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Yr 2 - Clinical Pathology > Haemoglobinopathies & Obstetric > Flashcards

Haemoglobinopathies & Obstetric Flashcards

1
Q

How are haemoglobinopathies tested for postnatally?

A

Heel prick test

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2
Q

How does pregnancy affect:

a) plasma volume
b) Hb levels
c) RBC mass/size
d) MCV (mean cell volume)

A

a) Plasma volume expands in pregnancy by 50%.
b) Increased plasma volume leads to dilution of blood and fall in Hb
c) Red cell mass expands by 25%
d) MCV increases

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3
Q

What is anaemia defined as in the 2nd and 3rd trimester?

A

CDC define anaemia as Hb <110 g/L 1st and 3rd trimester and <105 in the 2nd trimester

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4
Q

Why is iron deficiency the most common cause of anaemia in pregnancy?

A

Pregnancy increases requirements for iron and usually results in considerable mobilisation of iron stores

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5
Q

How does pregnancy affect folic acid requirements?

A

Increases requirements

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6
Q

How is white cell count affected during pregnancy?

A

Increase in white cell count - typically neutrophilia

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7
Q

Potential cause of leukocytosis in pregnancy?

A

Potentially due to secretion of G-CSF by placenta –> G-CSF is a glycoprotein that stimulates bone marrow to produce granulocytes and stem cells

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8
Q

A left shift in white cells may also be seen in pregnancy. What is this?

A

An increase in the number of immature cell types released from bone marrow leading to these cells being found in the blood.

E.g. myelocytes / metamyelocytes

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9
Q

Gestational thrombocytopenia is often seen in pregnancy.

Is this dangerous?

A
  • Not uncommon; seen in around 8% pregnancies
  • No pathological significance for mother or foetus; recovers rapidly following delivery

BUT can be dangerous if due to underlying issue

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10
Q

Pregnancy associated causes of gestational thrombocytopenia?

A
  • severe folate deficiency
  • Gestational
  • Pre-eclampsia and HELLP syndrome
  • AFLP
  • DIC e.g. in abruption
  • TTP/HUS
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11
Q

Coincidental causes of gestational thrombocytopenia?

A
  • Bone marrow/infiltration/hypoplasia
  • ITP: primary/secondary
  • Viral (HIV, EBV)
  • Sepsis
  • Type 2B vWD
  • Hypersplenism
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12
Q

How does pregnancy affect your coagulation state?

A 
• Pregnancy is a pro-thrombotic state:
o	Evidence of platelet activation
o	Increase in many procoagulant factors
o	Reduction in some natural anticoagulants
o	Reduction in fibrinolysis
o	Rise in markers of thrombin generation
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13
Q

How does pregnancy affect your coagulation factors?

A

o Marked increase in plasma fibrinogen and Factor VII
o Increase also in factor V, VIII, X, XII
o Greater increase in vWF than factor VIII (twofold in late pregnancy)
o Minimal increase in FIX and small decrease in FXI
o Initial increase in FXIII followed by reduction to approx 50% of non-pregnant value

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14
Q

Describe shape of normal RBCs?

A
  • Bi-concave disks

* No nucleus

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15
Q

What is the production of RBCs controlled by?

A

EPO produced in kidneys in response to tissue oxygen concentration

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16
Q

Structure of Hb?

A

Tetramer (formed of 4 subunits) of globin chains; each non-covalently bound to a Haem (haem can bind to both O2 and CO2)

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17
Q

What are the 3 main functions of globin chains?

A

o Protects haem from oxidation
o Renders the molecule soluble
o Permits variation in oxygen affinity

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18
Q

What are the 2 types of normal adult Hb?

A

o 2 alpha/2 beta –> HbA

o 2 alpha/2 delta –> HbA2

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19
Q

What is HbA2?

A

This is a normal variant of haemoglobin A that is found at low levels in human blood; 2x alpha 2x delta chains

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20
Q

What is foetal Hb?

