1
Q
Define erythroid debris
A
broken down erythrocyte’s parts
2
Q
define MCH
A
mean corpuscular haemoglobin, this refers to the average amount of haemoglobin found in the red blood cells in the body, this is caclaulated by dividing the total mass of haemoglobin by the number of red blood cells in a volume of blood, this is decreased in hypochromic anaemias
3
Q
name some different types of haemoglobin
A
- HbA (haemoglobin in adults) this is 2 alpha and 2 beta subunits
- HbF (fetal haemoglobin) this is 2 alpha and 2 gamma subunits
- HbA2 – 2 alpha and 2 delta subunits
- Hb Gower-1 – this is foetal haemoglobin that is formed in the first 6 weeks of fetal development, in the yolk sac and mesothelium
- Haemoglobin Barts – y4
- Haemoglobin H – 4 beta subunits
4
Q
what are the 3 sites of production of RBC in the foetus
A
- Mesoblastic - 3rd week
- Hepatic – 6 weeks
- Myeloid stage – 3rd month onwards (6-7 months becomes more important)
5
Q
describe the 3 sites of RBC production in the foetus
A
Mesoblastic
- Nucleated red blood cells form in the yolk sac and mesothelial layers of the placenta
Hepatic
- Erythropoiesis mainly starts happening in the liver and spleen, at this stage there is no bone marrow and the liver has developed enough
Myeloid
- Bone marrow gradually become the principal source of the red blood cell
6
Q
describe the site of production of RBC in adults
A
- As you get older the amount of bones that can-do erythropoiesis decreases
- 0-5 years there is bone marrow in all bones so they can all make red blood cells
- 5- 20-25 years – erythropoiesis happens in the long bones
- 25+ tends to happens in the membranous bones such as the vertebrae, sternum, ribs, cranial bones and ileum
7
Q
can the sites at which RBC are produced change
A
This is because there is gradual replacement on the bone marrow with fats this can reverse and do hemopoiesis if there is an increased demand for example anaemia, the liver and spleen can also do this
8
Q
definition of thalassemia
A
- Thalassaemia is a genetic defect that results in inadequate quantities of one or another of the subunits that make up haemoglobin
9
Q
what are the types of thalassemia
A
alpha
beta
10
Q
what are the genetics of alpha thalasemia
A
- The severity of alpha thalassemia depends on the number of gene alles that are either defective or missing
- Defect on chromosome 16
11
Q
what happens if you have one alpha gene defective
A
- known as alpha thalassemia minima
- minimal effect
- 3 alpha globin genes are enough to permit normal haemoglobin production
- no clinical symptoms
- silent carrier
- may have a slightly reduced mean corpuscular volume and mean corpuscular haemoglobin
12
Q
what happens if you have two alpha genes defective
A
- known as alpha thalassemia minor
- 2 alpha genes permit nearly normal production of RBC
- milld microcytic hypo chromic anaemia
- this is the part of the disease that can be mistaken for iron deficiency anaemia and treated with iron inappropriately
13
Q
what happens if you have three alpha genes defective
A
- this is haemoglobin H disease
- Two unstable haemoglobins are present in the blood: Haemoglobin Barts (γ4) and haemoglobin H (β4).
