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Module 3 > Week 3 > Flashcards

Week 3 Flashcards

1
Q
  • Raised RDW.
  • Blood film: Spherocytes, Howell-Jolly bodies, polychromatic cells
  • What is the most likely diagnosis?
A

-Hereditary Spherocytosis

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2
Q
  • Low Hb, Raised reticulocytes
    - Raised WBC
    - Blood film: red cell fragments, schistocytes, Heinz Bodies, bite cells
    - What is the most likely diagnosis?
A

-G6PD deficiency

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3
Q
  • Raised bilirubin, Raised ALT, Low Hb
    - Raised RDW
    - Coomb’s test -ve
    - Blood film: anisocytosis, spherocytes, bite cells, polychromatic cells.
    - What is the most likely diagnosis?
A 
-Dapsone induced haemolysis (or just drug induced)
			//Bite cells: think oxidative haemolysis
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4
Q

What are the main psychosocial problems in children with Sickle Cell Disease?

A
  • Emotional challenge: Coming to terms with the illness
  • Cognitive impairment leads to educational problems, where extra support may be required
  • Adherence to treatment is also a problem
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5
Q

-What is the location of the beta globin gene complex?

A

-Chromosome 11p15

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6
Q

-What is the location of the alpha globin gene complex

A

-Chromosome 16p13.3

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7
Q

What genes are involved in embryonic Hb production?

A

-Epsilon gene on the beta globin complex and the zeta 2 gene on the alpha globin complex

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8
Q

-What genes are involved in foetal Hb production?

A

-Ggamma and Agamma genes on the beta globin complex and the alpha 1 and 2 genes on the alpha globin complex

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9
Q

What are the normal ranges of HbA, HbA2 and HbF on High performance liquid chromatography (HPLC) in adults?

A
  • HbA: 95.5-96.5%
    • HbA2: 2.5-3.5%
    • HbF: <1%
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10
Q

What are the most common kinds of mutations assocviated with the alpha genes and the beta genes?

A
  • Alpha genes: deletions

- beta genes: point mutations

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11
Q

What are the 4 most common alpha thalassaemia mutations?

A
  • -alpha3.7
    - -alpha4.2
    - __SEA
    - __FIL
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12
Q

What variant haemoglobin is associated with delta-beta gene fusion?

A

-Hb Lepore

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13
Q

Once a sample has been taken for genetic testing, what methods are used to analyse the DNA?

A
  • GAP-PCR
    - MLPA (Multiplex ligation-dependent probe amplification)
    - Real time PCR
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14
Q

What is thew structural change in Hb that causes HbS?

A

-Glutamic acid is substituted for Valine at amino acid 7

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15
Q

What is the structural change in Hb that causes HbC?

A

-Glutamic acid is substituted for Lysine at amino acid 7

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16
Q

What is the structural change in Hb that causes HbD?

A

-Glutamic acid is substituted for Glysine at amino acid 122

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17
Q

What is the structural change in Hb that causes HbE?

A

-Glutamic acid is substituted for Lysine at amino acid 27

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18
Q

What is the characteristic finding of Beta thalassaemia on HPLC?

A

-Raised HbA2, (and sometimes HbF)

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19
Q

What is the characteristic finding of Alpha thalassaemia on HPLC?

A

-Normal HbA2 and HbF

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20
Q

Outline how a GAP PCR is performed (In the context of alpha thalassaemia)

A

-Primers are set up for a specific gene: one forward primer, one close reverse primer and one very distant reverse primer
-In a normal gene, with no deletion, the forward primer and distant reverse primer form a product that relates to the size of the specific gene
-A deletion brings the distant primer closer to form a smaller product
-Visualising the product shows the specific size of a deletion when compared to a control/ normal gene.
-The size of the deletion is used to identify the mutation
(-e.g allows comparison of –alpha3.7kb and –alpha4.2kb deletions)

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21
Q

Give three examples of different types of mutation that can cause thalassaemia

A
  • Mutations affecting transcriptional elements (e.g A mutation in the promoter regulatory elements)
    • Mutations affecting RNA processing (e.g A mutation in the splice junction)
    • Mutations affecting RNA translation (e.g A mutation in the initiation codon)
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22
Q

What molecular techniques are employed to detect point mutations (Such as in Beta thalassaemia)?

