THALASSAEMIA

DR WAN HANIFAH BT WAN HUSSIN PAEDIATRICS

introduction

Thallassaemia syndromes :
Inherited disorders of Hb production Characterized by reduction in globin synthesis

and thalassaemias are due to decrease or completely absent producton of globin chains Most common inherited single gene disorders, with highest prevalence in areas where malaria has been or remains endemic

Beta thalassaemia

Beta thalassaemia trait

Normal features with no health problems

Thalassaemia intermedia HbE-beta thalassaemia Beta thalassaemia major

Alpha thalassaemia

thalassaemia trait (one gene deletion)

Detected at birth by presence of Hb Bart

thalassaemia trait (2 gene deletion)

Low MCH and/or MCV Normal/reduced HbA2 HbH inclusion present

HbH disease (3 gene deletion)

More HbH inclusion

Pathophysiology of thalassaemia

Reduced lifespan of red blood cells Anemia Red blood cells undergo hemolysis (destruction) Jaundice Active but ineffective erythropoiesis (formation of red blood cells) Medullary (bone marrow) expansion Extra-medullary (hepatosplenomegaly) Blood transfusions leading to Iron overload Tranfusions-related infections Iron overload Organ damage and dysfunction

Clinical features

Anemia Facial deformity frontal bossing, maxillary hypoplasia Hypersplenism thrombocytopenia, leucopenia Pathological fracture extramedullary hematopoiesis (bone marrow expansion) Increased pigmentation and darkening of skin Skin ulcers

Clinical features

Pituitary gland short stature, delayed puberty, hypothyroidism Hypoparathyroidism Cardiomyopathy heart failure Liver fibrosis Pancreas diabetes mellitus Osteoporosis

Treatment of thalassaemia

Blood transfusion Iron chelation Splenectomy Folate supplement

General management

Vaccinations

As per normal individuals

May have problems of malocclusion and other dental problems due to maxillary hyperplasia Avoid foods rich in iron Strictly no iron supplements! Adequate calcium intake (supplements only if indicated) Folate Vitamin C (only taken with iron chelation) Vitamin E (adequate intake) Zinc (if levels are low and require monitoring)

Dental hygiene and care

Nutrition and diet

General management

Travelling

Take medical insurance Arrange for access to transfusion facility Precautions for infections (e.g. vaccinations) Continue with chelation
Should be encouraged with individual limits Caution if theres massive splenomegaly, heart disease, or osteoporosis Worsens lung dysfunction and osteoporosis Worsens iron damage to the liver and hepatitis

Physical activity

Smoking

Alcohol

When to start transfusion in Thal major

Inability to maintain Hb > 7 g/dl on 2 occasion, more than 2 weeks apart Hb > 7 g/dl with
Poor growth Extramedullary hematopoiesis

When to start transfusion in HbE-Beta

Inability to maintain Hb > 7 g/dl on 2 occasion, more than 2 weeks apart Failure to thrive Significant extramedullary hematopoiesis
Bony deformities Enlarging spleen Extramedullary masses

Pre transfusion investigations

Full phenotyping for ABO, Rh, Kell, Kidd, Duffy, MNS before first transfusion Screening for Viral markers before first transfusion and every 6 months
HBsAg AntiHCV AntiHIV

TRANSFUSION PROTOCOL

Pre transfusion Hb : 9-10 gm/dL

This value would allow a reduction of blood consumption and reduce excessive iron absorption from gut

Post transfusion Hb : 13.5-15 gm/dL

Avoid overtransfusion Taken 1 hour post completion of transfusion

TRANSFUSION PROTOCOL

Interval of transfusion

Depending on requirement of patient

Usually 2-4 weeks Hb fall by approximately 1 gm/dL each week

Depending on post transfusion Hb

11.5-12 g/dL : see in 2 weeks 12.5-13 g/dL : 3 weeks 13.5-14 g/dL : 4 weeks 14.5-15 g/dL : 5 weeks

TRANSFUSION PROTOCOL

Age of blood transfused

Less than 2 weeks old (preferably as fresh as possible) 2,3 DPG affect the ability of RBC to release oxygen, after 2 weeks, level falls by > 50% Older blood accelerates fall of Hb

TRANSFUSION PROTOCOL

Transfusion volume

15-120 mls/kg, not more than 2 units/day

Transfusion rate
Over 4 hours (5 ml/kg/hr) If in heart failure or Hb < 5 gm/dL, administer slower 2 mls/kg/hr or in smaller quantity to avoid worsening heart failure from circulatory overload

TYPE OF BLOOD

Blood must be compatible

Antigen matched blood for ABO and Rh blood Antigen negative blood for defined antibody should be given

Leucoreduced blood

Filtration
Bedside Blood bank

Complications - early

Acute hemolysis Febrile reactions Allergic reaction Bacterial contamination of blood Transfusion related Acute Lung Injury (TRALI)

Complications - early

Acute hemolysis
Rare, 1:38 000 1st few minutes into transfusion Almost always due to major ABO incompatibility Due to misidentification of intended recipient or mislabelling of specimen Can be prevented if blood transfusion guidelines stringently followed

