THALASSAEMIADr Foong Shing WeuMD UKM

INTRODUCTION Heritable, hypochromic anaemias-varying degrees of severity Originate from Greek language: ( Thalasso ), “sea” dan (Hemia) “blood”,

anemia Highest incident in countries around Mediterranean sea.

HAEMOGLOBIN Each complex consists of :

Four polypeptide chains, non-covalently bound Globins

Alpha family on chromosome 16 141 amino acids

Beta family on chromosome 11 146 amino acids

Heme Porphyrin ring and Fe

Defective synthesis of one or more globin chains results in Thalassaemia In Malaysia, the most common types are α and β thalassaemias The β thalassaemias together with its heterogenous interactions with HbE

disease constitute the bulk of patient’s load

VARYING SEVERITY These diseases form a spectrum, with 1 end being non–transfusion-

dependent Early recognition is vital to prevent placing children on lifelong transfusion

therapy

• Presentation at younger ages• Transfusion dependency

• Completely asymptomatic until adult life• Non–transfusion-dependent

SevereMild

Taher A, et al. Br J Haematol. 2011;152:512-523.

STATISTIC 2013 ACCORDING TO STATES AND RACES IN

MALAYSIA

NEGERI BILANGAN PESAKIT1 SABAH 15062 SELANGOR 7093 KUALA LUMPUR 5684 KEDAH 5415 JOHOR 4146 PERAK 3657 PULAU PENANG 3538 KELANTAN 3509 PAHANG 26310 TEERENGGANU 18811 MELAKA 17412 SARAWAK 15813 NEGERI SEMBILAN 13614 PERLIS 10915 LABUAN 1416 PUTRAJAYA 11

70%: Melayu 15%: Kadazan 14%: Cina 1%: India

Lelaki : 48.4% Perempuan: 51.6 %

CLINICAL DIAGNOSIS Thalassaemia major usually presents at 4-6 months / younger than 2 years

old

Anaemia Hepatosplenomegaly Jaundice Thalassaemia facies Growth failure/retardation

Thalassaemia intermedia presents at later age

Milder anemia Extensive thalassaemia facies Hepatosplenomegaly

LABORATORY DIAGNOSIS Screening test FBC

MCV (mean corpuscular volume) < 80 fl MCH (mean corpuscular haemoglobin) < 27 pg MCH more preferable – less susceptible to storage changes

RDW (red cell distribution width) – measure the degree of variation in red cell size IDA is characterized by increase in RDW Thalassaemia produce a uniform microcytic RBC – RDW not increase

Diagnostic test High Performance Liquid Chromatography (HPLC)

Quantification of HbA2 and HbF And identification and quantification of variant haemoglobin

β thalassaemia trait/intermedia- (heterozygous β° or severe βᶧ)- HbA2 usually 4 - 9%

Mild βᶧ thalassaemia HbA2 usually 3.6-4.2 % If HbA2 normal, ferritin normal- possible α thalassaemia- DNA analysis

HbA2 falsely lowered by low ferritin- thus IDA needs to be corrected first

Other useful haematological test

PBF Hb electrophoresis H-inclusion test

THALASSAEMIA MAJOR β thalassaemia Major - Homozygous β° (β° / β°), or with minimal HbA

synthesis (β°/ βᶧ)

Severe anemia (Hb< 7g/dl) RBC low, MCV low (<60 fl), MCH ( < 18 pg), MCHC reduced PBF- anisocytosis, poikilocytosis, hypochromia, microcyctic, fragments and

tear drop cells. Basophilic stippling and target cells HbF > 90% Complete absent of HbA indicates homozygous β° (β° / β°)

Thalassemia Blood Smears

Thalassaemia Intermedia

Anemia is moderate (8-10 g/dL) PBF- milder thalassaemia picture HbA2 with or without HbF elevation

DNA analysis Indications:

Inability to confirm a haemoglobinopathy by haematological tests Carriers of silent β thalassaemia or normal HbA2 β thalassaemia , α° thalassaemia and some αᶧ

thalassaemia Post transfusion / regular transfusion

Genetic counselling and prenatal diagnosis

MANAGEMENT AIM- suppress extramedullary haemopoiesis while minimizing

complications of under transfusion and maintaining normal well being Decision to start transfusion should be individualized after proper

assessment Started promptly when there is a clinical evidence of severe anemia

Cardiac failure, failure to thrive, and or/thalassaemia bone deformity

Pre-transfusion Phenotyped for ABO, Rh, Kell, Kidd, Duffy and MNs HBs surface antigen (HBsAg), Hepatitis C (Anti HCV), and HIV antibody (Anti HIV)

Regime Patient should be monitored closely (2weekly) to ascertain ability to maintain Hb

> 7 g/dL If unable to maintain/indications- transfuse Pre-transfusion Hb maintain at 9-10 g/dL - provide adequate extramedullary

suppression, allowing reduction of blood consumption and reduce excessive iron absorption from gut

Post transfusion should be 13.5-15.5 g/dL FBC should be taken at least 1 hour post transfusion Volume: 15-20 mls/kg (depending on pre-transfusion Hb and haematocrit of

packed cells) Preferably to use whole bag

Whenever possible, blood less than 14 days should be given Leucoreduced blood should be given to all thalassaemia patients

