell complications and mortality
– __________ level exhibit variability too great to reliably predict episodes
–___________ both elevated during VOC and acute chest syndrome
– ____________ – indicators in clinical practice
– ____________ – elevated before and during VOC
– Elevated Malondialdehyde (MDA) & depleted alpha-tocopherol–in lipid damage from oxidative
stress
– _____________rises during bouts of inflammation
– THE MOST PROMISING : _________________

A

WBC Count
ESR & CRP
CRP & sPLA2
IL6,IL10 and protein S
Annexin A5
Alpha tocopherol & CRP
IL6,IL10, Vascular cell adhesion molecule 1 (VCAM-1) and sPLA2

71
Q
  • Benign condition
  • Generally asymptomatic
  • No significant clinical or hematologic manifestations
  • Under extremely hypoxic conditions
    – Systemic sickling and vascular occlusion with pooling of
    sickled cells in the spleen, focal necrosis in the brain,
    rhabdomyolysis, and even death can occur
  • Patient may develop splenic infarcts and cause sickling
    – Severe respiratory infection, unpressurized flight at high
    altitudes and anesthesia
  • Failure to concentrate urine – CONSISTENT abnormality
    in SCT
  • Strenuous exercise and Military Recruits
A

Heterozygous state (Hb AS)

72
Q

Electrophoresis or HPLC - presence
of __________ and _____________

A

Hb S and Hb A

73
Q
  • Most common non sickling variant encountered
    in the US
A

Hemoglobin C

74
Q
  • 3RD most common in the world
A

Hemoglobin C

75
Q

____________________________
– Crystalizes in the oxygenated state

__________________________
– Less splenic sequestration and hemolysis

A

Hb C is less soluble than Hb A
* Shorter Hb C crystal does not alter RBC

76
Q
  • Form a short, thick crystal within the RBC
A

Hemoglobin C

77
Q

CLINICAL FEATURES

– Milder disease compared to SCD
– Mild splenomegaly and hemolysis
– No Vasoocclusive crises
– Heterozygous hemoglobin C trait
(Hb AC)
* Asymptomatic

A

Homozygous Hemoglobin C

78
Q
  • Seen in PBS
  • Seen on wet preparation
    HGB is concentrated within boundary of
    the crystal
  • Densely stained and vary in size
  • Appear oblong with pyramid-shaped or
    pointed ends
A

Hexagonal Crystals within RBCs

79
Q

Hemoglobin solubility – NEGATIVE
– DEFINITIVE DIAGNOSIS- using
electrophoresis, HPLC, or nucleic acid testing
– No Hb A is present in Hb CC
– Hb C is present > 90%
* Hg F < 7%
* HbA2 – 2%
– Hb AC trait
* Hb A – 60%
* Hb C – 30%

A

Hemoglobin C

80
Q
  • Double substitution on the B chain
    – Identical Hb S substitution
  • Valine for glutamic aside at position6 of the B chain
    – Same as the Hb Korle Bu Mutation
  • Substitution at position 73 of aspartic acid for asparagine
    – Abnormal hgb migrates with Hb C on alkaline hgb electrophoresis.
  • Heterozygous – asymptomatic
  • Heterzygosity for Hb S and Hb C- Harlem – similar crises with Hb SS disease
A

Hemoglobin C- Harlem (Hemoglobin CGeorgetown)

81
Q

Hemoglobin C- Harlem (Hemoglobin CGeorgetown)
Solubility test – ____________
* Confirmatory test – ______________

A

POSITIVE
hemoglobin
electrophoresis or HPLC

82
Q

First Describe in 1954

A

Hemoglobin E

83
Q

a Beta chain variant in which lysine is substituted for glutamic acid in
position 26

A

Hemoglobin E

84
Q

is both a qualitative defect (because of the amino acid
substitution in the globin chain) and quantitative defect with Beta thalassemia
phenotype (because of decreased production of the mutated globin chain)

A

Hb E mutation

85
Q

_____________is asymptomatoc

A

Hb E trait

86
Q

_____________ results in more severe, resembles the severity B-thalasemia, requiring regular blood
transfusions

A

Hb E-B0-Thal

87
Q

– Hb M migrates slightly more slowly than _________
– The electrophoresis should be performed on agar gel at pH _______
for clear separation.

A

Hb A
7.1

88
Q
A

HEMA LEC 2 (8 decks)

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