Haemoglobinopathies & Obstetric Haematology Flashcards
What is meant by “antenatal”?
before birth, during or relating to pregnancy
Why may someone receive an antenatal haemoglobinopathy screening?
looking at family origin and taking a full blood count (low prevalence)
or
high performance liquid chromatography (HPLC) (high prevalence)
+/- partner testing
What are the 2 different options for antenatal haemoglobinopathy screening?
prenatal diagnostic test:
- e.g. chorionic villus biopsy & genetic diagnosis at 8-12 weeks
- +/- termination of affected pregnancies
pre-implantation diagnostic testing
When may a newborn be screening for haemoglobinopathies?
How and why is this performed?
this is performed at 5 days
it involves a heel prick test and analysis of dried blood spot
the goal is early detection of sickle cell disease, allowing for parent education and antibiotic prophylaxis
How does plasma volume and red cell mass change in pregnancy?
plasma volume in pregnancy expands by 50%
red cell mass expands by 25%
what is haemodilution and when does it occur during pregnancy?
an increase in the fluid content of the blood, leading to a lower concentration of red blood cells
it occurs during pregnancy, maximally at 32 weeks
What is the definition of anaemia during pregnancy?
What is the most common cause of this and why?
Hb < 110 g / L during 1st and 3rd trimester
Hb < 105 g / L during 2nd trimester
the most common cause is iron deficiency
pregnancy increases requirements for iron and usually results in considerable mobilisation of Fe stores
How does MCV (mean cell volume) change during pregnancy?
MCV increases physiologically in pregnancy
pregnancy also increases folic acid requirements
What is leukocytosis?
When does it tend to be seen during pregnancy?
an increase in the number of white cells in the blood
this is mainly a neutrophilia rising from the 2nd month to a preak range of around 9 - 15 in the 2nd - 3rd trimester
left shift may also be seen (myelocytes / metamyelocytes)
What is meant by “left shift”?
an increase in the number of immature leukocytes in the peripheral blood, particularly neutrophil band cells
these are immature forms of neutrophils
What is normal platelet count?
What is platelet count in gestational thrombocytopenia?
normal platelet count is > 70 x 109 / L
platelet count < 150 x 109 / L in around 10% of women towards the end of pregnancy
When does platelet count fall in gestational thrombocytopenia?
How does this affect the mother and fetus?
platelet count falls after 20 weeks and thrombocytopenia is most marked in late pregnancy
there is no pathological significance for mother or foetus and there is rapid recovery following delivery
What is meant by a “prothrombotic state”?
an abnormality of blood coagulation that increases the risk of thrombosis
What factors contribute to pregnancy being 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
How do the levels of coagulation factors change in pregnancy?
- marked increase in plasma fibrinogen and factor VII
- increase in factors V, VIII, X and XII
- greater increase in vWF than factor VIII (twofold in late pregnancy)
- minimal increase in FIX and small decrease in FXI
- initial increase in FXIII followed by reduction to 50% of non-pregnant value
What is the function of normal red cells?
they are biconcave discs with no nucleus
the function is to transport oxygen bound to haemoglobin
How is production of erythrocytes controlled?
production is controlled by erythropoietin (EPO)
this is produced in the kidneys in response to tissue oxygen concentration
What is the structure of haemoglobin like?
it involves a tetramer of globin chains
each globin chain is non-covalently bound to a haem group
all normal haemoglobins have 2 alpha and 2 non-alpha chains
What are the roles of the globin chain within the haemoglobin molecule?
- protects haem from oxidation
- renders the molecule soluble
- permits variation in oxygen affinity
What chromosomes are involved in genetic control of globin chains?
genes that encode the alpha globin chains are found on chromosome 16
genes that encode the non-alpha globin chains are found on chromosome 11
multiple individual genes are expressed at each site
What is the most common form of normal adult Hb?
> 95% of people have Hb-A (2a / 2b)
3.5% of people have Hb-A2 (2a / 2d)
< 1% of people have Hb-F (2a / 2y)
What is meant by a haemoglobinopathy?
