APPROACH TO THALASSEMIA MAJOR

•	Pathophysiology.
•	Complications.
•	History.
•	Clinical examination.
•	Investigations.
•	Management

Pathophysiology

1.	Genetics

a.	The beta-globin gene is located on chromosome 11.

b.	The molecular defect includes gene deletion and substitution resulting in decreased or complete absence of beta-chain production.

c.	Autosomal recessive mode of inheritance.

2.	Cellular pathophysiology

a.	Normal synthesis of the -globin chain leading to accumulation of unstable aggregates within the RBCs, resulting in ineffective erythropoiesis and hemolysis. 

b.	Alpha chains accumulating in the red cell precursors are insoluble, precipitate in the cell and interact with the membrane causing significant damage.

c.	This leads to excessive intramedullary destruction of the red cell precursors.

d.	In addition, the surviving cells arriving in the peripheral blood with intracellular inclusion bodies are subject to hemolysis. 
Complications

1.	Anemia

a.	Pallor.

b.	Lethargy and reduced effort tolerance.

c.	Dyspnoea and exercise intolerance.

d.	Palpitations and cardiac failure in severe cases.

2.	Excessive erythropoiesis

a.	Bony changes to face:

i.	maxillary overgrowth.

ii.	protrusion of teeth.

iii.	separation of orbits.

iv.	frontal bossing.

v.	chronic sinusitis.

vi.	impaired hearing.

b.	Orthopaedic:

i.	cortical thinning and risk of fractures.

ii.	spinal cord compression (vertebral expansion).

c.	Lymphadenopathy (especially mediastinal).

d.	Hepatosplenomegaly.

3.	The ineffective erythropoiesis also creates a state of hypermetabolism associated with fever and failure to thrive.

4.	Iron overload is one of the major causes of morbidity: 

a.	Causes:

i.	heavy iron turnover in transfused blood.

ii.	increased iron absorption.

b.	Pathophysiology: deposition of iron in the major organs and endocrine organs of the body.

5.	Endocrine failure

a.	Short stature:

i.	growth is usually normal until 12 years, but no pubertal spurt occurs.

ii.	possible pituitary or hypothalamic defect.

b.	Delayed puberty.

c.	Estrogen and testosterone deficiency.

d.	Hypothyroidism.

e.	Diabetes mellitus.

f.	Hypoparathyroidism.

6.	Cardiac complications

a.	Cardiomyopathy.

b.	Pericarditis.

c.	Arrhythmias.

d.	Congestive cardiac failure. 

7.	Hepatic complications

a.	Cirrhosis and hepatic fibrosis.

b.	Gallstones present in 50 – 70% of patients by 15 years of age.

c.	Increased risk of Yersinia infection which can mimic appendicitis. 

History

1.	Present complaint: reason for current admission.

2.	Past history

a.	Ethnic origin.

b.	Diagnosis: age, where, how.

c.	Age at first transfusion and commence of desferrioxamine.

d.	Number of transfusions per year.

e.	Previous hospitalizations and surgery.

f.	Medications given and current management plan.

3.	Status of complications

a.	Anaemia.

b.	Excessive erythropoiesis.

c.	Iron overload.

4.	Family history

a.	Consanguinity of parents.

b.	Other affected members.

c.	Neonatal deaths in family.

d.	Plans for further children.

e.	Genetic counseling.

5.	Social history

a.	Disease impact on patient: behavior, school performance, amount of school missed, self-image, pubertal anxieties, peer group anxieties.

b.	Disease impact on parents: marriage stability, financial considerations.

c.	Disease impact on siblings.

d.	Social supports.

e.	Coping: compliance, degree of self-management, perception of disease and future plans. 

Clinical Examination

1.	Position patient: standing, fully undressed, then lying.

2.	Parameters: height, weight and percentiles.

3.	General Inspection

a.	Vital signs:

i.	comfortable and well: after PCT?

ii.	breathless and pale: before PCT?

iii.	febrile and toxic: infection.

b.	Color of skin:

i.	pigmentation: bronzing.

ii.	pallor.

iii.	jaundice.

c.	Facial features:

i.	frontal bossing.

ii.	chipmunk facies.

iii.	maxillary overgrowth.

iv.	dental malocclusion.

v.	prominent malar eminence.

vi.	broadened nasal bridge.

vii.	mongoloid eye slant.

viii.	epicanthic folds. 

4.	Hands

a.	Fingertip pricks.

b.	Palmar creases.

c.	Peripheral stigmata of CLD.

5.	Head and neck

a.	Eyes:

i.	conjunctival pallor.

ii.	scleral icterus.

iii.	cataracts (DFO).

iv.	retinopathy (DFO).

v.	eyeball bruit. 

b.	Teeth: dental malocclusion.

c.	Mouth: mucosal ulcers. 

d.	Neck: goitre (hypothyroidism).

6.	Chest

a.	Cardiomyopathy: displaced apex beat.

b.	CCF.

c.	Hemic murmur: severity of anemia.

d.	Lungs: pulmonary edema.

7.	Abdomen

a.	Distension.

b.	Palpable liver and spleen.

c.	Splenectomy scars.

d.	Injection sites: DFO, insulin.

e.	Tanner staging.

8.	Lower limbs and gait

a.	Malleolar ulcers.

b.	Ankle edema.

c.	Bony tenderness.

d.	Gait: long tract signs.

e.	Delayed ankle jerk relaxation.

f.	Back examination: lordosis, tenderness.

9.	Other

a.	Urinalysis for glucose.

b.	Chovostek’s and Trousseau’s signs (hypoparathyroidism).

c.	Hearing (sensorineural deafness from DFO).

