Flashcards in Haemaglobinopathies and Obstetric Haematology Deck (97):
How is the production of erythrocytes controlled?
By the production of EPO by the kidneys in response to tissue oxygen concentration
What are the 3 functions of the globin molecule in Hb?
1) Protects haem group from oxidation
2) Renders the molecule soluble
3) Permits variation in oxygen affinity
All normal Hb are made up of what?
Tetramer of globin chains, each non covalently bound to haem
All normal Hbs have 2 alpha and 2 non-alpha chains
The gene for the alpha chain in foetal and adult Hb is found on which Chr?
What is the composition of fetal Hb?
2 alpha chains
2 gamma chains
The gene for the gamma chain found in fetal Hb is found on which Chr?
What is the composition of the 2 types of adult Hb?
Hb-A2 = 2 alpha, 2 delta
Hb-A = 2 alpha, 2 beta
The genes for the beta and delta chains found in adult Hb are found on which Chr?
What 3 types of Hb are found in adults and what proportions does each make up?
Hb-A (2alpha2beta) = >95%
Hb-A2 (2alpha2delta) =
What are the 2 classes of haemoglobinopathies?
1) Structural Hb variants - usually a single base substitution in globin gene leads to altered structure/function
2) Thalassemias (alpha or beta) - change in globin expression leads to reduced rate of normal globin chains, pathology is due to imbalance of alpha and beta chain production (free globin chains damage red cell membranes)
Maternal testing for haemaglobinopathies is routinely offered to every mother in the UK, how are high risk pregnancies identified and what are they offered?
Mother tested and if positive father also tested, if both have traits then considered high risk
These people are offered pre natal diagnosis (chorionic villus biopsy and genetic testing at 8-12 weeks) with the option of termination
Why does physiological anaemia occur in pregnancy?
- Plasma volume expands by 50%
- Red cell mass expands by 25%
- Haemodilution thus occurs, this is maximal at 32 weeks
As physiological anaemia can occur, how is anaemia defined in pregnancy, what is the most common cause?
1st and 3rd trimester:
What happens to the MCV in pregnancy?
Why does the MCV increase physiologically in pregnancy?
- Pregnancy increases requirements for iron and usually results in considerable mobilisation of iron stores
- Pregnancy also increases folic acid requirements
What kind of leukocytosis occurs in pregnancy and when does it start to rise?
Mainly neutrophilia (may also see a left shift in myelocytes/metamyelocytes)
Rises from the 2nd month to a peak range of around 9-15 in the 2nd-3rd trimester
Gestational thrombocytopenia also occurs, when does the platelet count begin to fall and what is the biggest issue with gestational thrombocytopenia?
Platelet count falls after 20 weeks and thrombocytopenia is most marked in late pregnancy
There is no pathological significance for mother or fetus, it recovers rapidly following recovery but the main issue with it is differentiation from other causes
What are the 5 haematological changes which occur in pregnancy?
1) Physiological anaemia
2) Rise in MCV
3) Leukocytosis - mainly neutrophilia
4) Gestational thrombocytopenia
5) Pro-coagulant state
What are the 6 pregnancy associated causes of thrombocytopenia?
1) Severe folate deficiency
3) Pre-eclampsia and HELLP syndrome
4) AFLP (acute fatty liver in pregnancy)
6) TTP/ HUS - thrombotic thrombocytopenia purpura
What are the 6 coincidental causes of thrombocytopenia in pregnancy?
1) Bone marrow infiltration/ hypoplasia
2) ITP (primary/secondary) - Immune thrombocytopenic purpura
3) Viral (HIV, EBV)
5) Type 2B vWD
(Also congenital causes)
For what 5 reasons is pregnancy a pro-thombotic state?
1) Evidence of platelet activation
2) Increase in many pro-coagulant factors
3) Reduction in some natural anti-coagulants
4) Reduction in fibrinolysis
5) Rise in markers thrombin generation
How many weeks post partum do women recover from the pro thrombotic state of pregnancy?
Worldwide distribution of Hb disorders mirrors what disease and what does this suggest?
Mirrors falciparum malaria - Hb disorders give you a survival advantage against malaria
Structural Hb variants (Eg. sickle cell disease) can usually be detected using what procedure?
Detected by abnormal mobility on Haemaglobin electrophoresis - apply a charge and Hb seperates out, structurally abnormal Hb travel a different distance
How does a blood film and Hb electrophoresis of thalassemias appear?
Normal Hb electrophoresis
Small pale red cells (hypochromic and microcytic) resembling iron deficiency on blood film
What are the 4 main tests used to diagnose haemaglobinopathies?
1) FBC/ film
2) Hb electrophoresis
3) Isoelectric focussing
4) High performance liquid chromatography
What is the molecular basis of the Hb abnormality in sickle cell disease?
Valine substituted for glutamine at position 6 of the beta globin gene
What happens to RBCs 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
Why does haemolytic anaemia occur in sickle cell disease?
The sickled cells have a short lifespan in the blood
As well as the haemolytic component of sickle cell disease, what is the other problem?
