HaematologyTier 2Disease (DEADMAN)

Thalassaemia

Description

Quantitative globin defect: dec synthesis of one chain -> alpha:beta chain imbalance
- Disease comes from the excess unpaired chain, not the deficient one
Normal adult: HbA (a2b2) ~97%, HbA2 (a2d2) 2-3.5%, HbF (a2g2) <1%

Beta-thalassaemia spectrum

	Genotype	Phenotype
Trait / minor	1 abnormal beta	Nil-mild anaemia, low MCV. Asymptomatic
Intermedia (NTDT)	2 abnormal, >=1 mild (b+)	Mild-moderate anaemia, splenomegaly, bone change, iron loading
Major (TDT)	2 severe (b0/b0)	Severe anaemia from 6-12 mo, lifelong transfusion

Ameliorated by co-inherited alpha-thal or high HbF (both restore chain balance)

Alpha-thalassaemia spectrum - 4 alleles (aa/aa)

Genes lost		Phenotype
1	Silent carrier	Normal / low-normal MCV
2	Trait / minor	Low MCV, mild anaemia. cis (--/aa) SE Asian; trans (-a/-a) African
3	HbH disease	Lifelong haemolytic anaemia, splenomegaly, HbH inclusions
4	Hb Bart's	Hydrops fetalis, lethal in utero

Only cis deletion carriers can produce a Bart's pregnancy - determines antenatal counselling

Epidemiology

Commonest monogenic disorder worldwide; ~1.5% of world population carriers
Beta: Mediterranean, Middle East, South Asia, SE Asia
Alpha: SE Asia, southern China (cis --SEA), Africa (trans), Middle East
Distribution mirrors historical malaria - heterozygote protection against P. falciparum
Australia: migrant populations; antenatal screening = FBE + MCV/MCH, then HPLC and partner testing

Aetiopathogenesis

Beta: >200 point/splice mutations (b0 = no chain, b+ = reduced chain)
Alpha: predominantly deletions of HBA1/HBA2
- Non-deletional mutations (e.g. Hb Constant Spring) are more severe than deletions of the same gene number

Core mechanism (beta)

dec beta chains -> dec HbA
Excess free alpha -> insoluble inclusions -> membrane oxidative damage
- -> intramedullary destruction of erythroid precursors = ineffective erythropoiesis
- -> reticulocyte count inappropriately low for the degree of anaemia
- + peripheral haemolysis + splenic sequestration

Downstream consequences

Marrow expansion - thalassaemia facies, cortical thinning, fracture, extramedullary haematopoiesis (paraspinal masses, cord compression)
Iron loading without transfusion
- inc erythroferrone -> dec hepcidin -> inc ferroportin -> inc duodenal iron absorption
- Explains iron overload in never-transfused NTDT
Hypercoagulability - phosphatidylserine exposed on damaged RBC membranes, activated platelets, endothelial activation

Alpha-specific

HbH = beta4 tetramer: no haem-haem cooperativity, very high O2 affinity, does not unload
- Subtract the HbH fraction from total Hb to estimate "effective" Hb
Hb Bart's = gamma4, same problem in utero
Alpha chains are required for HbF -> severe alpha-thal manifests before birth
- Beta-thal spared in utero, declares at the HbF -> HbA switch (6-12 months)

Diagnosis

Screening FBE

Low MCV/MCH with normal or high RBC count, anaemia milder than the indices suggest
- Mentzer index (MCV/RBC) <13 favours thal, >13 favours IDA
Film: microcytosis, hypochromia, target cells, basophilic stippling
*Exclude iron deficiency first - it lowers HbA2 and can mask beta-trait*

HPLC / electrophoresis

	HbA2	HbF	Other
Beta-trait	inc >3.5%	Mildly inc	No abnormal band
Beta-major	inc	inc, dominant	HbA absent/minimal
Alpha-trait (1-2 genes)	Normal	Normal	Nothing to find - missed on standard screening
HbH disease	Normal/low	Normal	Fast-moving HbH band

HbH inclusion bodies: brilliant cresyl blue supravital stain ("golf balls")
Alpha-globin genotyping (gap-PCR / MLPA) required where microcytosis + iron replete + normal HPLC

Iron overload assessment

Test	Use
Ferritin	Trend only. Acute-phase reactant, distorted by inflammation and liver disease - poor guide to cardiac iron
*Liver R2/T2\ MRI (FerriScan)**	LIC - best proxy for total body iron; high values track fibrosis and prognosis
Cardiac T2\*	<20 ms = myocardial iron; <10 ms = severe, high risk of LV dysfunction

Annual surveillance (TDT)