Thalassaemia Intermedia Regular transfusion is indicated when there is growth failure, bone deformities, or

extramedullary massed such as paraspinal Regime similar to thal major

EXPECTED HB RISE WITH HAEMATOCRIT LEVELS

Transfusion volume = weight (kg) x increment in Hb (g/dL) x 3 (hematocrit [Hct] level of RBCs) Important formula:

For patient weighing 20 kg, 360mls transfusion every 4 weeks; average Hct 60% Annual blood requirement = 13 transfusion X 360 mls / 20 kg = 234

ml/kg/yr Annual pure RBC requirement = 234 X 60% = 140.4 ml/kg/yr

NORMAL TRANSFUSION REQUIREMENT = 180 mls/kg/yr pure RBC

SPLENECTOMY Consider

Increase transfusion requirement 1.5 times than usual, or exceeding 200-250 ml/kg/year of pure RBC

Evidence of hypersplenism- splenomegaly with persistent leucopenia OR thrombocytopenia

Massive splenomegaly causing discomfort and risk of infarct or rupture from trauma Complications

Sepsis OPSI – mortality 39-69% Usually from encapsulated organism; Streptococcus pneumonia, Haemophilus, Nisseria Immunized – 23-valent polysaccharide + HIB vaccine 2 weeks before, meningococcal in

endemic area Life-long post splenectomy chemoprophylaxis- IM Benzathine penicillin 3-4 weekly or oral

Penicillin V

Thrombotic risk Risk increased in thalassaemia intermedia (4-10%) than thalassaemia major (0.9-4%). Post splenectomy, risk increased up to 30% Short term anti-coagulation may be indicated during periods of increased risk e.g

immobilization and post-surgery

Thrombocytosis Consider use of low dose Aspirin or dypyridamole if platelet count > 800 x 109 /L.

ASSESMENT OF IRON BURDEN Monthly packed RBC transfusion- iron intake 0.3-0.5 mg/kg/day Around 10-20 transfusion, most patients will have serum level exceeding

1000 µg/L Warrant iron chelation therapy

Serum ferritin Correlated with number of transfusion received Important to monitor trend There are limitations on SF measurement and they may not accurately reflect

total body iron stores, e.g. may have low SF level for years but severe myocardial siderosis

MRI Direct quantitative methods that use MRI T2*, T2 or R2, R2*

Liver iron concentration (LIC) Constant fraction of total body iron Measured by liver biopsy Invasive and may be affected by sampling error e.g. cirrhosis and hepatits

COMPLICATIONS Endocrine complications

Short stature & growth failure Delayed puberty and hypogonadism Hypothyroidism Osteoporosis/osteopaenia Hypoparathyroidism

Cardiac complications Cardiac siderosis

Infection Hepatitis B Hepatitis C HIV infection

Bacterial infection Apart of iron overload, infection is the main cause of death in TDTD Risk factor for severe infections

Post-splenectomy Previous history of meliodosis Iron overload

Klebsiella spp in Asia, Yersinia enterocolitica in western countriesVento S. Cainelli, Caesario F

Meliodosis, Pseudomonas

IRON CHELATION THERAPY Treatment for iron overload in blood transfusion dependent thalassaemia Serum ferritin should be kept below 1000 µg/L as is it associated with less

iron overload complications Serum ferritin level less than 2500 µg/L significantly improve cardiac

disease free survival LIC be kept 3-7 mg Fe / g DW and cardiac MRI T2* > 20 ms

DESFERRIOXAMINE (DFO) Standard treatment- slow subcutaneous infusion over at least 8 hours per

night for 5 nights per week Dose – 20-40 mg/kg/day (children) and may be increased up to 50-60

mg/kg/day (adults) Use with caution in children under 3 years old in view of its potential

toxicity to bone development and growth Poor compliance ( 59-78 %) due to tedious and unpleasant subcutaneous

drug regime Can also be used as rescue therapy in patient with acute cardiac problems-

reverse cardiomyopathy

MONITORING Auditory/eye assessment annually If high fever, should be stopped immediately

DEFERIPRONE (DFP) Dose- 75 mg/kg/day divided to tds dosing Effective in children > 6 years old Compliance – 79-98%

MONITORING FBC and differentials weekly ALT 3 monthly

Risk oof agranulocytosis

DEFERASIROX (DFX) Used in children > 2 years old Dose 20-40 mg/kg/day taken with stomach empty

MONITORING Serum creatinine, ALT, proteinuria monthly Auditory and eye assessment annually

WHEN TO START IRON CHELATION?? All patients with iron overload (SF > 1000 µg/L on 2 occasions in at least 2

weeks apart)

HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) HSCT from HLA identifcal family donors is an established curative treatment options 3 patient classes identified on following risk factors

Inadequate iron chelation Presence of liver fibrosis Hepatomegaly

Class I - non of the above Probabilities of survival = 93% and disease free = 91% Risk of rejection = 2% and risk of transplant-related mortality = 8%

Class II – having one or two Probabilities of survival = 87% and disease free = 83% Risk of rejection = 3% and risk of transplant-related mortality = 15%

Class III – having all three characteristics Probabilities of survival = 79% and disease free = 58% Risk of rejection = 28%

Should be consider at an early age/ before complications of iron overload have developed

HLA-matched sibling donors

NUTRITION AND SUPPLEMENTS Vitamin E Vitamin C Folic acid

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