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MEH > Lecture 9 > Flashcards

Lecture 9 Flashcards

1
Q

What are haemoglobinopathies? (Inherited disorders?

A

Defect in the Hb chain synthesis
-sickle cell (abnormalities of chains- variance, so difference in stability/function)
-thalassaemia (reduced/absent expression of NORMAL globin chains)
(Inherited disorders)

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2
Q

What are the types of Hb as you age?

A
  • embryonic Hb’s
  • Hb F (2 alpha + 2 gamma) (Foetal)
  • Hb A (2 alpha + 2 beta) (adult)
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3
Q

How many alpha globin genes does a person have?

A

4

2 on each chromosome

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4
Q

What is thalassaemia?

A

Defect in regulation of expression of globin genes
Beta/alpha gene expression affected (often in excess)
-genetic

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5
Q

What are the 4 types of alpha thalassaemia?

A
  1. HYDROPS FETALIS: No alpha genes remaining-results in early uterine death
  2. SILENT CARRIER STATE: 3 functional alpha globin genes (asymptomatic)
  3. ALPHA THALASSAEMIA TRAIT: 2 globin genes (both on 1 chromosome, or 1 on each chromosome 16 deleted)- microcytic and hypochromic RBC’s.
  4. HAEMOGLOBIN H DISEASE: 3 alpha globin genes deleted- moderately severe
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6
Q

Different types of B thalassaemia?

A 
B0= total absence of production from the gene 
B+= reduction of globin chain production
  • B thalassaemia minor/trait: asymptomatic, mild anaemia with microcytic/hypochromic RBC’s (carrier of abnormal gene)
  • B thalassaemia intermedia: severe anaemia, not enough to require blood transfusion
  • B thalassamia major:transfusion dependent anaemia (homozygous)
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7
Q

What does relative excess of unaffected globin chain cause?

A

In B thalassaemia you get insoluble aggregates of the alpha chains, which can be oxidised, causing premature death of erythropoietin precursors- ineffective erythropoiesis

  • more RBC’s are being destroyed than being released into blood = reduced oxygen capacity
  • spleen destroys RBC’s leading to shortened survival (haemolytic anaemia)
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8
Q

What does a blood smear for someone with thalassaemia look like?

A

-hypochromic
-microcytic
(Due to low Hb)
-target cells, Heinz bodies, uncleared red blood cells due to bone marrow working really hard

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9
Q

What are the consequences of thalassaemia?

A
  • extramedullary haemopoiesis (results in splenomegaly, hepatomegaly,expansion of haemopoises to cortex of bone= as occurring in other sites than the marrow)
  • reduced oxygen delivery= stimulation of erythropoietin making more defective RBC’s
  • causes iron overload
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10
Q

What are some treatments for thalassaemia?

A
  • red cell transfusion
  • iron chelation (binding of iron to reduce iron loading into tissues)
  • folic acid (to support ertyhropoiesis)
  • holistic care (cardio, endocrine, psychological, ophthalmology-these are affected by iron overload)
  • immunisation
  • stem cell transplantation (to replace defective RBC production)
  • pre-conception counselling for at risk couples + antenatal screening
  • pre-conception counselling
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11
Q

What is sickle cell disease?

A

-autosomal recessive (HbSS: homozygous causes severe sickling)
-mutation in B globin gene
-have valine where glutamic acid should’ve been
Mutant Hb molecule containing the mutated B globin gene protein is HbS
-irreversible sickle cells cause occlusion in small blood vessels

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12
Q

Why is anaemia usually mild in sickle cell?

A

-HbS more readily gives up oxygen compared to HbA
-problems occur in low oxygen state: deoxygenated HbS forms polymers causing a sickle shape
(These sickle cells can bounce back to normal)
-eventually the sickle cells wil become irreversibly sickled which are less deformable so cause vasocclusion

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13
Q

When is the sickle shape permanent?

A

Repeated sickling of cells

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14
Q

How does sickle cell clinically present?

A

-end organ damage due to acute thromboses of oxygen depriveation
-retinopathy
-splenic atrophy
-avascular necrosis
-stroke (blood circulation affected in brain)
-acute chest syndrome
-osteomyelitis
-skin ulcers (as skin becomes oxygen deprived)
-kidney infarcts
-priapism (unwanted erection for long time)
All reduced life expectancy

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15
Q

Where can haemolysis occur?

A
  • blood vessels (intravascular haemolysis)

- spleen/wider RES (extravascular haemolysis)

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16
Q

Can bone marrow compensate for haemolysis?

A
  • it can compensate by increasing production of EPO: but only up to a point
  • if haemolysis exceeds capacity of marrow to compensate (6 fold increase), rate of destruction exceeds rate of production leading to anaemia
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17
Q

What are some symptoms of haemolytic anaemia?

A
  • overworking of red pulp leading to splenomegaly
  • accumulation of bilirubin > jaundice
  • pigment gallstones made of bilirubin and calcium salts
  • massive sudden haemolysis can cause cardiac arrest due to lack of oxygen delivery
  • cause hyperkalaemia due to release of intracellular contents
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18
Q

Lab findings in haemolytic anaemia?

A
  • raised reticulocytes (as marrow tries to compensate)
  • raised bilirubin (breakdown of haem)
  • raised LDG (red cells rich in this enzyme)
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19
Q

What are some causes of haemolytic anaemia?

A

Inherited (defective gene making cells more fragile)

  • glycolysis defect
  • membrane protein (hereditary spherocytosis)
  • defect in Hb (sickle cell)
  • pentose P pathway (G6PDH deficiency leads to oxidative damage)

Acquired (damage to cells)

  • mechanical damage
  • antibody damage (autoimmune)
  • oxidant damage
  • heat damage
  • enzymatic damage (snake venom)
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20
Q

How do symptoms present on sudden haemolytic anaemia ?

