HEMATOLOGY > Hemoglobinopathies > Flashcards

Hemoglobinopathies Flashcards

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1
Q

Hemoglobinopathies can be caused by all of the following structural defects except:

A defective heme gene
Substitution of amino acids in a globin chain
Deletion of an amino acid in a globin chain
Addition of an amino acid in a globin chain
Fusion of globin chains.

A

A defective heme gene

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2
Q

To produce hemoglobin S, glutamic acid that is normally present in the sixth position on the beta globin chain is substituted with which of the following?

Cystine
Guanine
Lysine
Valine

A

Valine

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3
Q

To produce hemoglobin C, glutamic acid that is normally present in the sixth position on the beta globin chain is substituted with?

A

Lysine

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4
Q

True or False: The first time a cell containing Hb SS is deoxygenated, it forms an irreversibly sickled cell.

A

False
Initially, sickling is reversible. Upon repeated sickling and unsickling, cells with Hb SS tactoids become irreversibly sickled

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5
Q

What are the clinical manifestation of sickle cell disease?

A

Chronic hemolytic anemia
Fatigue, weakness, pallor
Prone to infections
Cardiomegaly (due to iron deposits from frequent transfusions)
Priapism (constant painful erection of the penis lasting more than 4 hours)
Children with SCD will experience slow growth and development

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6
Q

What is Sickle Cell Trait

A

If an individual inherits a sickle gene (S) from one parent and one normal gene (A) from the other parent, the disorder is a heterozygous condition known as sickle cell trait (Hb SA)

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7
Q

What is Sickle Cell Anemia

A

If an individual inherits “S” genes from both parents, the disorder is a homozygous condition known as sickle cell anemia (Hb SS)

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8
Q

Why does valine lead to sickling?

A

Glutamic Acid is replaced by Valine in a point mutation on the Beta chain in the 6th position
Glutamic Acid is polar and hydrophilic while valine is nonpolar and hydrophobic. When oxygen in low, valine will fit into the hydrophobic pocket of another hemoglobin and cause the hemoglobins to stick together. This will lead to hemoglobins polymerizing into long chains, which will distort the RBC into the wrong shape.

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9
Q

How does Persistance of Hemoglobin F also affect those with Hemoglobin S?
Hb S/HPFH

A

Persons with Hb S/HPFH have a milder anemia than individuals with SCD who have none to normal levels of Hb F.
Increased fetal hemoglobin protects the cell from sickling because of its higher affinity for oxygen.

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10
Q

Describe the steps in the sickling process?

A

Nucleation: when HbS is deoxygenated the hydrophobic valine becomes exposed and stick to other hemoglobin forming a small aggregate (nucleus).
Growth: Once the aggregate is formed, the HbS polymers will elongate into thin rigid fibers
Alignment: Mulitple fibers will align together and form a bundle, this will push against the RBC membrane and cause the cell to be in a distorted shape, characteristic sickle shape.

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11
Q

Define Vascular Occlusions

A

Blocking of blood flow in a vessel preventing oxygen and nutrients from reaching the tissue

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12
Q

How does sickle cell lead to vascular occlusions?

A

Early sickle cells (reticulocytes that contain Hb SS) tend to be more “sticky” and adhere to endothelium. Abnormal receptors on these cells allow platelets to form a bridge between sickled RBCs and endothelial cells.

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13
Q

What causes cellular dehydration in cells containing hemoglobin S?

A

Cells containing hemoglobin S have a decreased capacity to maintain normal levels of potassium (K+). As K+ leaves the cell, water follows.
Two mechanisms are responsible for maintaining intracellular ion levels, the Gardos channel and the K+-Cl- cotransporter channel (KCC). Both channels are abnormally activated in patients with sickle cell disease. The resulting loss of water from the cell increases the hemoglobin concentration and the chances for sickling

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14
Q

What causes the pain that sickle cell patients experience?

A

The main symptom in SCD is pain. Pain is a warning sign that is related to vaso-occlusion.

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15
Q

What causes a vaso-occlusion crisis?

A
  1. Hb SS contains reticulocytes that increased amount of CD36 expression which allows platelets to form a bridge between the reticulocytes and the endothelium. This slows down blood flow and reduce oxygen which leads to sickle cells.
  2. Sickled cells are rigid and less deformable allow them to get stuck in blood vessel and form a plug in small vessels. This can lead to tissue damage and organ infarction.
  3. WBC may also adhere to the endothelium in response to the inflammatory process. This allows neutrophils to capture additional RBC.
  4. Decreased level of L-argnine in SCD. L-arginine produces nitric oxide which is a vessel dilator and anti-inflammatory and anti-platelet properties. A decrease in NO will lead to increased cellular adherance to the endothelium
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16
Q

What are the clinical presentation for vaso-occlusions?

A

Bone and joint pathology, stroke, acute chest syndrome, nephropathies, and infections.
Organs affected include the bone marrow, brain, lungs, kidneys, liver, and spleen.