Complications - early

Febrile reactions

11 in 100 to 500 transfusion Not life threatening, end or few hours after completing transfusion Tx : PCM Prevention : prestorage leucoreduction
Most common 1 in 100 to 250 transfusion Not life threatening, occurs during transfusion Due to soluble plasma proteins Recurrent episodes :premedicate with chlorpheniramine

Allergic reactions

Complications - early

Bacterial contamination of blood

1 in 100 to 15 000 Cause : donor bacteremia, skin contamination, contamination during processing of blood bags Severity depends on organisms, Gm negative more severe Other org : Coagulase ve staph, Yersinia, High fever, chills, hypotension during transfusion Prevention : vigilant donor screening, proper skin decontamination

Complications - early

Transfusion related Acute Lung Injury (TRALI)

1 in 10 000 Syndrome similar to ARDS 1-6 hrs after transfusion Fever , hypotension, severe hypoxaemia, pulmonary infiltrates on CXR Improve after 2-3 days with aggressive respiratory support

ASSESSMENT OF IRON OVERLOAD

1. Serum markers

2. Liver Iron

Ferritin Iron, iron binding capacity Transferrin saturation Nontransferrin bound iron

Biopsy SQUID CT MRI

3. Cardiac T2 (MRI)

IRON CHELATORS

Monotherapy
Desferioxamine Deferiprone(L1) Deferasirox (Exjade)

Combination therapy
DFO + DFP ?DFO + DFX ?DFP + DFX ?DFO + DFP + DFX

Comparison of iron chelators

property Dose (mg/kg/d) DFO 25-60 Deferiprone 75 Deferasirox 20-30

Route
Half life Excretion Adverse effects

Sc, iv (8-12 hours, 5-6 days/week)

20-30 min Urinary, fecal local reactions, opthalmologic, auditory, growth retardation, allergic

Oral 3 times daily

3-4 hours Urinary

Oral Once daily

12-16 hours Fecal

GIT disturbances, GIT disturbances, agranulocytosis/neu rash, mild nontropenia, arthralgia progressive serum creatinine rise, auditory, opthalmologic FBC weekly Se creatinine monthly

Monitor

growth

In the optimal setting

Start monotherapy as soon as it is necessary Maintain iron as near normal as possible Monitor for side effects Modify dose or use alternative chelator/s

Optimal chelation
Start iron chelation therapy if serum ferritin > 1000 ug/ml

MONOTHERAPPY DFO @ DFX @ DFP

Adequate chelation Se ferritin < 2500 ug/ml T2 heart > 20 ms LIC < 7 mgFe/gm DW

Inadequate chelation Se ferritin > 2500 ug/ml T2 heart < 20 ms LIC > 7 mg Fe/gm DW

Continue current iron chelator and aim for se ferritin < 1000 ug/ml

CHECK COMPLIANCE OPTIMISE MONOTHERAPY CONSIDER COMBINATION

splenectomy

Increased in annual transfusion requirements

Patients requiring >200-220 mls/kg/year of packed red cells Especially if iron overload is also a major problem Usually taken as >5cm Especially accompanied by symptoms of left upper quadrant pain
Presence of leucopenia or thrombocytopenia

Splenic enlargement

Hypersplenism

splenectomy

Timing

Usually delayed until patients are at least 5 years of age (due to risk of infection if done before this age)

Surgical approach
Open or laparoscopic Total or partial (rarely done)

splenectomy

Post-operative complications

Thrombocytosis

If >800,000/mm3, will need low-dose aspirin

Overwhelming sepsis

Risk higher in those < 2 years of age, and during 1-4 years post surgery, and those with poor immune status

Immunoprotective and preventive measures

Meningococcal, Pneumococcal vaccine and Hib vaccines Oral penicillin

Management of specific complications

Iron overload

Iron chelation Anti-failure drugs Intensive chelation

Cardiac failure due to cardiomyopathy

24-hours IV infusion of desferrioxamine Combination treatment with oral chelator

Osteoporosis and osteopenia

Calcium and Vitamin D Biphosphonates (may be useful) Lamivudine (Hepatitis B) Pegylated-interferon and Ribavirin (Hepatitis C)

Hepatitis

Management of specific complications

Delayed puberty

Ethinyl estradiol Testosterone

Ensure optimal Hb level Treat folate deficiency Thyroxine Diet and weight reduction Insulin

Short stature

Hypothyroidism

Diabetes

THALASSAEMIA INTERMEDIA

Patients with TI suffer various complications that are uncommon in Thal Major patients which includes :

Folic acid deficiencies Gallstones Leg ulcers Pulmonary hypertension Pregnancy & infertility Thrombosis Extramedullary hematopoiesis

Other options

Prevent thalassaemia births Invest in Preimplantation Genetic Diagnosis (PGD) In-vivo fertilisation Micro-biopsy technique Molecular diagnosis on single cell Polar body biopsy Revisit selective abortion option Current local Fatwa prohibits abortion of affected fetus unless life or health of the mother is severely compromised

Other options

Investment in research Find a Cure for Thalassaemia Gene therapy stem cell research BMT/Stem Cell Transplant Explore alternative stem cell sources Unrelated cord blood Haploidentical donors Minimise mortality & morbidity Reduce graft rejection Hb F induction