A
  • Sanger sequencing
  • RFLP (Restriction fragment length polymorphism)
  • Allele specific/ARMS (Amplification-refractory mutation system)
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23
Q

What molecular techniques are employed to detect point mutations (Such as in Alpha thalassaemia)?

A
  • GAP-PCR

- MPLA (Multiplex ligation-dependent probe amplification)

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24
Q

What molecular technique is employed in analysing unknown mutations?

A

-Next generation sequencing (NGS)

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25
Q

What is the main cause of inherited extravascular haemolysis?

A

Hereditary Spherocytosis

26
Q

Describe the pathogenesis of hereditary spherocytosis

A
  • A defect in the proteins involved with interactions between the cytoskeleton and lipid bilayer of the red cell causes ineffective membrane formation (e.g Ankyrin deficiency)
    - Red cells are produced normally by the bone marrow but lose membrane
  • The loss of membrane causes a decrease in the surface area to volume ratio, leading to spherical shaped red cells.
    - Sphereocytes are not able to pass though microcirculation, especially the spleen.
    - As a result, the spherocytes die prematurely
27
Q
  • Splenomegaly, Low Hb, Low MCV. Reticulocyte count 16%
    - Blood film: Spherocytosis
    - Most likely diagnosis?
A

-Hereditary spherocytosis

28
Q

How is hereditary spherocytosis treated?

A
  • Splenectomy

- Folic acid in severe cases

29
Q

Describe the pathogenesis of Hereditary Elliptocytosis

A

-It is usually caused by the failure of spectrin heterodimers to self-associate into heterotetramers.

30
Q
  • Splenomegaly, Low Hb, Low MCV. Reticulocyte count 16%
    - Blood film: Elliptocytes
    - Most likely diagnosis?
A

-Hereditary Elliptocytosis

31
Q

-What pathway does pyruvate kinase deficiency affect?

A

-The Embden-Meyerhof pathway

32
Q

What are the consequences of inherited haemolytic anaemias?

A

Anaemia

		- Erythroid hyperplasia: increased red cell production and reticulocytes
		- Increased folate demand
		- Susceptibility to the effect of parvovirus B19
		- Increased risk of: gallstones, Iron overload, Osteoporosis
33
Q

What is the difference between intravascular and extravascular haemolysis?

A
  • Extravascular haemolysis describes when red cells are excessively removed by the RE system (Reticuloendothelial system/Macrophage system).
  • Intravascular haemolysis describes when red cells are broken down directly within the circulation
34
Q

Describe the pathogenesis of pyruvate kiniase deficiency

A

-Pyruvate kinase deficiency affects the Embden-Meyerhof pathway, leading to decreased ATP production
-Decreased ATP formation causes red cells to become rigid
-Red cells have an increased tendency to burst in the circulation, causing haemolysis and anaemia
//-A rise in intracellular 2,3-DPG causes a shift to the right in the oxygen dissociation curve, leading to the anaemia being well tolerated.

35
Q

Explain how mutations in globin genes can cause functional abnormalities in haemoglobin

A 
-Mutations can change the amino acid sequence and structure of the globin chains or the haem group, causing either an increased oxygen affinity, reduced oxygen affinity, increased tendency to oxidise or an unstable quaternary structure.
		//Histidine residues hold the haem in place
36
Q

What kinds of mutation in the globin genes cause high affinity haemoglobin?

A
  • A mutation that interferes with the alpha1Beta2 bonds, affecting rotation and co-cooperativity
  • A mutation that affects the carboxyterminal end of the protein, leading to hindered movement of the tetramer
  • A mutation that interferes with 2-3-DPG binding
  • Any of these can lead to high affinity haemoglobin
  • e.g Hb Luton
37
Q

What kinds of mutation in the globin gene cause a low affinity haemoglobin?