- both of these haemoglobin have a higher affinity for oxygen that normal haemoglobin - thus this results in poor release of oxygen in tissues
- there is a microcytic hypo chromic anaemia
14
Q
what happens if you have 4 alpha genes defective
A
- foetus can’t live outside the uterus
- may not survive gestation
- most are born with hydros fetallis
- they have little circulating haemoglobin and the haemoglobin that is present is all tetrameric gamma chains ( haemoglobin parts)
15
Q
what are the complications of alpha thalasemeia
A
- excess iron
- bone deformities and broken bones
- enlarged spleen
- infections
- slower growth rates
16
Q
what are the symptoms fo alpha thalaseemia
A
- fatigue
- pale appearance or yellow colour to the skin
- irritability
- deformities of the facial bone
- slow growth
- swollen abdomen
- dark urine
17
Q
what is the genetics of beta thalassemia
A
- caused by mutations in the haemoglobin β gene on chromosome 11, inherited in an autosomal recessive disease
18
Q
what is another word for beta thalassemia
A
cooleys anaemia
19
Q
what are the types of beta thalassmeia
A
- heterozygous (thalassaemia trait, beta thalasaemia minor, β+) - more severe
- homozygous (beta thalassaemia major, βo)
- Beta thalassemia intermedia – this occurs when both of the beta globin genes are mutated but still able to make some beta chains
20
Q
what are the effects of beta thalaseemia
A
- Due to loss of synthesis of beta globins, excess alpha globins are produced in developing erythroblasts in marrow. The alpha tetramers are unstable and precipitate on the erythrocyte membrane
- This causes intra-medullary destruction of developing erythroblasts, erythroid hyperplasia and ineffective erythropoiesis- causes damage of the bone marrow in this condition,
- Result: (severe) hypochromic microcytic anaemia
- This is mild in heterozygous disease but severe in homozygous disease
21
Q
what are the complications of beta thalasemia
A
- Hypochromic, Microcytic Anaemia.
- Bone marrow expansion, splenomegaly
- Bone deformity, extramedullary erythropoietic masses
- Failure to thrive from about 6 months of age
- Heart failure and death by age 3-4
22
Q
what are the symptoms of beta thalassemia
A
- Only start to show after the 3-6 months after birth when the haemoglobin is changing from the gamma chains to the beta chain synthesis
- Tiredness
- Shortness of breath
- Fast heartbeat
- Pale skin
- Yellow skin and eyes – jaundice
- Moodiness
- Slow growth
23
Q
what is the treatment for alpha and beta thalasemai
A
- Regular transfusions (but can cause iron overload)
- Iron chelation therapy
- Splenectomy (not usually necessary now)
- Allogeneic bone marrow transplant (for young children if sibling donor available)
- Alternative treatments under trial: HbF modulating agents,
- The future: Gene therapy
24
Q
how do you diagnose thalassemia
A
- Chorionic villus sampling donw about 11 weeks into pregnancy – removes a tiny piece of the placenta for testing
- Amniocentesis – done 16 weeks into pregnancy removes a sample of fluid that surrounds the fetus to check for signs and problems
- Heel prick test – also tests for sickle cell disease, cystic fibrosis, congenital hypothyroidism, PKU, medium chain acyl-CoA dehydrogenase deficiency, IVA, MSUD, GA1, HCU
25
what does the heel prick test test for
- Heel prick test – also tests for sickle cell disease, cystic fibrosis, congenital hypothyroidism, PKU, medium chain acyl-CoA dehydrogenase deficiency, IVA, MSUD, GA1, HCU
26
describe the management of thalassemia
- Have a healthy balanced diet
- Exercise regularly
- Avoid smoking and drinking excessive amounts of alcohol
- Avoid infection
- Find out if partner is a carrier of thalassaemia
- Let know MDT before surgery
27
explain the signs and symptoms of the patient
- 2-3 months symptoms started – point which foetal haemoglobin switches to adult haemoglobin
- Feeding poorly - due to failure to thrive and fullness with heptosplenomagly
- Pale - anaemic
- Swollen abdomen – hepatosplenomegaly - due to extramedullary erythropoeiss and increased rate of haemolysis
- Conjuctivae were mildy jaundiced - incresed haemolysis causing increased amount of bilirubin
- little subcutnaeous fat - increased metbaolic rate of anaemia and red blood cell production using fat stores
- Palpable enlarged liver and spleen – due to increased destruction of red blood cells and extra medullary haemopoietic, (erythropoiesis could be taking part in the liver and spleen)
- Hypochronic microcytic anaemia – marker of beta thalaseemia
- High reticulocytes – due to increased red blood cell production as there is increased red blood cell breakdown in thalassemia
