Lecture 18 - Thalassemia

Question 1

Compositions of hemoglobin

• Embryonic
• Foetal
• Adult

Answer 1

• Embryonic: Hb portland (Z2,Y2), Hb Gower1 (Z2E2), Gower2 (A2,E2)
• Foetal: Hbf: a2y2
• Adult: HBA: a2b2 / HBA2: a2d2

Question 2

Thalassemia and malaria

Answer 2

• ThaI carriers protected against malaria
• b thalassemia in Sardinia: less common in mountainous regions where malarial transmission is low
• A thalassemia in PNG and surrounding islands: altitude related effect in PNG, Malarial transmission - distribution gradient in PNG, melanesia, caledonia

Question 3

B thalassemia

Answer 3

• reduced production of b-globin chains
• single base mutation - most common molecular defect
• mendelian inheritance
  BN/bN: normal
  bN/bThaI: heterozygote carrier (thalassemia trait/minor)
  bthaI/bThaI: thalassemia major

Question 4

B thalassemia mechanism

Answer 4

• excess a chain cause cells in BM not to survive
• decrease a2/b2 cause anemia and microcytic blood films

Thalassemia trait: hypochromic microcytic. Raised a2 because d gene not affected -> diagnostic

Question 5

B-thalassemia mutation

Answer 5

• more than 200 mutations
• according to the severity of depletion of b glob
  B+: reduced b globin
  BO: absent b-globin

Major: b0/b0: no globin chain being produced
Intermedia: mildb+/bO, or mild B+/severeB+
trait: severe b+/ bN

Question 6

Pathophysiology of b thalassemia

Answer 6

• increased production of y chain and a chain -> increase a2y2 -> increase HBF -> higher affinity for O2, shift of Hb curve to left -> kidney produce Hpo
• increased a chain, decrease b chain -> eexcess a chain precipitates -> ineffective erythropoiesis, hemolysis -> anemia, marrow expensiaon -> increase iron absorption -> iron loading, bone deformity, weight lost, wasting, gout…

Question 7

B-thalassemia major - clinical phenotype

Answer 7

• transfusion dependent
• extramedullary haemopoiesis: bone deformities, hepatosplenomegaly
• iron accumulation: downside of transfusion. Endocrine organs, liver cirrhosis, cardiac failure
• susceptibility to infection
• hypermetabolism - wasting, gout

Question 8

B-thalassemia major haematological phenotype

Answer 8

• hypochromic microcytic anemia
• anisopoikilocytosis, target cells, basophilic stippling, nucleated red cells, tear drops
• absent HbA in b0thal, HbA2 variable
• rise in HbF

Question 9

B thalassemia trait

Answer 9

• asymptomatic carrier
• normal Hb
• hypochromic microcytosis: low MCV, low MCH
• occasional tear drop poikilocytes and target cells
• raised HbA2
• beware co-existent iron deficiency

Question 10

B thalassemia/HbE

Answer 10

• most common severe form of thalassemia in SE asia and india
• mutation in codon 26 of b-globin gene
• bE/bE: minimal anemia, microcytic
• bE/bN: asymptomatic
• bE/b/ThaI: often severe, resembles b0 thal major

Question 11

A thalassemia: 5 deletions, 4 phenotypes

Answer 11

Normal: 4 normal a genes
A+ trait: heterozygous (1 gene deleted) or homozygous (2 gene deleted on the 2 separate alleles)
- a0 trait: 2 gene deleted in same allele
- HbH disease: deletion of 3
- hydrops phetalis: deletion of all 4

Question 12

Epidemiology of A thalassemia

Answer 12

• HbH: 3 gene deletion, SE asia and mediterranean
• Hb Barts hydrops fetalis: 4 gene deletion: SE asia and mediteranean
• a+ thalaasemia: west africa, india, pacific islands

Question 13

A thalassemia

Answer 13

• deficiency of a globin chains
• excess of b-like globin chains
• HbH: b4: HbH bodies on blood film
• Hb Barts: y4 -> 4 y chains come together due to lack of a chain -> dont give up oxygen

Question 14

hbH bodies

Answer 14

• golf ball red cells

- due to precipitation of HbH out

Question 15

Pathophysiology of a thalassemia

Answer 15

• defective haemoglobin synthesis
• peripheral haemolysis - HbH unstable, precipitates in aged red cells
• High oxygen affinity of HbH and Hb Barts -> physiologically useless for O2 delivery