What are the 2 different types?
changes in globin genes or their expression leads to disease
can be structural Hb variants or thalassaemias (alpha or beta)
What causes a structural Hb variant?
usually a single base substitution in globin gene
this leads to an altered structure and function
e.g. HbS (sickle), C, D, E, etc.
What causes a thalassaemia?
change in globin gene expression leads to reduced rate of synthesis of normal globin chains
pathology is due to an imbalance of alpha and beta chain production
free globin chains damage the red cell membrane
In autosomal recessive inheritance, if both parents are carriers what are the chances that the children will be affected?
1 in 4 chance that child will be normal
1 in 4 chance that child will be affected
1 in 2 chance that child will be a heterozygous carrier
What are the main methods used in the diagnosis of haemoglobinopathies?
full blood count / film
- haemoglobin electrophoresis
- isoelectric focusing
- high performance liquid chromatography (HPLC)
What are less common methods that can be used in the diagnosis if haemoglobinopathies?
- heat stability, isopropanol (unstable Hbs)
- oxygen dissociation curve (p50, high affinity)
- DNA analysis (genetic counselling, prenatal diagnosis)
- mass spectrometry
- Kleihauer testing, supravital staining, sickle solubility
What is the purpose of haemoglobin electrophoresis?
it is a blood test that measures the different types of haemoglobin within red blood cells
What is meant by “sickle cell trait”?
What would the patient’s blood count be like?
the patient is heterozygous (Hb A / S)
they have one abnormal allele of the haemoglobin beta gene, but do not display severe symptoms of sickle cell disease
their blood count would be normal
What would Hb electrophoresis show in someone with sickle cell trait?
What is the clinical picture?
Hb-S - 45%
Hb-A - 55%
no problems present except when there is severe hypoxia or dehydration
What happens in sickle cell disease?
sickle Hb (Hb-S) polymerises to form long fibrils which distort the red cell membrane and produce the classical sickle shape
What may reduce polymerisation in sickle cell disease?
polymerisation is reduced if other haemoglobins are present in the red cell
e.g. Hb-F in foetus or neonate
What type of anaemia is associated with sickle cell disease?
haemolytic anaemia
the sickled red blood cells have a short lifespan in the blood
How does haemolysis - associated haemostatic activation work?
- intravascular haemolysis releases haemoglobin into plasma
- haemoglobin quenches nitric oxide and generates reactive oxygen species
- arginase I is released from red blood cells during haemolysis, and metabolises arginine, the substrate for NO synthesis
- this further impairs NO homeostasis
- depletion of NO associated with platelet activation and coagulation
What would the blood count and blood film look like in someone who had sickle cell disease?
What would the Hb electrophoresis results show?
blood count shows anaemia - Hb 60 - 80 g / L
blood film shows sickle cells
Hb electrophoresis shows:
Hb-S > 95%
Hb-A - 0%
What is the frequency of sickle cell disease like?
1 in 200 afrocarribbeans
1 in 60 west africans
around 12,000 patients in the UK
What are the acute complications of sickle cell disease?
vaso-occlusive crisis:
- dactylitis (hands and feet)
- chest syndrome
- abdominal pain (mesenteric)
- bones (long bones, ribs, spine)
- brain
- priapism
septicaemia
aplastic crisis
sequestration crisis:
- affecting the spleen and liver
What happens in a vaso-occlusive crisis?
the microcirculation is obstructed by sickled RBCs
this causes ischaemic injury to the organ supplied and resulting pain
What happens in an aplastic crisis?
the body does not make enough new red blood cells to replace the ones that are already in the blood
in SCD, the bone marrow suddenly stops producing RBCs leading to sudden and severe anaemia
What happens in splenic sequestration crisis?
splenic vaso-occlusion causes a large percentage of total blood volume to become trapped within the spleen
What are the chronic complications of sickle cell disease?