Sickle cells block vessels and cause ischaemia, this results in pain and chronic recurrent obstruction can result in end organ damage. This was thought to be due to the fact sickled cells were inflexible but is now thought to be haemolysis-associated haemostatic activation - ie. haemolysis leads to endothelium expressing adhesion molecules and cells sticking to the endothelium
What is meant by sickle cell trait?
Heterozygous Sickle cell disease ie. Hb A/S
What is the blood count in sickle cell trait?
Normal blood count
What does Hb electrophoresis show about the relative proportions of Hb S and A in sickle cell trait?
Hb-A = 55%
Hb-S = 45%
What are the clinical features of Sickle cell trait?
No problems except when extreme hypoxia or dehydration eg. very bad anaesthetia, flying unpressurised military air craft
What is the difference between sickle cell trait and sickle cell disease?
Sickle cell disease = homozygous ie HbS/HbS
Sickle cell trait = heterozygous ie HbA/HbS
What is the blood count in sickle cell disease?
Anaemia - Hb 6-8g/dL
What does Hb electrophoresis show about the relative proportions of Hb S and Hb A in sickle cell disease?
Hb A = 0%
Hb S = >95%
In which groups is sickle cell disease most common?
West Africans (1 in 60) and Afrocaribeans (1 in 200)
(Around 12000 pts in UK compared to 5000 haemophiliacs)
What are the 4 serious acute complications of sickle cell disease?
1) Vaso-occlusive crisis
3) Aplastic crisis (if for any reason red cell production is interrupted for when people die of simple anaemia as sickle cells have a shorter life span)
4) Sequestration crisis (sickle cells block circulation and cause rapid organ enlargement)
What 6 things make up a vaso-occlusive crisis?
1) Hands and feet - dactylitis
2) Chest syndrome
3) Abdominal pain - mesenteric
4) Bones - long bones, ribs, spine
6) Priapism (persistent and painful erection of the penis)
What are the 9 chronic complications of sickle cell disease?
1) Hyposplenism - due to infarction and atrophy of the spleen
2) Renal disease
3) Avascular necrosis - femoral/ humeral heads
4) Leg ulcers
6) Gall stones
8) Cardiac complications
9) Respiratory complications
What renal disease occurs in sickle cell disease?
Get medullar infarction with papillary necrosis
Tubular damage so cant concentrate urine (bed wetting at night)
Chronic renal failure requiring dialysis
What medication is given to treat sickle cell disease from 6 months?
What is the 3 treatments from a vaso-occlusive crisis?
1) Analgesia (usually opiates)
2) Hydration (to maintain red cell water)
3) Treatment of precipitants
What is the treatment for priapism in sickle cell disease? 3
2) Intracorporeal phenylephrine
3) Recurrent - etilefrine
In what 3 ways is transfusion used as treatment in sickle cell disease?
1) Top up - splenic sequestration, aplastic crisis, pre-operative, acute chest crisis
2) Exchange - acute chest crisis, acute stroke, pre-operative
3) Regular exchange - primary and secondary stroke prevention
Why is hydroxycarbamide used to treat sickle cell disease and in what situation?
Increases HbF (fetal Hb contains no beta chains which are abnormal in Hb S)
Considered as treatment I f patient has >3 admissions with painful crisis in 12 months or 2 chest crisis
How are the chronic complications of sickle cell disease treated? 5
1) Transcranial Doppler
2) AVN (avascular necrosis) - MRI and made need joint replacement
3) Cholecystectomy for symptomatic biliary disease
4) Renal disease - U&Es, BP, Ix haematuria
5) Ophthalmic - annual review
Name the 1 curative treatment for sickle cell disease?
Bone marrow transplant (there is a mortality associated with it though)
How can sickle cell disease be prevented?
Genetic counselling and pre natal diagnosis, avoiding precipitants
What is the percentage mortality per annum associated with sickle cell disease in the uK?
0.5% per annum
In addition to inheritance of 2 Hb S, how else can sickle cell disease be caused?
Co inheritance of betaS and another beta chain abnormality - eg. S/O-Arab (Severe), S/Beta-thalassemia
What are the most common single gene disorders?
What are the 4 types of thalassemia?
gamma delta beta
Divided according to which globin chain is reduced
How are the globin chains effected in thalassemia?
In some no globin chain is produced eg. alpha 0
In some the globin chain is produced at a lower rate eg. alpha +
Which types of haemoglobin are affected in alpha-thalassemia?
Both Hb A (adult Hb) and Hb F (fetal Hb) as they both contain 2 alpha chains
What is Hb Barts and what condition does it cause?
Hb Barts = homozygous inheritance of alpha0 - ie no alpha chains produced
Causes hydrops fetalis
What is Hb H disease?
Also called alpha thalassemia intermedia - when only 1 of the four alpha genes is functioning, get a tetramer of beta chains
What is alpha-trait, what are the clinical features?
Single gene defect or loss of 1 alpha gene from each parent (each parent has 2 alpha genes) - Hb will be normal and patient will be clinically well
What are the 3 types of alpha thalassemia?