A
  • A mutation affecting the alpha beta 2 contacts lead to the molecule favouring deoxy form, due to alteration of the angle of the haem group.
  • Hb S is a low affinity haemoglobin
  • Hb Kansas is another example
38
Q

What kinds of mutation in the globin gene can cause methaemoglobinaemia?

A
  • Methaemoglobinaemia is caused by haemoglobins that have an increased tendency to oxidise.
  • This can be caused by a mutation that replaces a histidine residue in the haem group with a tyrosine.
  • This leads to iron being stabilised in its ferric state, the haemoglobin is ‘frozen’ or ‘paralysed’.
  • Hb M (e.g Hyde Park, a sub type) is an example of a haemoglobin that leads to methaemoglobinaemia
39
Q

What kinds of mutation in the globin gene can lead to unstable haemoglobins?

A
  • A mutation can affect the secondary structure of haemoglobin and the alpha1beta1 contacts or the ‘haem pocket’. (Histidines that hold the haem together)
  • When this structure is affected by a mutation, it can allow water to enter the haem pocket and cause oxidative damage.
  • Oxidation leads to precipitation of haemoglobin (Heinz bodies) and damages the cell so it becomes more rigid.
  • Hb Koln is an example of an unstable haemoglobin
40
Q

Inherited causes of HLH (Haemophagocytic lymphohistiocytosis)?

A
  • Familial (FHL)

- Immune deficiency syndromes (Eg Griscelli syndrome II)

41
Q

Acquired causes of HLH (Haemophagocytic lymphohistiocytosis)?

A
  • Infections (eg leishmanial)
    - Tumours (eg EBV associated lymphomas)
    - Autoimmune disorders (eg SLE)
42
Q

What are the clinical manifestations of HLH (Haemophagocytic lymphohistiocytosis)?

A
  • Organ infiltration by T cells causing
    - Haemophagocytosis (Macrophages engulfing red cells)
    - Cytokine storm (By T cells and macrophages)
  • These effects result in: Fever, hepatosplenomegaly, lymphadenopathy, bone marrow failure (And many more)
43
Q

Describe the pathogenesis of HLH (Haemophagocytic lymphohistiocytosis)?

A
  • Perforin is an essential protein in inducing apoptosis by CTLS or NKs
  • Perforin failure
  • CTLs cannot execute apoptosis, causing upregulation
  • Homeostasis of cytotoxic lymphocyte responses becomes deregulated
    - Clonal and polyclonal expansion of CTLs
44
Q

Describe the histology of the spleen

A
  • Two types of tissue within a capsule
    - White pulp: Made of lymphoid follicles
    - Red pulp:
    - Consists of splenic cords
    - It contains mononuclear-phagocyte tissue
45
Q

-Describe the functional unit of the spleen

A

Main route of blood thrugh spleen

  • Inflow from artery
    - Perifollicular zone
    - Sinus of endothelial cells and basal fibers
    - Post-sinusal venule
    - Outflow to vein
    - Alternate route:
    - Inflow from artery
    - Cords of the red pulp
    - Slow, open circulation
    - Flow into sinus
    - Post-sinusal venule
    - Outflow to vein
46
Q

Infectious causes of splenomegaly?

A
  • Visceral Leishamaniasis
    - Malaria
    - Viruses (Glandular fever)
47
Q

Haematological causes of splenomegaly?

A
  • Literally anything lol
    - Thalassaemia
    - Haemolytic anaemia
    - Sickle cell disease(s)
    - Myeloproliferative neoplasms
    - Lymphomas
    - Acute leukaemia, etc.
48
Q

Indications of splenectomy?

A
  • Autoimmune thrombocytopenic purpura (ITP)
    - Hereditary Spherocytosis
    - Lymphomas
    - Myeloproliferative neoplasms
    - Thalassaemia intermedia
49
Q

Complications of splenectomy?

A
  • Bleeding
    - Early infections
    - Thrombocytosis due to increased platelet count (7-12 days)
    - Thromboembolism
50
Q

Haematological features of hyposplenism?

A
  • Thrombocytosis
    - Leucocytosis
    - Lymphocytosis
    - Increased reticulocyte count
    - Morphology: Howell-Jolly bodies, Heinz bodies, siderocytes, target cells
51
Q

What is the clinical definition of iron overload?

