Haemoglobinopathies and obstetric haematology Flashcards Preview

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Flashcards in Haemoglobinopathies and obstetric haematology Deck (47):
1

Where is erythropoietin (EPO) produced and why?

Produced in the kidneys in response to tissue O2 concentration.

2

What are the various types of normal haemoglobin?

Hb-A = 2alpha/2beta

Hb-F = 2alpha/2gamma

HbA2 = 2alpha/2delta

All normal Hb have 2 alpha and 2 non-alpha chains

3

The gene for alpha globin is on which chromosome?

16

4

The genes for gamma, delta and beta haemoglobins is on which chromosome?

11

5

What percentage of a normal adult's Hb is Hb-A?

>95%

6

What percentage of a normal adult's Hb is Hb-A2?

>3.5%

7

What percentage of a normal adult's Hb is Hb-F?

>1.0%

8

What are the haemoglobinopathies?

Structural Hb variants - eg HbS (Sickle), C, D, E etc, usually a single base substitution in globin gene = altered structure/function

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

9

Why might physiological anaemia and macrocytosis occur during pregnancy?

Plasma volume expands in pregnancy by 50%.

Red cell mass expands by 25%

Haemodilution occurs, maximally at 32 weeks

CDC define anaemia as Hb <11g/dL 1st and 3rd trimester and <10.5 in the 2nd trimester

10

What are the features of obstetric leukocytosis?

Mainly a neutrophilia, rising from the 2nd month to a peak range of around 9-15 in the 2nd-3rd trimester

Left shift may also be seen (myelocytes/metamyelocytes)

11

What are the features of gestational thrombocytopenia?

Platelet count usually >70x10^9/l

Platelet count falls after 20weeks and thrombocytopenia is most marked in late pregnancy

No pathological significance for mother or fetus

Recovers rapidly following delivery

Main issue in management is differentiation from other causes

12

What are the pregnancy-associated causes of thrombocytopenia?

Production failure: - severe folate deficiency

Consumptive 

Gestational

- Pre-eclampsia and HELLP syndrome

- AFLP

- DIC eg in abruption

- TTP/HUS

13

What are the coincidental causes of thrombocytopenia?

Production failure: - bone marrow infiltration/hypoplasia

Consumptive:

ITP: primary/secondary -

Viral (HIV, EBV) 

Sepsis Type 2B vWD

Hypersplenism Congenital

14

Why is pregnancy a pro-thrombotic state?

Evidence of platelet activation

Increase in many procoagulant factors

Reduction in some natural anticoagulants

Reduction in fibrinolysis

Rise in markers of thrombin generation

Rise in certain coagulation factors

15

What is the test of choice for diagnosing structural Hb abnormalities?

Hb electrophoresis

16

What are the microscopic features of thalassemic RBCs?

Small pale red cells (hypochromic/microcytic)

17

What battery of tests is performed for the diagnosis of haemoglobinopathies?

FBC/Film

Haemoglobin electrophoresis

Isoelectric focusing

High performance liquid chromatography (HPLC)

Heat stability, isopropanol (unstable Hb’s)

Oxygen dissociation curve (p50, high affinity)

DNA analysis (genetic counseling, prenatal Dx)

Mass spectometry

Kleihauer testing, Supravital staining, Sickle solubility

18

What is the the molecular basis of sickle cell disease?

- valine substituted for glutamine at position 6 of the β-globin gene

19

Why does the RBC 'sickle' in sickle cell disease?

Sickle Hb (Hb-S) polymerises at low oxygen tensions to form long fibrils (“tactoids”) which distort the red cell membrane and produce the classical sickle shape.

20

Why do the sickle cells have a short lifespan?

Haemolytic anaemia

21

What is haemolysis-associated haemostatic activation?

- Intravascular haemolysis releases Hb into plasma which quenches NO and generates ROS - The depletion of NO is associated with pathological platelet activation and tissue factor expression

22

What is sickle cell trait?

Hb Electrophoresis: Hb-S 45%, Hb-A 55%

Heterozygous Hb/HbS

23

What is sickle cell disease?

Blood count: anaemia (Hb 6-8g/dl)

Blood film: sickle cells

Hb Electrophoresis: Hb-S >95%, Hb-A 0%

Frequency: 1 in 200 African-Caribbeans, 1 in 60 West Africans

24

What are the acute complications of sickle cell disease?

Vaso-occlusive crisis - hands and feet (dactylitis), chest syndrome, abdominal pain (mesenteric), bones (long bones, ribs, spine), brain, priapism

Septicaemia

Aplastic crisis

Sequestration crisis (spleen, liver)

25

What are the chronic complications of sickle cell disease\/

- Hyposplenism - due to infarction and atrophy of spleen.

Renal disease: medullary infarction with papillary necrosis. Tubular damage - can’t concentrate urine (bed-wetting at night).

Glomerular – chronic renal failure/dialysis

Avascular necrosis (AVN) –femoral/humeral heads

Leg ulcers, osteomyelitis, gall stones, retinopathy, cardiac, respiratory

Mortality: ~ 0.5% per annum in UK

26

Why would you transfuse a sickle cell patient?