1) Hb Barts - hydrops fetalis
2) Hb H disease
In which part of the world are the most serious forms of alpha-thalassemia found?
SE asia and some Mediterranean islands
How many beta genes does each parental chromosome contain?
What is beta-thalassemia?
Reduced rate of production of beta globin genes
What causes the pathology in beta thalassemia?
Excess alpha chains due to reduced beta chains
What is beta thalassemia minor?
Carriers of beta thalassemia - ie. have one normal and one faulty beta gene
How does beta thalassemia minor present clinically?
What is beta-thalassemia major?
How does beta-thalassemia major present clinically?
Have severe disease which is usually fatal if untreated can produce little in any Hb-A and die of severe anaemia
How does a blood film for beta thalassemia minor appear?
Blood picture resembles iron deficiency - small, pale red cells
How is Hb level affected in beta thalassemia minor?
Total Hb level normal or only slightly reduced
Are transfusions required in thalassemia intermedia?
No absolute requirement for regular transfusions in order to survive during the first 3-5 years of life
What are the 5 possible complication of thalassemia intermedia?
1) Pulmonary hypertension2
2) Extramedullary haematopoiesis
3) Bone changes and osteoporosis - because of increased cell turnover
4) Endocrine and fertility
5) Leg ulcers
How does beta-thalassemia major present?
Present with very severe anaemia at 1-2 years of age
What is the appearance of a blood film in beta thalassemia major?
Very abnormal with lots of nucleated red cells
What are the 2 main reasons for the clinical features of beta thalassemia?
1) Severe anaemia
2) Attempt to make more red cells in bone marrow to compensate
What are the 3 causes of the pathology in beta thalassemia major?
1) Alpha chain excess
2) Increased marrow activity
3) Enlarged and overactive spleen
What does the alpha chain excess in beta thalassemia major lead to? 2
Ineffective erythropoiesis (red cells die in marrow)
Shortened red cell lifespan (haemolysis)
Both lead to anaemia
What 3 things does the increased marrow activity in beta thalassemia major lead to?
1) Skeletal deformity, stunted growth
2) Increased iron absorption and organ damage (exacerbated by blood transfusion)
3) Protein malnutrition
What 2 things does the enlarged and overactive spleen in beta thalassemia major lead to?
1) pooling of red cells (increased anaemia)
2) Increased transfusion requirement
Why do patients with beta thalassemia major have short stature and distorted limb growth?
Due to premature closure of epiphyses in long bones
What is extra medullary haematopoiesis?
haematopoiesis occurring outside of the medulla of the bone
Why do you get an enlarged liver and spleen in beta thalassemia major?
Due to extramedullary haematopoiesis
What 3 things make up thalassaemic facies which can occur in beta-thalassemia major?
1) Maxillary hypertrophy
2) Abnormal dentition
3) Frontal bossing due to expanded bone marrow
What is the x-ray appearance of the skull in beta thalassemia major and why?
'Hair on end' skull due to widening of diploic cavities by bone marrow expansion
What is the main treatment for beta thalassemia major?
Transfusion - suppresses marrow red cell production and prevents skeletal deformity and liver/spleen enlargement
3-4 weekly transfusions from the first year of life
What is the main complication of treating beta thalassemia with transfusions?
Each unit of red cells contains 200-250mg Fe and the body has no excretory mechanism for iron
By 10-12 years of age there is severe iron overload and toxicity
What 4 things does iron overload cause?
1) Gonads/hypothalamus - failure of puberty/ growth failure
2) Pancreas - diabetes
3) Heart - dilated cardiomyopathy and HF
4) Liver - cirrhosis
Aswell as the major complication of iron overloading what are the 2 other complications of using transfusion to treat beta thalassemia major?
1) Transmission of infection
2) Allo-immunisation - body makes Ab against proteins on red cell and its gets harder and harder to find matching blood
What therapy is used to prevent death from iron overload in beta thalassemia major patients?
Iron chelation therapy which promotes excretion of iron in urine and faeces
What are the 2 options for iron chelation therapy?
1) Desferrioxamine: given via SC infusion
2) New oral iron chelators - include deferiprone and deferasirox
In what 3 ways is chelation monitored in beta thalassemia?
1) Ferritin (acute phase)
2) Liver biopsy
Why is the risk of infection increased in beta thalassemia major? 5
1) Decreased CD4/8 ratio
2) Defective neutrophil chemotaxis
3) Increased virulence with excess iron
4) Line infections
5) Transfusion transmitted infection
How are endocrine complications in beta-thalassemia major managed?
1) Monitoring growth and development
2) Screening for glucose intolerance
3) Screening for hypothyroidism
4) Screening for hypoparathyroidism
In treating beta--thalassemia major what 6 things need to be monitored?
3) Liver disease
4) Infection risk
6) Endocrine complications
What is the current life expectancy in beta thalassemia major?
Patients now live into their 4th and 5th decades of life although there are significant quality of life issues
Which 2 kind of treatments are being development for more effective treatment of beta thalassemia?
1) Bone marrow transplantation
2) Gene therapy