- MCH low – decreased haemoglobin beta subunits
- High serum bilirubin – haemolytic anaemia – breakdown produced from haemoglobin
- High serum lactate acid dehydrogenase – hameolysis – released from damaged erythroblasts and red cells
28
what is the structure of haemoglobin
- adult
- HbA2
- fetal
Oxygen carrying molecule made up of 4 globin subunits
Normal adult Hb = HbA = alpha2beta2 - 3 months after birth
Another adult Hb = HbA2 = alpha2delta2 - also from 3 months after birth
Fetal Hb = HbF = alpha2gamma2 - 3 months to 3 months after birth
Hb gower - 2 zeta and 2 epsilion - 3 weeks to 3 months
29
what chromosome is the beta globin gene on
chromosome 11
30
what inheritnacne is beta thalassmeia
autosomal recessive
31
what are the types of beta thalassemia
Β-thalassaemia trait = -/β2
Parents
B-thalassaemia intermedia = -/β0 (inherintance of one absent and one mutated beta globin) or β+/β+(inheritance of two mutated beta globin)
Partial loss of β-globin production
- have a more severe phenotype than traits but less severe than major
B-thalassaemia major = -/-
Kadheer
32
what type of beta thalassemia does Kadheers parents have
Β-thalassaemia trait = -/β2
| Parents
33
what is the pathophysiology of beta thalassemia
Begins to manifest after transition from fetal to adult haemoglobin
- Approximately 3 months of age
Lack of beta-chains means that haemoglobin is made up of 4-alpha chains
- Alpha chains precipitate and cause ineffective erythropoiesis of maturing cells
34
what is the result of beta thalassaemia
Anaemia
Compensatory erythroid hyperplasia (RBC development outside the normal sites of production)
- Liver, spleen, bones of cranium
- Expansion of bone marrow in long bones (normal sites of production)
35
what are the problems of beta thalassaemia
Usually within first year of life
Failure to thrive
- Ineffective erythropoiesis creates a hyper-metabolic state + anaemia reduces oxygen to growing tissues
Heptaosplenomegaly
- Erythropoiesis taking place in liver and spleen
- Increased destruction of red blood cells puts these organs under stress
Bony deformities
- Frontal bossing, prominent facial bones
Pallor and jaundice
Exercise intolerance - due to anaemia
Family history
36
what is jaundice in beta thalassemia caused by
due to increased red blood cell breakdown and production of bilirubin
- this is because there is increased breakdown of red blood cells in thalassemia
37
why is there hepatosplenomegaly and bone deformites in beta thalassemia
erythropoiesis taking place in abnormal places therefore these tissues expand
38
what is thalassaemic faceis
- expansion of cranial bones - particularly maxilla for erythropoiesis
39
How do you diagnose beta thalassmeia
Diagnosis
FBC
Blood smear
Reticulocytes – raised
Haemoglobin analysis
- Major: no HbA, elevated HbF and HbA2
- Intermedia: decreased HbA, elevated HbF and HbA2
- Trait: mostly HbA, elevated HbF and HbA2
Liver function tests – elevated bilirubin and LDH
Imaging of skull, abdomen and long bones
Genetic testing
40
describe what is found in the hameoglobin analysis for each of major, intermeida and trait of thalassemia
- Major: no HbA, elevated HbF and HbA2
- Intermedia: decreased HbA, elevated HbF and HbA2
- Trait: mostly HbA, elevated HbF and HbA2
41
describe the parents blood count
ents have mild microcytic anaemia = characteristic of Beta-thalassaemia trait. Usually asymptomatic.
Abnormal percentages of Hb in parents and patient. Raised levels of HbA2 and HbF to compensate for abnormal HbA (parents less so as have one functional beta gene)
42
How do you manage beta thalassaemia
Trait: nothing as usually asymptomatic
Intermedia: non-transfusion dependent
Major
- Regular red cell transfusions
Iron chelation therapy
- Iron overload = collection of iron in heart, liver, pancreas causing fibrosis and eventual organ failure
Iron chelators
- Bind excess iron and facilitate excretion
- Desferrioxamine, deferasirox and deferiprone
Stem cell transplantation – only potential cure
Splenectomy
43
describe the action of iron chelaters
desferrioxamine = short half life; parenteral infusion used in emergency settings to reduce iron levels quickly
- deferasirox = once daily oral administration; maintains a tolerable iron burden
- deferiprone = short half life; orally 3-4 times/day; more side effects; used in combination with others if iron chelation not being achieved
44
what is the national haemoglobinopathy registry
Database of patients in the UK living with red blood cell disorders
Data on patient diagnosis, demographics and genetic mutations