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17
Q

What can trigger a vaso-occlusion crisis?

A

Triggering mechanisms for this crisis include infection, fever, acidosis, dehydration, cold temperatures, anxiety, stress, and depression.

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18
Q

What is sequestration crisis?

A

Sequestration crisis occurs in SCD when large numbers of RBCs are suddenly pooled in the spleen and liver. These organs can enlarge rapidly causing pain, hypoxemia, and hypovolemic shock.

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19
Q

What kind of anemia is Sickle Cell Anemia?

A

Hemolytic Anemia (both intravascular and extravascular)

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20
Q

Is haptoglobin increased or decreased in intravascular hemolysis?

A

Decreased. Haptoglobin binds to free hemoglobin in the plasma and its cleared by the liver.

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21
Q

Describe autosplenctomy

A

This occurs when the spleen has multiple infarctions, followed by fibrosis, which renders the spleen nonfunctional.

Usually seen in adults in hemolytic crisis.

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22
Q

What is aplastic crisis?

A

An aplastic crisis occurs when the bone marrow shuts down temporarily due to the continual stimulus for production of erythrocytes.

During this time, a severe anemia may be present due to the shortened life span of the RBCs

Infections that sickle cell patients experience may also arrest RBC production and produce a pancytopenia

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23
Q

What causes aplastic crisis in SCD?

A

Parvovirus B19

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24
Q

What is parvovirus B19

A

Parvovirus B19 is a small, non-enveloped, single-stranded DNA virus that infects human red blood cell precursors. This virus can temporarily shut down erythropoesis leading to sudden and severe anemia