10.	Presentation

a.	Features of thalassemia.

b.	Assess complications. 

Investigations

1.	Aims

a.	Confirm diagnosis.

b.	Assess complications.

2.	Full blood count

a.	Hb: ranges from 2 – 8 g/dL.

b.	MCV and MCH are usually low.

c.	WBC: for infection.

d.	Platelets: thrombocytopenia secondary to hypersplenism.

3.	Peripheral blood flim

a.	Microcytic hypochromic anemia.

b.	Target cells.

c.	Anisopoikilocytosis.

d.	Basophilic stippling.

e.	Fragmentation.

f.	Erythroblastosis. 

4.	Fe / TIBC / Ferritin: to exclude iron deficiency.

5.	Thalassemia screen

a.	Hemoglobin electrophoresis:

i.	HbF: 70 – 90%.

ii.	HbA2: 2%.

iii.	HbA: 0 – 20%.

b.	Hb inclusion bodies: negative.

c.	Osmotic fragility: resistant.

d.	Glycerol lysis: prolonged. 

6.	Other blood tests

a.	U&E: decreased calcium and phosphate levels.

b.	BSL: for DM.

c.	LFT: for liver cirrhosis.

7.	Imaging studies

a.	Skull X-ray: ‘hair on end’ appearance of the skull.

b.	Chest X-ray: evaluate cardiac size and shape.

8.	ECG

a.	Ventricular hypertrophy.

b.	SVTs and other arrhythmias.

c.	Signs of cardiac failure. 

9.	Bone marrow aspiration

a.	Needed in initial diagnosis to exclude other conditions that may present as thalassemia major.

b.	Hyperactive marrow with erythroid hyperplasia. 

Management

1.	Blood transfusion

a.	Regimes:

i.	Supertransfusion: aim to achieve Hb > 12 g/dL.

ii.	Hypertransfusion: aim to achieve Hb > 10 g/dL.

b.	Regular transfusions every 4 – 6 weeks.

c.	Timing of first transfusion usually at hemoglobin < 6 g/dL.

d.	Use packed cells, fresh, white cell-poor, triple washed, or filtered red blood cells, negative for hepatitis B, C and HIV.

e.	Investigations:

i.	prior to treatment: study the case, do complete red cell typing: ABO, rhesus.

ii.	before each transfusion: cross match and test for atypical red cell antibodies in the serum; record the date of transfusions, amount of blood transfused and the pre-transfusion Hb.

iii.	after each transfusion: if feasible, measure the post-transfusion Hb (at 30 min or > after the end of transfusions).

f.	Cardiomyopathy or when Hb < 5 g/dL:

i.	frusemide 1 – 2 mg/kg.

ii.	use fresh blood.

iii.	do not transfuse more than 5 ml/kg of blood at one session.

iv.	do not transfuse faster than 2 mg/kg.

v.	use short intertransfusion intervals.

g.	If the child needs more frequent transfusions than previously:

i.	development of hypersplenism.

ii.	development of red cell antibodies.

iii.	concurrent gastrointestinal blood loss.

2.	Iron chelation therapy

a.	Principles:

i.	choice of agent is desferrioxamine which is not absorbed in the gut.

ii.	start when ferritin level is around 100 – 2000 ug/L.

iii.	dosage is 40 mg/kg subcutaneously over 8 – 10 hours, 5 days per week. 

b.	Side effects:

i.	local irritation.

ii.	hypotension.

iii.	vision: cataracts, night blindness, visual field defects, visual loss.

iv.	sensorineural deafness.

v.	bone abnormalities: pseudorickets.

vi.	altered renal function.

c.	Prechelation evaluation:

i.	bone X-rays.

ii.	ferritin level.

iii.	FBC.

iv.	LFT.

v.	thyroid function tests.

vi.	fasting BSL. 

d.	DPO treatment is suspended if the patient has sepsis as DFO promotes Yersinia enterocolitica gastroenteritis. 

3.	Splenectomy

a.	Indications:

i.	hypersplenism: increased transfusion requirements.

ii.	large spleen causing mechanical pain.

b.	Procedure:

i.	give anti-pneumococcal vaccine 4 – 6 weeks prior to splenectomy.

ii.	inform patients and their family of the increased risk of infections following splenectomy.

iii.	consider cholecystectomy (gallstones) and appendicectomy at the same time. 

c.	Give prophylactic penicillin for life.

d.	Infective episodes should be carefully observed and treated aggressively.

4.	Medications

a.	Vitamin C.

b.	Vitamin E.

c.	Folate.

5.	Immunization

a.	Hepatitis B.

b.	Pneumococcus.

c.	Meningococcus.

d.	Influenza.

6.	Bone marrow transplantation

a.	BMTx from an HLA identical sibling can cure beta-thalassemia.

b.	Risk factors:

i.	size of liver.

ii.	presence of liver fibrosis.

iii.	adherence to regular high-quality iron chelation.

c.	There is around a 90% event-free survival.

d.	Cord blood-derived stem cell transplantation: this requires cord blood collected from the patient’s sibling fetus, who is HLA-identical to the patient. 

7.	Prenatal diagnosis

a.	Detection of decrease in beta chains.

b.	Chronic villi sampling.

c.	Fetal blood sampling: method of choice at the moment. 

8.	Follow-up

a.	Check ferritin level every 3 – 6 months. 

b.	Every 6 months:

i.	Ca / PO.

ii.	LFT.

iii.	U&E.

iv.	thyroid function tests. 

c.	Every year:

i.	growth and pubertal status.

ii.	desferrioxamine toxicity.

iii.	cardiac assessment.

iv.	dental examination: antibiotic prophylaxis in dental procedures.