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Block 4 - Heamatology > Lecture 18 - Thalassemia > Flashcards

Lecture 18 - Thalassemia Flashcards

1
Q

Compositions of hemoglobin

  • Embryonic
  • Foetal
  • Adult
A
  • Embryonic: Hb portland (Z2,Y2), Hb Gower1 (Z2E2), Gower2 (A2,E2)
  • Foetal: Hbf: a2y2
  • Adult: HBA: a2b2 / HBA2: a2d2
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2
Q

Thalassemia and malaria

A
  • 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
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3
Q

B thalassemia

A
  • 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
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4
Q

B thalassemia mechanism

A
  • 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

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5
Q

B-thalassemia mutation

A
  • 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

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6
Q

Pathophysiology of b thalassemia

A
  • 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…
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7
Q

B-thalassemia major - clinical phenotype

A
  • transfusion dependent
  • extramedullary haemopoiesis: bone deformities, hepatosplenomegaly
  • iron accumulation: downside of transfusion. Endocrine organs, liver cirrhosis, cardiac failure
  • susceptibility to infection
  • hypermetabolism - wasting, gout
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8
Q

B-thalassemia major haematological phenotype

A
  • hypochromic microcytic anemia
  • anisopoikilocytosis, target cells, basophilic stippling, nucleated red cells, tear drops
  • absent HbA in b0thal, HbA2 variable
  • rise in HbF
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9
Q

B thalassemia trait

A
  • asymptomatic carrier
  • normal Hb
  • hypochromic microcytosis: low MCV, low MCH
  • occasional tear drop poikilocytes and target cells
  • raised HbA2
  • beware co-existent iron deficiency
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10
Q

B thalassemia/HbE

A
  • 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
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11
Q

A thalassemia: 5 deletions, 4 phenotypes

A

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

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12
Q

Epidemiology of A thalassemia

A
  • 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
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13
Q

A thalassemia

A
  • 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
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14
Q

hbH bodies

A
  • golf ball red cells

- due to precipitation of HbH out

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15
Q

Pathophysiology of a thalassemia

A
  • 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
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16
Q
  • a thalassemia carriers
A
  • 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
17
Q

HbH disease

A
  • most survive into adulthood
  • variable anemia
  • HbH 5-40%
  • splenomegaly
  • exacerbations of hemolysis
  • bone changes/growth retardation rare
18
Q

Hb Barts hydrops fetalis

A
  • 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%
19
Q

Hb constant spring

A
  • common in SE Asia
  • TAA (STOP) to CAA (glutamine(
  • elongated a globin chain, synthesized at a reduced rate
20
Q

Management of HbH disease

A
  • transfusion during episoded of increased hemolysis
  • occasionally splenectomy may be required
  • disordered iron metabolism much less common than b-thalassemia major
21
Q

Management of b-thalassemia

A
  • 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
22
Q

Blood transfusion programme

A
  • 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
23
Q

Organ systems affected by iron overload

A
  • pituitary: hypogonadotrophic, hypogonadism
  • thyroid: hypothyroidism
  • parathyroid: hypoparathyroidism
  • heart: cardiomyopathy
  • liver: cirrhosis, carcinoma
  • Pancreas: diabetes
  • Gonads: hypogonadotrophic, hypogonadism
24
Q

Iron chelation by desferrioxamine

A
  • 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
25
Q

Desferroxamine toxicity

A
  • local: painful hypersensitive lumps, infection, absesses
  • hypersensitivity: desensitisation possible
  • ototoxicity: dose realted-
  • ophtalmic changes
  • bone changes and short stature
  • Yersinia infection
26
Q

Problems in management of iron chelation

A
  • balance between effectiveness and toxicity
  • assessment of total body Fe burden
  • COMPLIANCE
27
Q

Oral Fe Chelators

A
  • Deferasirox: Exjade

- Deferiprone: ferriprox

28
Q

Deferasirox: Exjade

A
  • 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
29
Q

Deferasirox: Exjade

A
  • 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
30
Q

Deferiprone: L1, Ferriprox

A
  • 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
31
Q

Deferiprone side effects

A
  • agranulocytosis and neutropenia
  • joint effusion
  • Zinc deficiency
  • abnormal LFT
32
Q

Splenectomy for thalassemia major

A
  • increased susceptibility to encapsulated organisms
  • pre-operative vaccination
  • penicillin prophylaxis
  • not considered before age 6
33
Q

Stem cell transplant

A
  • matched sibling transplant: most
34
Q

Experiemntal approaches of management:

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

Block 4 - Heamatology (23 decks)

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