Growth/puberty, TFT, OGTT, Ca/PTH/vit D, DEXA, echo, LFT, viral serology

Management

A. Transfusion-dependent (TDT)

Hypertransfusion - pre-transfusion Hb target 90-100 g/L
- Suppresses erythropoietic drive -> prevents facies, marrow expansion, extramedullary haematopoiesis
- Extended phenotype-matched (Rh + Kell) red cells from the first transfusion -> dec alloimmunisation
Chelation - start after ~10-20 transfusions or ferritin >1000 microg/L

Agent	Route	Key points
Deferasirox	Oral daily	Usual first-line. Renal impairment, GI upset, GI haemorrhage, hepatic
Deferiprone	Oral tds	Best cardiac iron removal; combine with DFO for severe cardiac load. Agranulocytosis 1-2% - weekly FBE, arthralgia
Desferrioxamine	SC/IV infusion 8-12 h, 5-7 nights/wk	1:1 binding. Ototoxicity, retinopathy, metaphyseal dysplasia, Yersinia

Targets: ferritin <1000 microg/L, cardiac T2\* >20 ms
- Ferritin <1000 -> lower morbidity/mortality; >2500 -> inc cardiac and endocrine disease
- Over-chelation is toxic - reduce dose as iron falls
Luspatercept - TGF-beta superfamily ligand trap, promotes late-stage erythroid maturation
- dec transfusion burden; for TDT inadequately controlled on transfusion alone
Curative
- Allo-HSCT - best outcome if young, matched sibling, low Pesaro risk
- Gene therapy: betibeglogene autotemcel (beta-globin gene addition), exagamglogene autotemcel (CRISPR BCL11A -> reinduce HbF)
  - Transfusion independence in the majority; myeloablative busulfan conditioning; access and cost limiting
Splenectomy - now largely avoided; only if RBC requirement >200-250 mL/kg/yr
- inc thrombosis + encapsulated organism sepsis - vaccinate, penicillin prophylaxis

B. Non-transfusion-dependent (intermedia, HbH)

Managed by complication, not by protocol

Iron overload - chelate even if never transfused (gut absorption)
Extramedullary haematopoiesis / bone disease - transfusion, hydroxyurea (inc HbF), radiotherapy if cord compression
Leg ulcers - transfusion, zinc, hyperbaric O2, antibiotics, surgery
Splenomegaly - splenectomy last resort (thrombophilia)
Pulmonary hypertension, high-output cardiac failure
Folate replacement; *do not give iron* unless deficiency proven
Mitapivat (oral PK activator) - phase 3 positive in NTDT and TDT

C. All patients

Fever on a chelator = Yersinia enterocolitica until excluded - stop chelator, cover (cipro/3rd-gen ceph)
Osteoporosis - Ca/vit D, treat hypogonadism, bisphosphonate
Endocrine replacement: sex steroids, thyroxine, insulin
Iron cardiomyopathy -> intensive combination chelation + standard HF therapy
HCV - cure with DAA (historical transfusion cohort)
Preconception: partner screening, prenatal diagnosis / PGD offered

Associations

Heterozygote protection against falciparum malaria
Co-inherited structural variants: HbE/beta-thal (severe, commonest TDT genotype in SE Asia), HbS/beta-thal (sickling phenotype)
Red cell alloimmunisation, febrile and allergic transfusion reactions
Transfusion-transmitted HCV/HBV in pre-1990 cohorts
Pigment gallstones, cholecystitis
Gilbert syndrome co-inheritance -> higher bilirubin, more gallstones
Hypercoagulability - marked after splenectomy

Natural history & complications

Untreated beta-major: death in childhood from anaemia and cardiac failure
Well transfused + chelated: survival now into the 5th-6th decade

Two different complication phenotypes

Under-transfused -> erythroid drive: facies, pathological fracture, extramedullary masses, cachexia, hepatosplenomegaly
Adequately transfused -> iron: cardiac, endocrine, hepatic, renal (free haem)

Iron overload

Iron cardiomyopathy is the leading cause of death
- Restrictive then dilated; arrhythmia
- Reversible with intensive chelation if detected on T2\ before LV dysfunction*
Endocrine (iron is pituitary- and pancreas-avid): hypogonadotrophic hypogonadism commonest, then DM, hypothyroidism, hypoparathyroidism, short stature
Liver: fibrosis -> cirrhosis; HCC risk persists after HCV cure
Osteopenia/osteoporosis - marrow expansion + hypogonadism + chelator toxicity

Other

VTE and arterial thrombosis; silent cerebral infarcts in NTDT
Pulmonary hypertension - commoner in NTDT and post-splenectomy
Trait: normal life expectancy, not a cause of symptomatic anaemia
- Do not treat with iron - look for a second cause if symptomatic

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