Thalassemia

Question 1

what is the normal concentration fo haemoglobin in adults

Answer 1

120-165g/L

Question 2

describe when Hb synthesis occurs

Answer 2

Synthesis occurs during development of RBC and begins in pro-erythroblast:
65% erythroblast stage
35% reticulocyte stage

Question 3

describe Hb structure

Answer 3

made of Haem + globin
Haem (synthesised in mitochondria)
Globin (synthesised in ribosomes)

Question 4

how is haem synthesised

Answer 4

Combination of protoporphyrin ring with central iron atom (ferroprotoporphyrin)
Synthesised mainly in mitochondria which contain the enzyme ALAS
Iron usually in ferrous form (Fe2+)
Able to combine reversibly with oxygen

Question 5

which other proteins contain haem

Answer 5

myoglobin, cytochromes, peroxidases, catalases, tryptophan

Question 6

strcuture of heam

Answer 6

central Fe surrounded by protoporphyrin ring (connected by 4x Nitrogen connections)

Question 7

synthesis of globin

Answer 7

Various types which combine with haem to form different haemoglobin molecules

Eight functional globin chains, arranged in two clusters:

Question 8

what are the 2 clusters of globin chains

Answer 8

b- cluster (b, g, d and e globin genes) on the short arm of chromosome 11

a- cluster (a and z globin genes) on the short arm of chromosome 16

Question 9

what are the normal Hb structures (composition and % in body)

Answer 9

Hb A α2β2 (96-98%)
Hb A2 α2δ2 (1.5-3.2%)
Hb F α2γ2 (0.5-0.8%)

Question 10

how is glycated Hb detected

Answer 10

Each Hb type has a glycated fraction however only glycated HbA is normally present in sufficient quantity to be visible on a HPLC chromatogram and then only up to approximately 5%

Question 11

Globin primary/secondary structure

Answer 11

Primary: α 141 AA
Non- α 146 AA
Secondary: 75% α and b chains-helical arrangement

Question 12

Tertiary globin structure

Answer 12

Approximate sphere
Hydrophilic surface (charged polar side chains), hydrophobic core
Haem pocket

Question 13

describe key features of Hb-oxygen dissociation curve

Answer 13

O2 carrying capacity of Hb at different pO2

Sigmoid shape
Binding of one molecule facilitate the second molecule binding (cooperativity)

P 50 (partial pressure of O2 at which Hb is half saturated with O2) 26.6mmHg

Question 14

The normal position of curve depends on

Answer 14

Concentration of 2,3-DPG
H+ ion concentration (pH)
CO2 in red blood cells
Structure of Hb

Question 15

what causes Right shift

Answer 15

(easy oxygen delivery)
High 2,3-DPG
High H+
High CO2
HbS

Question 16

what causes left shift

Answer 16

(give up oxygen less readily)
Low 2,3-DPG
HbF
Low H+

Question 17

what is Hemoglobinopathy give examples

Answer 17

Genetic disorders characterized by a defect of globin chain synthesis:

Structural variants of haemoglobin
Defects in globin chain synthesis (thalassaemia)

Most common inherited single gene disorder worldwide

Question 18

Classification of thalassaemia

Answer 18

Globin type affected

Clinical severity:
minor “trait”
intermedia
major

Question 19

what is Beta (b) thalassaemia, where is it prevalent

Answer 19

Deletion or mutation in b globin gene(s)
Reduced or absent production of b globin chains
Prevalence – mainly Mediterranean countries

Question 20

describe Inheritance of Beta thalassaemia, characteristics of carriers

Answer 20

Beta Thalassaemia is inherited in a recessive mendelian fashion.

(beta -o = no globing production, b+ = decreased globin production which gives rise to major/media

The Carriers are asymptomatic save for the microcytic hypochromic indices

Question 21

how can thalassaemia be diagnosed

Answer 21

FBC- Microcytic Hypochromic indices, Increased RBCs relative to Hb

THERE IS ABSENCE OF IRON DEFFICIENCY

Film- Target cells, poikilocytosis but no anisocytosis

High Performance Liquid Chromatography
(in beta thal. raised HbA2/HbF

Globin Chain synthesis/ DNA studies = only reliable

Question 22

what is the main feature of thalassaeimia

Answer 22

a microcytic hypochromic blood picture in the absence of iron deficiency.
RBC count is relatively high when compared to the haemoglobin.