- Top up: splenic sequestration, aplastic crisis, pre-operative, acute chest crisis (usually when Hb <5g/dl)

27

What is the function of hydroxycarbamide and why would it be used?

Increases Hb F (time delay to polymerisation, reduced adhesion to endothelium, enhances NO)

Consider if >3 admissions with painful crisis in 12 months or 2 chest crisis (MSH study 1995)

28

What are the curative treatments for sickle cell disease?

Bone marrow transplant from normal donor

Gene therapy

29

What perioperative care is required for people with sickle anaemia?

Transfusion

Avoid local tourniquet

30

What are the other possible causes of sickle cell disease?

Co-inheritance of βs and another β chain abnormality

SC disease – fewer crisis, risk AVN and retinopathy

S/O-Arab (severe)

S/β-thalassaemia, S/Lepore, S/D-punjab (moderate)

S/HPFH, S/δβ0, S/E (mild)

31

How are the thalassemias classified?

Divided into α, β, δβ and γδβ according to which globin chain is reduced.

32

What is alpha thalassemia?

Results from one or more defective alpha globin genes.

33

What are the different types of Alpha thalassemia?

Alpha thalassemia minima: only one allele affected, minimal pathology

Alpha thalassemia minor: two alleles affected but still almost normal production of RBCs. Mild microcytic hyperchromatic anaemia.

Haemoglobin H disease: two unstable haemoglobins are present in the blood: Haemoglobin Barts (tetrameric γ chains) and Haemoglobin H (tetrameric β chains). Both of these unstable haemoglobins have a higher affinity for oxygen than normal haemoglobin, resulting in poor oxygen delivery to tissues.

Alpha thalassemia major:  Foetuses are oedematous and have little circulating hemoglobin, and the haemoglobin that is present is all tetrameric γ chains (also called haemoglobin Barts). When all four alleles are affected, the foetus likely will not survive gestation without in utero intervention: most infants with alpha thalassemia major are stillborn with hydrops fetalis, and those who do not receive in utero treatment and are born alive die shortly after birth.

34

What is beta thalassemia?

Reduced rate of production of beta-globin chains (pathology caused by excess alpha chains)

Many molecular variants arising in different locations worldwide

Carriers (Thalassaemia Minor) are clinically normal

Homozygotes (Thalassaemia Major) have a severe disease which is usually fatal if untreated – can produce little, if any, Hb-A and die of severe anaemia

35

What are the microscopic features of beta thalassemia minor?

Blood picture resembles iron deficiency (small, pale red cells)

Total Hb level normal or only slightly reduced

Hb-A2 level >3.5% - “target cells” on film

36

What are the features of beta thalassemia intermedia?

Pulmonary hypertension

ECHO

Extramedullary haematopoiesis

Bone changes and osteoporosis

DEXA

Endocrine and fertility (DM, Hypothyroid)

Leg ulcers

37

What are the features of beta thalassemia major?

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

blood film very abnormal with lots of nucleated red cells

clinical features due to severe anaemia and attempt to make more red cells in marrow to compensate

38

Describe the pathology of beta thalassemia major.

Alpha chain excess - ineffective erythropoiesis, shortened RBC lifespan (haemolysis) = anaemia

Increased marrow activity - skeletal deformity, stunted growth, increased iron absorption and organ damage (exacerbated by blood transfusion), protein malnutrition

Enlarged and overactive spleen - pooling of red cells (increased anaemia), increased tranfusion requirement

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

Enlarged liver and spleen “extramedullary haemopoiesis”

39

What are thalassaemic facies?

Maxillary hypertrophy

Abnormal dentition

Frontal bossing due to expanded bone marrow

40

What is a classic feature of beta thalassemia seen on x-ray?

“hair on end” skull due to widening of diploic cavities by marrow expansion

41

How is transfusion a useful treatment for beta thalassemia major?

to maintain mean Hb 12g/dl (pre-transfusion Hb 9.5-10)

suppresses marrow red cell production and prevents skeletal deformity and liver/spleen enlargement

3 to 4 weekly transfusions from 1st year of life

42

What are the problems associated with treating beta thalassemia with transfusion?

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: gonads/hypothalamus – failure of puberty, growth failure, pancreas – diabetes, heart – dilated cardiomyopathy and heart failure, liver - cirrhosis

43

What are the top five causes of death in thalassemia?

1. Heart failure

2. Infection

3. Arrhythmia

4. Cirrhosis/thrombosis

5. Diabetes

44

How is death from iron overload prevented in patients with beta thalassemia?

Iron chelation therapy from 2nd year of life

Desferrioxamine is given by 8-12 hourly subcutaneous infusion via a syringe-pump as home-treatment on at least 5 nights a week to prevent the accumulation of iron

New Oral Iron Chelators include Deferiprone and Deferasirox

45

How is bone health maintained in patients with beta thalassemia?

Timely transfusion, no over-chelation, diet, hormone replacement of hypogonadism, monitoring for OP, treatment with bisphosphanates

46

How is fertility maintained in patients with beta thalassemia?

Good chelation, fertility clinic advice, may need induction.

Cardiac, thyroid, diabetic and bone assessments.

Obstetric supervision

47

What is the cure rate for bone marrow transplantation for patients with beta thalassemia?

60-80%

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