A

HbF have; 2 alpha/2 gamma

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21
Q

On which chromosome are alpha chains produced?

A

16

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22
Q

On which chromosome are beta, delta and gamma chains produced?

A

11

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23
Q

Describe the location of production of Hb in the foetus

A
  • In early embryonic life, Hb is synthesised in the yolk sac
  • From the 10th to 12th week, Hb is synthesised in the liver and spleen
  • Eventually, bone marrow takes over Hb production; increasingly producing HbA
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24
Q

Changes in globin genes or their expression leads to disease.

What is the main example of a disease caused by a STRUCTURAL variant in globin genes?

A

HbS (sickle)

These are usually a single base substitution in globin gene –> altered structure/function

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25
Q

Cause of thalassaemias (alpha or beta)?

A

o Change in globin gene expression leads to reduced rate of synthesis of NORMAL globin chains.
o Pathology is due to imbalance of alpha and beta chain production (free globin chains damage red cell membrane)

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26
Q

What inheritance pattern is seen in haemoglobinopathies?

A

Autosomal recessive inheritance pattern

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27
Q

Why are haemoglobinopathies seen more commonly in Africa?

A

Being a carrier affords some resistance to malaria.

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28
Q

What is sickle cell trait?

A

Heterozygous; have inherited one sickle cell gene and one normal gene) –> HbA/S

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29
Q

Describe the

a) blood count
b) Hb electrophoresis
c) clinical features

in sickle cell trait?

A

a) normal
b) Hb-S 45%, Hb-A 55%
c) no problems except when extreme hypoxia/dehydration (e.g. very bad anaesthesia, flying unpressurised military aircraft)

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30
Q

In sickle cell disease, the patient is homozygous (HbS/S).
Describe the

a) blood count
b) Hb electrophoresis
c) blood film

A

a) anaemia
b) Hb-S >95% Hb-A 0%
c) sickle cells

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31
Q

Inheritance pattern of sickle cell?

A

Autosomal recessive

32
Q

Describe the changes of RBCs in sickle cell

A

RBCs undergo a change in shape upon deoxygenation because of polymerisation of the abnormal sickle Hb (HbS).

Sickle Hb (Hb-S) polymerises to form long fibrils which distort the red cell membrane and produce the classical sickle shape (less flexible).

33
Q

Describe the lifespan of sickled red cells. What does this lead to?

A

The sickled red cells have a short lifespan in the blood as more fragile –> haemolytic anaemia

34
Q

Haemolysis in sickle cell can lead to free Hb in the blood. What are the dangers of this?

A

Binds and inactivates NO which leads to systemic vasoconstriction

35
Q

Why doesn’t sickle cell disease present immediately at birth?

A

Polymerisation is reduced if other haemoglobins are present in the red cell e.g. HbF

36
Q

What is a ‘sickle cell crisis’?

A

Sickle-shaped RBCs obstruct capillaries and restrict blood flow to organ –> pain, ischaemia, necrosis and organ damage

37
Q

What are the acute complications of sickle cell disease?

A

o Vaso-occlusive crisis - hands and feet (dactylitis), chest syndrome, abdominal pain (mesenteric), bones (long bones, ribs, spine), brain, priapism (a prolonged erection)
o Septicaemia
o Aplastic crisis
o Sequestration crisis (spleen, liver)

38
Q

What is a splenic sequestration crisis of sickle cell

A

Sickle cells block the blood vessels out of the spleen, so RBCs become trapped in the spleen –> causes spleen to become enlarged and blood counts to fall

39
Q

How can a chronic sickle cell eventually lead to hyposplenism?

A

due to infarction and atrophy of spleen.

40
Q

What are the chronic complications of sickle cell disease?