- hyposplenism
- renal disease
- avascular necrosis
- leg ulcers, osteomyelitis, gall stones, retinopathy, cardiac and respiratory issues
Why does hyposplenism occur in sickle cell disease?
due to infarction and atrophy of the spleen
What is the renal disease like in sickle cell disease?
medullary infarction with papillary necrosis
tubular damage means the patient cannot concentrate the urine and will often wet the bed at night
glomerular damage leads to chronic renal failure and dialysis
What structures are affected by avascular necrosis in sickle cell disease?
femoral / humeral heads
What is the initial treatment for sickle cell disease?
penicillin from 6 months of age
identified through neonatal screening
What is the treatment for vaso-occlusive crisis in SCD?
analgesia - usually opiates
hydration to maintain red cell water
treatment of precipitants
What is priapism?
What is the treatment given in acute and recurrent cases?
persistent and painful erection of the penis
acute treatment is intracorporeal phenylephrine
recurrent treatment is etilefrine
When is a transfusion used to treat sickle cell disease?
top-up:
- splenic sequestration
- aplastic crisis
- pre-operative
- acute chest crisis (Hb < 50 g / L)
exchange:
- acute chest crisis
- acute stroke
- pre-operative
regular exchange:
- primary and secondary stroke prevention
What does hydroxycarbamide do?
When is it prescribed to someone with sickle cell disease?
it increases Hb-F which causes time delay to polymerisation, reduced adhesion to endothelium, enhanced NO
consider if > 3 admissions with painful crisis in 12 months
or
2 chest crisis
What preventative tests / procedures are performed in someone with sickle cell disease?
- transcranial doppler - annual from 3 years
- MRI to check for avascular necrosis as joint replacement may be needed
- perioperative care - transfusion, avoid local tourniquet
- cholecystectomy for symptomatic biliary disease
- annual opthalmic review
- U&E, BP, Ix haematuria in renal disease
What is involved in curative treatment and prevention of sickle cell disease?
curative:
- bone marrow transplant from normal donor
- gene therapy
prevention:
- genetic counselling / prenatal diagnosis
- avoiding precipitants
What are other causes of sickle cell disease?
co-inheritance of Bs and another B chain abnormality
- SC disease - fewer crisis, increased risk of AVN and retinopathy
- S/O-Arab (severe)
- S/B-thalassaemia , S/Lepore , S/D-punjab (moderate)
- S-HPFH, S/E (mild)
How are thalassaemias divided into categories?
divided into a, b, db and ydb according to which globin chain is reduced
in some, no globin chain is produced (e.g. a0)
in others they are produced at a reduced rate (e.g. a+)
Why do people with thalassaemia become anaemic?
people with thalassaemia produce either no or too little haemoglobin, which is used by RBCs to carry oxygen around the body
What types of haemoglobin are affected in a-thalassaemia?
Where are the most severe forms found?
most serious forms restricted to SE Asia and some Mediterranean islands
both Hb-A and Hb-F have alpha chains
What is meant by haemoglobin Barts (Hb Barts) as a form of a-thalassaemia?
it involves homozygous inheritance of a0
the abnormal haemoglobin consists of 4 gamma globin chains
it is moderately insoluble so accumulates in RBCs
it has an extremely high affinity for oxygen, resulting in almost no oxygen delivery to the tissues
What condition in the foetus is Hb Barts associated with?
hydrops fetalis
this is a condition in the foetus characterised by an accumulation of fluid (oedema) in at least two foetal compartments
What is HbH disease?
a form of a-thalassaemia in which moderately severe anaemia develops due to reduced formation of alpha globin chains
it involves inheritance of only one out of the four normal alpha-globin genes
What is meant by “a-trait”?
being a carrier of a-thalassaemia but not experiencing any symptoms of the disease
What is B-thalassaemia?
reduced rate of production of beta-globin chains
the pathology is caused by excess alpha chains
What would the blood film look like in someone with B-thalassaemia trait?
blood film shows small, pale red cells (resembles iron deficiency)
total Hb level is normal or only slightly reduced
Hb-A2 level > 3.5%
there are no clincal problems
What is meant by beta-thalassaemia intermedia?
a milder form of B-thalassaemia
it is characterised by mild to moderate anaemia
What is the treatment for thalassaemia intermedia?
no absolute requirement for regular transfusions in order to survive during the first 3-5 years of life
the clinical picture and genetic basis can be highly variable
What are some of the symptoms and signs of thalassaemia intermedia?