Question 16

• a thalassemia carriers

Answer 16

• asymptomatic
• two gene deletion easier to pick up: mild anemia, hypochromic microcytosis, no elevation in HbA2, +/- Hb Barts in neonatal period, +/- HbH bodies
• single gene deletion: normal Hb, very mild reduction in MCV and MCH, occasionally hb barts 1-3%
• DNA studies are the only definitive test if HbH bodies not seen

Question 17

HbH disease

Answer 17

• most survive into adulthood
• variable anemia
• HbH 5-40%
• splenomegaly
• exacerbations of hemolysis
• bone changes/growth retardation rare

Question 18

Hb Barts hydrops fetalis

Answer 18

• retain fluid in at least 2 compartments
• still born or premature and die very early after birgh
• no a chains or y chains
• pallor, generalised oedema, massive hepatosplenomealy
• Hb 60-80, gross thalassemic changes on blood film
• Hb barts 80%, Hb portland 20%

Question 19

Hb constant spring

Answer 19

• common in SE Asia
• TAA (STOP) to CAA (glutamine(
• elongated a globin chain, synthesized at a reduced rate

Question 20

Management of HbH disease

Answer 20

• transfusion during episoded of increased hemolysis
• occasionally splenectomy may be required
• disordered iron metabolism much less common than b-thalassemia major

Question 21

Management of b-thalassemia

Answer 21

• blood transfusion programme
• iron chelation
• management of endocrine, hepatic and cardiac complication
• splenectomy - indications and precautions
• stem cell transplant
• gene therapy and other experimental therapies

Question 22

Blood transfusion programme

Answer 22

• 4-weekly; aim for Hb>90 g/L
• donor blood matched for allo-antigens - prevent allosensitisation
• white cell filters - prevent febrile reaction; now no longer required dur to leucodepletion at source
• hep B vaccination
• yearly testing for HCV

Question 23

Organ systems affected by iron overload

Answer 23

• pituitary: hypogonadotrophic, hypogonadism
• thyroid: hypothyroidism
• parathyroid: hypoparathyroidism
• heart: cardiomyopathy
• liver: cirrhosis, carcinoma
• Pancreas: diabetes
• Gonads: hypogonadotrophic, hypogonadism

Question 24

Iron chelation by desferrioxamine

Answer 24

• subcutaneous, portable syringe driver pump
• commence when serum ferritin reaches 1500-2000 ug/L
• DFO should not be commenced before age 4
• 4-5 nights/week
• VitC to increase iron excretion
• monitored by serum ferritin, transferrin saturation
• compliance is a major problem

Question 25

Desferroxamine toxicity

Answer 25

• local: painful hypersensitive lumps, infection, absesses
• hypersensitivity: desensitisation possible
• ototoxicity: dose realted-
• ophtalmic changes
• bone changes and short stature
• Yersinia infection

Question 26

Problems in management of iron chelation

Answer 26

• balance between effectiveness and toxicity
• assessment of total body Fe burden
• COMPLIANCE

Question 27

Oral Fe Chelators

Answer 27

• Deferasirox: Exjade

- Deferiprone: ferriprox

Question 28

Deferasirox: Exjade

Answer 28

• 2-5x potency of DFO, 10x Deferiprone
• highly selective for Fe
• Good oral bioavailibility
• mean plasma clearance: T1/2: 11-16 hours
• once daily
• Faecal excretion of chelated Fe

Question 29

Deferasirox: Exjade

Answer 29

• used in first line
• maintains or reduces liver iron
• effective in chelating cardiac iron, further study in progress
• side effects: gastrointestinal, skin rash, raised creatinine/renal impairment, abnormal LFT

Question 30

Deferiprone: L1, Ferriprox

Answer 30

• Rapid absorption: peak 45-60 minute
• plasma clearance: 53-166
• high selevtivity for Fe3+, but binds Cu> Zn > Mg
• Fe excretion in urine
• approved by TgA: when desferroxamine ineffective or inappropriate
• has been used in combination with desferrioxamine -> improved efficacy in chelating cardiac iron

Question 31

Deferiprone side effects

Answer 31

• agranulocytosis and neutropenia
• joint effusion
• Zinc deficiency
• abnormal LFT

Question 32

Splenectomy for thalassemia major

Answer 32

• increased susceptibility to encapsulated organisms
• pre-operative vaccination
• penicillin prophylaxis
• not considered before age 6

Question 33

Stem cell transplant

Answer 33

• matched sibling transplant: most

Question 34

Experiemntal approaches of management:

Answer 34

• induction of HbF synthesis: cytotoxic agents, butyrate
• EPO
• gene therapy