A

Badly

-if chronic body manages to adapt slightly so oxygen dissociation curve shifts

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21
Q

What is jaundice and how does it present?

A

Build up of bilirubin

  • yellow discolouration of skin and sclera of eye
  • urine dark due to conjugated bilirubin
22
Q

What are some causes of acquired damage of haemolytic anaemia?

A
  • microangiopathic haemolytic anaemia (from mechanical stress: defective heart valve-stenosis, snagging on fibrin strands where there is activation of clotting cascade)
  • heat damage from burns
  • osmotic damage (drowning)
23
Q

What is autoimmune haemolytic anaemia?

A
  • self antibodies binding to red cell membrane proteins
  • differentially bind at different temperatures depending on the antibody
  • spleen recognises antibody bound cells as abnormal and removes them
24
Q

How are haemoglobinopathies usually inherited?

A

Autosomal recessive

24
Q

What chromosome is the alpha globin gene on?

A

Chromosome 16 (2 on paternal chromosome, 2 on maternal chromosome- so 4 in total)

25
Q

Where is the beta globin chain found?

A

On chromosome 11

Along with alpha, gamma and delta

26
Q

Why are there so many globin gene types?

A

To form different Hb tetramers from different combinations of globin chains.

27
Q

How many beta globin genes does a person have?

A

2 (1 on each chromosome)

28
Q

What is normal expression of globin genes?

A

Under tight control

1:1 ratio of alpha: non-alpha globin chains

29
Q

In what populations is thalassaemia more prevalent?

A

South Asian, Mediterranean, Middle East (beta), Far East (alpha)

30
Q

What occurs in Hydrops fetalis?

A

All 4 alpha globin genes deleted.

Excess of gamma globin genes, which form teramers in foetus (Hb Bart) which is unable to deliver oxygen to the tissues.

31
Q

In alpha-thalassaemia trait do you get anaemia?

A

Minimal/none

32
Q

What occurs in Haemoglobin H disease?

A

Tetramers of B globin chains form (HbH)

RBC’s are microcytic and hypochromic, with target cells & Heinz bodies

33
Q

What is Beta thalassaemia usually due to?

A

Caused often by gene mutation rather than deletion

34
Q

What is Beta thalassaemia trait/minor usually mistaken for?

A 
Iron deficiency 
(But in thalassaemia the degree of microcytic/hypochromic RBC’s is much higher for the degree of anaemia)
35
Q

What is Beta thalassaemia intermedia?

A

Severe anaemia but not enough to require blood transfusion.
-physiology of individual will adapt, so oxygen is given up to tissues
-adulthood: iron loading problems
(Heterozygous)

36
Q

What is B thalassaemia major?

A

Severe transfusion dependent anaemia.
Homozygous (B0/B0 or B+/B+)
(Manifests 6-9 months after birth as synthesis switches from HbF to HbA)

Often seen in places without screening

37
Q

What is haemolytic anaemia?

A

When the RBC’s are prematurely destroyed.

38
Q

Why do children with thalassaemia have impaired growth?

A

Short stature
Skeletal abnormalities (bones swell)
-haemopoiesis in bone marrow moves to cortex

39
Q

What is the major premature cause of death in thalassaemia?

A

Iron overload

Occurs due to excessive absorption of iron, blood transfusions

40
Q

What does ineffective erythropoiesis lead to?

A

Increased dietary iron absorption

41
Q

Is the heterozygous HbS state symptomatic?

A

Only mildly causes asymptomatic anaemia

-carrier state

42
Q

Where in the world is the HbS gene common?

A

West Africa (protects against malaria)

43
Q

Other than HbSS, what Hb causes sickling disorder?

A

HbS being coinherited with another abnormal Hb

HbSC

44
Q

How is the sickle shape permanently adopted in a RBC?

A

-tetramers of HbS form under normal oxygen tension
-HbS forms polymers under low oxygen tension forming sickle shape
REPEATED SICKLING CYCLES
-irreversibly sickled RBC causing occlusion of small vessels

45
Q

What are the 3 crises of sickle cell disease?

A

Crises- medical manifestations of sickle cell

  1. Vaso-occlusive (cause bone crises, organ damage)
  2. Aplastic (bone marrow stops working-triggered by parvovirus)
  3. Haemolytic
46
Q

What are pigment gallstones due to?

A

Composed of bilirubin and calcium salts

47
Q

What are some inherited defects in red cell membrane structure?

A
  • hereditary spherocytosis (cells take sphere shape, so less flexible and easily damaged)
  • hereditary eliptocytosis (elliptical shape)
  • hereditary pyropikilocytosis (severe form of eliptocytosis, abnormal sensitivity of RBC’s to heat)
48
Q

What proteins are effected in hereditary spherocytosis/eliptocytosis/pyropikilocytosis?

A

Spherocytosis: ankyrin, spectrin, protein 4.2, Band 3 defects disrupt the membrane/cytoskeleton interactions

Eliptocytosis: spectrin defect most common (defects in band 3, band 4.1, glycophorin C proteins)

Pyropikilocytosis: spectrin defect

49
Q

What are damaged fragments resulting from mechanical damage called?

A

Schistocytes

50
Q

Why could self antibodies be present on RBC’s?

A
  • infection

- cancer of immune system which can produce these antibodies

51
Q

What immunoglobulins bind at cold/warm temperatures to the RBC?

A

Warm: IgG
Cold: IgM

MEH (22 decks)

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