- pulmonary hypertension
- extramedullary haematopoiesis
- bone changes and osteoporosis
- endocrine and fertility problems
- leg ulcers
What is meant by extramedullary haematopoiesis?
haematopoiesis occurring outside of the medulla of the bone (bone marrow)
How does someone with B-thalassaemia major present?
What would their blood film look like?
they present with very severe anaemia at 1 - 2 years of age
their blood film is very abnormal with lots of nucleated red cells
clinical features are due to severe anaemia and attempt to make more red cells in marrow to compensate
How does alpha chain excess lead to anaemia in B-thalassaemia major?
alpha chain excess leads to:
ineffective erythropoiesis:
- red cells die within the bone marrow
shortened red cell lifespan:
- due to haemolysis
these lead to anaemia
What does increased marrow activity in B-thalassaemia major lead to?
- skeletal deformity , stunted growth
- increased iron absorption and organ damage (exacerbated by blood transfusion)
- protein malnutrition
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What does an enlarged and overactive spleen in B-thalassaemia lead to?
- pooling of red cells (increased anaemia)
- increased transfusion requirement
What does a child with B-thalassaemia look like?
- short stature and distorted limb growth due to premature closure of epiphyses in long bones
- enlarged liver and spleen due to extramedullary haemopoiesis
What does the face of someone with B-thalassaemia look like?
maxillary hypertrophy, abnormal dentition and frontal bossing due to expanded bone marrow
What does an X-ray of someone with B-thalassaemia major look like?
X-ray showing classical “hair on end” skull due to widening of diploic cavities by marrow expansion
Why is transfusion a treatment for B-thalassaemia major?
How often are they performed?
transfusion maintains mean Hb at 120 g / L
it suppresses marrow red cell production and prevents skeletal deformity and liver/spleen enlargement
3-4 weekly transfusions from 1st year of life
What is the drawback to using blood transfusions to treat B-thalassaemia major?
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
What are the symptoms of severe iron load and toxicity?
- failure of puberty and growth failure
- diabetes
- dilated cardiomyopathy and heart failure
- cirrhosis
What are other complications of transfusion in B-thlassaemia?
- transmission of infection
- allo-immunisation
this is an immune response to foreign antigens after exposure to genetically different cells
What are the main causes of death in thalassaemia?
- heart failure (60%)
- infection
- arrhythmia
- myocardial infarction
What is used to prevent death from iron overload in patients with B-thalassaemia major?
patients are started on iron chelation therapy from the 2nd year of life
this promotes excretion of iron in urine and faeces
What is the main drug used in iron chelation therapy?
What is target ferritin?
desferrioxamine is given by 8-12 hourly subcutaenous infusion via a syringe-pump as a home treatment on at least 5 nights a week
new oral iron chelators include deferiprone and deferasirox
target ferritin around 1000 - 1500 ug /L
How is chelation monitored?
by looking at acute phase ferritin, liver biopsy and MRI
Why are B-thalassaemia major patients more prone to infection?
- decreased CD4/8 ratio and defective neutrophil chemotaxis
- increased virulence with excess iron
- line infections
- transfusion transmitted infection
What are the endocrine complications of B-thalassaemia major?
growth and development problems
screening for glucose intolerance, hypothyroidism and hypoparathyroidism
How is liver disease monitored in B-thalassaemia?
LFTs, ferritin, hepatic serology
How is bone preserved in treatment of B-thalassaemia major?
- timely transfusion
- no over-chelation
- restricted diet
- hormone replacement for hypogonadism
- monitoring for osteoporosis
- treatment with bisphosphanates
How is fertility monitored and protected in B-thalassaemia major?
- good chelation and fertility clinic advice
- may need induction
- cardiac, thyroid, diabetic and bone assessments