A

-Serum ferritin >1000mg/ml with inflammation OR serum ferritin >2500mg/ml in the absence of inflammation

52
Q

What are the main causes of iron overload?

A
  • Primary (Genetic haemochromatosis)
    - Disorder of iron haemostasis
    - Types 1-4 (e.g, type 1: mutations in HFE gene)
    - Secondary
    - Basically, any form of iron overload, through multiple mechanisms
    - Transfusion
    - Increased absorption due to ineffective erythropoiesis
    - (eg Beta thal, other anaemias)
    - Excessive iron administration, oral or parenteral
53
Q

Outline the investigation and assessment of iron overload

A
  • Serum ferritin is measured as an indirect indicator of iron storage
  • Correlation with LIC varies in transfusional and non-transfusional iron overload
    - Liver iron concentration (LIC) on biopsy
    - Reflects total body iron but may not accurately indicate cardiac iron status
    - Evaluation of liver and cardiac iron by MRI (Or ‘SQUID’, whatever that is)
    - General tests of organ function
54
Q

Outline the treatment and monitoring of iron overload

A
  • Monitoring: Serum ferritin, LIC, MRI
    - Primary iron overload (Genetic haemochromatosis):
    - Removal of excess iron by phlebotomy
    - To maintain tf saturation <50%
    - Secondary iron overload:
  • Monitoring:
  • Keeping record of the volume or weight of the administered units.
  • The haematocrit of each unit given, or an average
  • The patient’s weight is also monitored
    - Iron chelation therapy: (eg deferiprone)
55
Q

How iron is metabolised?

A
  • Dietary iron enters duodenal enterocytes
    - Ferrous iron enters the cytoplasmic iron pool
    - Iron enters the systemic circulation via ferroportin
  • Transferrin is the major iron-carrying protein. Iron remains bound to this in circulation. IT’s called TBI (Transferrin-bound iron)
  • TBI is taken up into cells by TfR1 (transferrin receptor 1)
    - Non-transferrin-bound iron (NTBI) increased when iron increases
  • This is imported by DMT1 and converted to Fe2+ by DCYTB (duodenal cytochrome B)
56
Q

In what diseases is measuring serum ferritin not reliable?

A

-Sickle cell disease and viral hepatitis

57
Q

What are the main causes of neonatal anaemia?

A
  • Haemolysis: Immune, red cell membrane disorders, red cell enzymopathies
    - Blood loss
    - Red cell aplasia
58
Q
  • Term baby, with high jaundice on day 2, no anaemia, not responding to double dose phototherapy for 12 hours
    - Bilirubin 380 micro micromol/l (High)
    - DCT +ve
    - What is the most likely diagnosis? //(what further investigations would you do?)
A 
-Haemolytic disease of the newborn (HDN)
			//Further investigations: ABO/ Rh blood groups
			//-Can either be due to ABO or Rh blood groups
59
Q
  • High jaundice and mild anaemia at 12 hours age
    - Bilirubin raised
    - DCT negative
    - Indian mother has a blood disorder diagnosised in India
    - Maternal blood group: A Rh-
    - What is the most likely diagnosis?
A

-Hereditary Spherocytosis

60
Q
  • Greek boy, 2 siblings had neonatal jaundice
  • Term neonate with anaemia and jaundice at 6 days
    - Raised Biliruben
    - Maternal blood group: A RhD +ve
    - What is the most likely diagnosis?
A

-G6PD deficiency

61
Q

What red cell enzymopathies present with neonatal haemolysis?

A
  • G6PD deficiency
    - Pyruvate kinase deficiency
    - Glutathione peroxidase deficiency
62
Q
  • Preterm baby (28+weeks)
    - Hb 42g/l (vlow)
    - MCH abnormal
    - nRBC 280/100 wbc
    - Thrombocytopenia, high bilirubin
    - DCT negative
    - Maternal blood film: H- bodies (Golf ball appearance)
    - What is the most likely diagnosis?
A

-Alpha thalassaemia major

Module 3 (3 decks)

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