Question 23

What is Thalassaemia Major

Answer 23

Carry 2 abnormal copies of the beta globin gene

Severe anaemia, incompatible with life without regular blood transfusions

Clinical presentation usually after 4-6 months of life

Question 24

Name an extra indicator of beta thal major on peripheral blood film

Answer 24

Often Howell Jolly bodies and nucleated RBC’s will be present as a result of splenectophy/hyper plastic bone

Question 25

RBC inclusions in b Thalassaemia

Answer 25

alpha chain precipitates Pappenheimer Bodies (using Perls stain)

Question 26

Clinical presentation of Thalassaemia Major

Answer 26

Severe anaemia usually presenting after 4 months Hepatosplenomegaly Blood film shows gross hypochromia, poikilocytosis and many NRBCs Bone marrow - erythroid hyperplasia Extra-medullary haematopoiesis

Question 27

b Thalassaemia – clinical features

Answer 27

``` Chronic fatigue Failure to thrive Jaundice Delay in growth and puberty Skeletal deformity Splenomegaly Iron overload ```

Question 28

Other complications of b thalassaemia

Answer 28

Cholelithiasis and biliary sepsis Cardiac failure Endocrinopathies Liver failure

Question 29

what is most likely cause low death in b thal

Answer 29

Cardiac disease | less likely - infections > liver

Question 30

Thalassaemia Major- treatment

Answer 30

``` Regular blood transfusions Iron chelation therapy Splenectomy Supportive medical care Hormone therapy Hydroxyurea to boost HbF Bone marrow transplant ```

Question 31

describe transfusion treatment

Answer 31

Phenotyped red cells Aim for pre-transfusion Hb 95-100g/L Regular transfusion 2-4 weekly If high requirement, consider splenectomy

Question 32

common infections

Answer 32

Yersinia | Other Gram negative sepsis

Question 33

infection management

Answer 33

Prophylaxis in splenectomised patients – immunisation and antibiotics

Question 34

Name 2 iron chelators

Answer 34

Deferiprone | Deferasirox

Question 35

describe Deferasirox

Answer 35

Oral - specific and controls body iron well | SE: rash, GI symptoms, hepatitis, renal impairment

Question 36

describe Desferrioxamine

Answer 36

Sc infusion (or IV in cardiac iron overload) SE: ocular/auditory/skeletal vertebral dysplasia, pseudo-rickets, retinopathy, high tone sensorineural loss, increased risk of Yersinia infection Parental = compliance issues

Question 37

describe Deferiprone

Answer 37

Oral Effective in reducing myocardial iron SE: GI disturbance, hepatic impairment, neutropenia, agranulocytosis, arthropathy

Question 38

Monitoring of iron overload

Answer 38

Serum ferritin >2500 associated with significantly increased complications Liver biopsy T2* cardiac and hepatic MRI Ferriscan – R2 MRI

Question 39

what is HbE Beta Thalassaemia

Answer 39

Very common combination in South East Asia Clinically variable in expression can be as severe as thalassaemia major

Question 40

what is Alpha Thalassaemia

Answer 40

Deletion or mutation in a globin gene(s) Reduced or absent production of a globin chains Affects both foetus and adult Excess beta and gamma chains form tetramers of HbH and Hb Barts respectively

Question 41

what is severity of alpha thal dependent on

Answer 41

Severity depends on number of  globin genes affected

Question 42

what is a thalassaemia carrier

Answer 42

Also known as Thalassaemia minor / trait Carry a single abnormal copy of the beta globin gene Usually asymptomatic Mild anaemia

Question 43

Problems Associated with Treatment in Developing Countries

Answer 43

Lack of awareness/experience Availability of blood Cost and compliance with iron chelation therapy Availability of bone marrow transplant

Question 44

Screening and Prevention

Answer 44

health education for thalassaemics, family members and general public Extended family screening Pre-marital screening/Discourage marriage between relatives? Antenatal testing Pre-natal diagnosis (CVS)