A

o Hyposplenism
o Renal disease: medullary infarction with papillary necrosis. Tubular damage - can’t concentrate urine (bed-wetting at night). Glomerular – chronic renal failure/dialysis
o Avascular necrosis (AVN): femoral/humeral heads
o Leg ulcers, osteomyelitis, gall stones, retinopathy, cardiac, respiratory
o Stroke

41
Q

What is the only curative treatment for sickle cell disease?

A

Bone marrow transplant

42
Q

Why are children with sickle cell disease regularly given Penicillin from 6 months?

A

Children with sickle cell disease and those without a spleen have difficulty fighting infections, particularly pneumococcal infection, and they risk becoming seriously ill. By giving penicillin V regularly, you can protect your child from these infections.

43
Q

How are the acute vaso-occlusive symptoms of sickle cell disease treated?

A
  • Analgesia (usually opiates)

- Hydration (to maintain red cell water)

44
Q

What is a priapism attack?

A

Sickled red blood cells block the supply and flow of blood in the penis. A priapism attack is a sickle cell crisis that is localised to the penis. Leads to a prolonged erection.

45
Q

Treatment of priapsim?

A
  • Acute (minor/major, intracorporeal phenylephrine)

* Recurrent – etilefrine?

46
Q

What is the most important therapeutic intervention in patients with sickle cell disease (SCD)?

A

Blood transfusion, aiming to:

1) increase the oxygen carrying capacity of blood
2) reduce the complications of vaso-occlusion

47
Q

Hydroxycarbamide is a medicine used in the treatment of sickle cell disease.

How does it work?

A

Hydroxycarbamide stimulates production of HbF which results in;

a) time delay to polymerisation
b) reduced adhesion to endothelium
c) enhances NO
d) anti-inflammatory

and overall reduces sickling

48
Q

What is a transcranial doppler? What is it used for?

A

A safe, non-invasive way of investigating the circulation in your head. It measures the speed and direction of blood flow around the base of your brain, and can be a useful diagnostic test if you have a circulation disorder.

49
Q

Thalassaemia is a Mendelian disorder. What does this mean?

A

single gene disorder

50
Q

What is thalassaemia?

A

A genetic disorder in which there is decreased production of one of the globin chains found in Hb.

In some, no globin chain is produced (e.g. α^0), in others they are produced at a reduced rate (e.g. α^+)

51
Q

Which globin chain is there are decreased quantity of in alpha thalassaemia?

A

Alpha chains

52
Q

What is the normal structure of adult Hb (HbA)?

A

2x alpha chains

2x beta chains

53
Q

What is Hb Barts?

A

An abnormal type of Hb that consist of 4x gamma chains:
o Homozygous inheritance of α^0 (i.e. no alpha chains) - hydrops fetalis
o Foetus is usually stillborn

54
Q

What is HbH disease?

A

A form of alpha thalassaemia in which moderately severe anaemia develops due to reduced formation of alpha globin chains (missing 3 alpha thalassemia genes)

55
Q

What are the 4 different types of alpha thalassaemia? What is the clinical presentation of each?

A

o Missing one alpha thalassemia gene (silent carriers): a silent carrier does not have any symptoms.

o Missing two alpha thalassemia genes (alpha thalassemia trait): this normally does not cause health problems but can cause anaemia) and small red blood cells.

o Missing three alpha thalassemia genes (HbH disease): this disease causes health problems and requires treatment.

o Missing four genes (Hydrops fetalis/Hb Barts): this is a life-threatening disease.

56
Q

Which globin chain is there are decreased quantity of in beta thalassaemia? What is the resulting pathology caused by?

A

beta globin chains - pathology caused by excess alpha chains

57
Q

What are the 3 types of beta thalassaemia?

A

1) Beta thalassaemia minor (also called beta thalassaemia trait)
2) Beta thalassaemia intermedia
3) Beta thalassaemia major

58
Q

Why can beta-thalassaemia be diagnosed with a simple Hb electrophoresis test?

A

Hb-A2 levels are characteristically elevated >3.5%

59
Q

What defines beta thalassaemia intermedia?