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25
In sickle cell anemia, an increased amount of which of the following surface antigens on reticulocytes may allow platelets to form a bridge between the reticulocytes and endothelial cells, ultimately leading to vaso-occlusion?
CD36
26
Which of the following will not increase during hemolysis? Plasma LDH concentration Plasma bilirubin concentration Reticulocytes Haptoglobin
Haptoglobin is decreased and the haptoglobin-hemoglobin complex is quickly cleared by the liver Hemolysis is characterized by increased levels of plasma LDH and bilirubin and an increased number of reticulocytes
27
What are the risk factors for SCD?
Abrupt temperature, high altitudes, fever, dehydration, or hypoxia. Physical exertion, pregnancies and psychological stress.
28
How many sickle cell crisis episode are required to be considered poor prognosis?
3 or more crisis per year is associated with poor prognosis
29
Which of the following options could cause a sickling event? Excessive intake of water Fluctuations in temperature Oxygen inhalation Sedentary lifestyle
Fluctuations in temperatue
30
What are the treament of sickle cell anemia?
Palliative care (supportive care and pain management) Preventive treatment Curative treatment (transplantation and gene therapy)
31
What are the three major classes of compounds used to manage pain in SCD?
1. Opioids include codeine, levophanol, morphine, oxycodone, and pethidine, among others. 2. Non-opioids include salicylates, nonacetylated salicylates, acetic acid derivatives, anthranilic acid derivatives, proprionic acid derivatives, and oxicams. 3. Adjuvants include anticonvulsants, antidepressants, antihistamines, and benzodiazepines.
32
What are the expected WBC and platelets levels in SCD?
Neutrophilic leukocytosis and Thrombocytosis
33
What is the solubility test?
The buffer is made up of dibasic and monobasic potassium phosphates, saponin, and dithionate. A 1:100 dilution of blood into buffer is made, incubated for 5 minutes, and turbidity is observed against a white background with black line The solubility test should only be used as a screening test as it is not reliable for diagnosing sickle cell disease.
34
Is hemoglobin S soluble or nonsoluble?
Hb S is not soluble
35
What is the result of a positive solubility test?
A positive result is indicated by a turbid solution
36
What does a negative solubility test look like?
A negative result is obtained when lines are visible through the solution.
37
What can cause a false postive solubility test?
1. Increased amounts of RBC (polycythemia vera) 2. Extremely high WBC (leukemias) 3. Extremely high platelet counts 4. High lipids or globulins 5. Too much blood is added
38
# ei What can cause a false negative solubility test?
1. Severely decreased hemoglobin/hematocrit 2. Recent transfusion 3. Infants less than 6 months old (increased levels of HbF) 4. Too little blood is added 5. Wrong sized test tubes 6. Deteriorated reagents 7. Test tube too close to the background when reading the results
39
Describe alkaline hemoglobin electrophoresis
Performed at an alkaline pH (8.4-8.6) Hemoglobin molecules carry a net negative charge and when an electric feild is applied, hemoglobins migrate toward the anode (+) The rate of migration depends on the charge difference
39
What is hemoglobin electrophoresis?
The movement of hemoglobin proteins in an electric field at a fixed pH. Various hemoglobins are compromised on different combinations of globin chains (normal and abnormal) they will demonstrate different degrees of mobility
40
What is used as a support medium for alkaline electrophoresis?
Cellulose acetate Holds the sample in place and allows hemoglobin molecules to migrate under an electic field, inorder to produce distinct bands.
41
When is alkaline electrophoresis used?
To diagnose thalassemia and hemoglobinopathies
42
Why is acid electrophoresis used to confirm alkaline electrophoresis
HbS and HbD and HbE can co-migrate and appear in the same position in alkaline electrophoresis, so acid electrophoresis used for confirmation
43
Describe acid electrophoresis
Performed at acidic pH (6.0-6.2) Uses agar gel and citrate buffer to distinguish hemoglobin variants that overlap on alkaline electrophoresis Hemoglobins will still move towards the anode (+) as in alkaline electrophoresis however the bands will be more separated and the migration order will change
44
What is the migration order on alkaline electrophoresis?
Closest to the cathode: Hb A2/C/E HbS HbF HbA (fastest normal Hb) Hb Bart (faster than A) Hb H (fastes) Closest to the anode
45
What is the migration pattern of acidic electrophoresis?
Closest to the cathode: HbF HbA and HbD HbS HbC Closest to the anode
46
What is a densitometer?
Used to measure an quantify the intensity of bands or spots on electrophoresis gels or membrane.
46
The gel electrophoresis pattern for hemoglobin S shows which of the following migration patterns? Hb S migrates alone in alkaline and with D in acid electrophoresis. Hb S migrates with D in alkaline and A in acid electrophoresis. Hb S migrates with D in alkaline and alone in acid electrophoresis. Hb S migrates with A in alkaline and D in acid electrophoresis.
Hb S migrates with D in alkaline and alone in acid electrophoresis.
47
Describe HPLC
High Performance Liquid Chromatography is used to separate, identify and quantify hemoglobin variants based on how they interact with chromatography column. Most used a cation-exchanges chromatography in which hemoglobins have different charges and bind to the column with different strengths A buffer gradient gradually elutes hemoglobins and each hemoglobin exits (elutes) at a characteristics retention time.
48
Explain capillary electrophoresis
Separate hemoglobin variants based on electrophoretic motility inside a narrow capilllary. Hemoglobins migrate according to their charge to mass ratio. Hemolyzed blood is injected into the capillary An electric field is applied Hemoglobins separate as they migrate A detector measures absorbance as each faction migrates Output is an electropherogram (peak vs migration time) Peak area = percentage of each hemoglobin
49
A technique that utilizes high voltage and separates hemoglobin on a polyacrylamide gel is called:
Isoelectric focusing In this method, the hemoglobins move through the polyacrylamide gel to the point where their net charge is zero
50
What RBC morphology is seen in sickle cell trait?
Codocytes (target cells), this is because there is a decrease in mean corpuscular hemoglobin concentration (MCHC) Sickle cell trait will not usually show completely sickled cells because of hemoglobin A which makes up more than 60% of HbSA
51
What is the RBC morphology in Sickle Cell Disease (HbSS)
Drepanocytes (sickle cell) Polychcromasia (increased reticulocytes) NRBC
52
What are xerocytes?
Cells that have their hemoglobin pooled to one side. This occurs when HbSC becomes dehydrated
53
Hemoglobin S will result in a positive or negative solubility test?
Positive because HbS does not dissolve and will result in turbidity
54
Which of these hemoglobins is known to migrate with Hb S in alkaline electrophoresis?
Hemoglobin D
54
Complaints of pain from a patient with sickle cell disease are most likely associated with which of the following conditions/events?
Vaso-occlusive crisis
55
The reason that the sickle cell mutation can lead to polymerization and thus sickling of the RBC is because:
A non-polar amino acid is substituted for a polar amino acid at a critical location; therefore, bonding with other hemoglobin molecules occurs instead of bonding with water.
56
Which group of conditions increases the risk of Hb S polymerization?
Low pH, dehydration, increased level of 2,3-DPG, Increased temperature (above 37 degrees)
57
The heterozygous state of Hb S, which is referred to as the sickle cell trait, contains which of the following hemoglobins in combination with S?
Hb A
58
Nitric oxide is associated with the prevention of vaso-occlusion by decreasing cellular adherence to the endothelium. Which amino acid is decreasedin patients with sickle cell disease and is needed as a substrate to produce nitric oxide?
The amino acid L-arginine is a substrate needed to produce nitric oxide.
59
Which hemoglobin, when elevated, acts as a protection against sickling in patients with Hb S?
Hemoglobin F has a high affinity for oxygen. When Hb F is elevated, cells containing Hb S are more oxygenated and do not sickle as readily as they would if Hb F were not present or present in small quantities.
59
Which of the following laboratory test results indicates that a sickle cell patient may be in aplastic crisis?
A decreased reticulocyte count may indicate a halt in the production of red blood cells. Decreased haptoglobin, increased bilirubin, and increased LDH are all consistent with hemolysis and not an aplastic condition.
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