A

Patients whose anaemia is not so severe as to need regular transfusions –> No absolute requirement for regular transfusions in order to survive during the first 3-5 years of life

60
Q

Clinical features of beta thalassaemia intermedia?

A 
o	Pulmonary hypertension - ECHO
o	Extramedullary haematopoiesis
o	Bone changes and osteoporosis - DEXA
o	Endocrine and fertility (DM, Hypothyroid)
o	Leg ulcers
61
Q

What is the most severe form of thalassaemia?

A

beta-thalassaemia major

62
Q

How does beta-thalassaemia major present in infants?

A

Present with very severe anaemia at 1 to 2 years of age

63
Q

What are the clinical features of beta-thalassaemia major?

A

o Short stature and distorted limb growth due to premature closure of epiphyses in long bones

o Enlarged liver and spleen “extramedullary haemopoiesis”

o Thalassaemic facies: Maxillary hypertrophy, abnormal dentition and frontal bossing due to expanded bone marrow

o Infection – decreased CD4/8 ratio and defective neutrophil chemotaxis, increased virulence with excess iron (yersinia and DFO), line infections, transfusion transmitted infection.

o Endocrine disorders

o Liver disease

o Bone – bone marrow expansion can lead to brittle bones

o Infertility; mainly due to iron deposition to endocrine organs after overtransfusion

64
Q

How many transfusions are required in beta-thalassaemia major?

A

3 to 4 weekly transfusions from 1st year of life

65
Q

By the age of 10-12, what is the effect of beta-thalassaemia major? Why?

A

Each unit of red cells contains 200-250mg Iron and the body has no excretory mechanism for iron. By 10-12 years of age there is severe iron overload and toxicity.

66
Q

How can a severe iron overload and toxicity affect the:

a) gonads/hypothalamus
b) pancreas
c) heart
d) liver

A

a) failure of puberty, growth failure
b) diabetes
c) dilated cardiomyopathy and heart failure
d) cirrhosis

67
Q

What is iron chelation therapy?

A

Iron chelation therapy is the removal of excess iron from the body with special drugs.

Patients who have anemia (low Hb) and iron overload at the same time cannot tolerate phlebotomy.

68
Q

In patients with beta-thalassaemia major, when are patients started on iron chelation therapy? Why?

A

To prevent death from iron overload patients are started on IRON CHELATION THERAPY from 2nd year of life to promote excretion of iron in urine and faeces

69
Q

Deferoxamine;

a) what is it used to treat?
b) method of administration?

A

a) used to remove excess iron from the body in anemia or thalassemia patients who have many blood transfusion
b) subcutaneous infusio

70
Q

There are currently three licensed iron chelation drugs.

What are these?

A

1) Deferoxamine (DFO)
2) Deferiprone (DFP)
3) Deferasirox (DFX)

71
Q

How can alpha chain excess lead to anaemia?

A

1) Ineffective erythropoiesis (red cells die in marrow)

2) Shortened red cell lifespan (haemolysis)

72
Q

What are the 3 major effects of increased marrow activity?

A

1) skeletal deformity, stunted growth
2) increased iron absorption and organ damage (exacerbated by blood transfusion)
3) protein malnutrition

73
Q

What are the effects of an enlarged and overactive spleen?

A

1) pooling of red cells (increased anaemia)

2) increased transfusion requirement

74
Q

What is a ‘hair on end’ skull?

A

The hair on end sign refers to a radiographic appearance of the diploic space of the skull vault which results from a thickening of trabeculae as the diploic space expands.

75
Q

Causes of the chronic inflammatory state in sickle cell anaemia?

A

Is associated with several factors such as the following: a) endothelial damage

b) increased production of reactive oxygen species
c) haemolysis; increased expression of adhesion molecules by leukocytes, erythrocytes, and platelets
d) increased production of proinflammatory cytokines

Yr 2 - Clinical Pathology (80 decks)

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