Pearls of guidelines for the management of transfusion dependent thalassaemia

1. Pearls of
GUIDELINES FOR THE MANAGEMENT OF
TRANSFUSION DEPENDENT THALASSAEMIA
DR. KHAZA AMIRUL ISLAM
RESIDENT,PHASE-B
DEPARTMENT OF HAEMATOLOGY,BSMMU

2. Whom to Transfuse
1. Confirmed diagnosis of thalassaemia.
2. Laboratory criteria:
Haemoglobin level (Hb) <7 g/dl on 2 occasions, > 2 weeks apart (excluding all other
contributory causes such as infections)
3. Clinical criteria irrespective of haemoglobin level:
Haemoglobin > 7 g/dl with any of the following:
> Facial changes
> Poor growth
> Fractures
> Clinically significant extramedullary haematopoiesis

3. Compatibility Testing
Development of one or more specific red cell antibodies (alloimmunisation) is an important
complication of chronic transfusion therapy .
It is recommended that:
• Before embarking on transfusion therapy, patients should have extended red cell antigen
typing that includes at least C, c, D, E, e, and Kell, (though preferably a full red cell
phenotype/genotype panel) in order to help identify and characterise antibodies in case of
later immunization.
• If the patient is already transfused, antigen typing can be performed using molecular
rather than serologic testing.
• All patients with thalassaemia should be transfused with ABO and Rh(C, c, D, E, e) and
Kell compatible blood in order to avoid alloimmunisation against these antigens.

4. Terget pre-transfusion haemoglobin level
The recommended treatment for thalassaemia major involves lifelong regular
blood transfusions, usually administered every two to five weeks, to maintain
the pre-transfusion haemoglobin level above 9-10.5 g/dl.
This transfusion regimen
◦ promotes normal growth
◦ allows normal physical activities
◦ adequately suppresses bone marrow activity in most patients
◦ minimises transfusional iron accumulation
A higher target pre-transfusion haemoglobin level of 11-12 g/dl may be appropriate for patients with
◦ heart disease,
◦ clinically significant extramedullary haematopoeisis or other medical conditions, and
◦ for those patients who do not achieve adequate suppression of bone marrow activity at the lower
haemoglobin level.

5. (Desired – actual Hb) x weight x 3/haematocrit of transfused
unit = ml to be transfused

6. Terget post-transfusion haemoglobin
level
The post-transfusion haemoglobin should not be greater than 14-15 g/dl as
higher post transfusion haemoglobin values risk hyperviscocity and stroke.
Post transfusion haemoglobin should be measured occasionally to assess the
rate of fall in the haemoglobin level between transfusions.
This decline may be helpful in evaluating the effects of changes in the
transfusion regimen, the degree of hypersplenism, or unexplained changes in
response to transfusion.

7. Thus the currently accepted
Pre-transfusion haemoglobin of 9.0-10.5 g/dl.
post-transfusion haemoglobin of 14-15 g/dl
 mean target is 12 g/dl
This overall approach to transfusion has been shown to
promote normal growth
allow normal physical activities
adequately suppress bone marrow activity

10. Use with vitamin C during chelation
Vitamin C increases iron excretion by increasing the availability of chelatable
iron, but if given in excessive doses may increase the toxicity of iron.
It is recommended not to give more than 2-3 mg/kg/day as supplements,
taken at the time of the DFO infusion so that liberated iron is rapidly chelated

11. CARDIAC COMPLICATIONS IN THALASSAEMIA MAJOR
Cardiovascular complications of thalassaemia can be considered in two major clinical categories:
1. Iron overload complications
a. Reversible myocyte failure.
b. Arrhythmia, including heart block.
c. Arterial changes - loss of vascular compliance.
2. Non-iron overload complications
a. Pulmonary hypertension.
b. Arrhythmia – particularly Atrial Fibrillation (AF) later in life.
c. Thrombotic stroke, linked to AF.
d. Cardiac function changes due to restriction / diastolic dysfunction / fibrosis.
e. Arterial changes - loss of vascular compliance.

12. Recommendations for cardiac disease
Thalassaemia major patients with heart failure should be managed at (or in close
consultation with) a tertiary center experienced in thalassaemia (C).
Combined therapy with deferoxamine and deferiprone represent the best available intensive
chelation for thalassaemia major patients with severe cardiac iron deposition, with or without
over heart failure (B).
Lifestyle choices that promote vascular health (absence of smoking, regular physical activity,
weight control, vegetable and nitrate rich diet) should be vigorously promoted in thalassaemia
patients (C).

13. Liver disease
Hepatic iron overload
Chronic Hepatitis C
Chronic Hepatitis B
Non Alcoholic Fatty Liver Disease

14. Recommendation for liver disease
Hepatic iron excess should be evaluated using a non-invasive strategy based on combined
serum ferritin values and MRI data. Liver biopsy is often not necessary.
Serum ferritin interpretation should be rigorous, excluding causes of false positive results
such as inflammation, cytolysis, dysmetabolism and alcoholism.
Reversal of hepatic iron excess is a key objective not only to protect the liver but also the
rest of the body.
Deferasirox is effective in producing a negative iron balance and decreasing hepatic
damage.
Diagnosis and treatment of HCV and/or HBV chronic hepatitis remain important.

15. Indications for Splenectomy

17. Concomitant other surgery during
Splenectomy
An evaluation for gallstones should be performed prior to surgery, especially if
the patient has experienced symptoms suggestive of biliary tract disease. In
some cases, positive findings will lead to cholecystectomy at the same time as
splenectomy.
Removal of the appendix at the time of splenectomy may prevent later
problems in distinguishing infection with Yersinia enterocolitica from
appendicitis.
Good opportunity for a liver biopsy to assess the liver histology and iron
concentration.

19. How they die?
Infections and their complications were previously the
second commonest cause of death in transfusion-dependent
thalassaemia (TDT), prior to the new millennium .
Infections are becoming the leading cause of death in
western countries due, in part, to a significant reduction in
the number of deaths from iron induced cardiac disease.

21. Etiology of risks of infections in transfusion dependent thalassaemia
Therapy related factorsTHERAPY RELATED FACTORS
Allogeneic blood transfusions
- Transfusion transmitted infections
- Transfusion related immune modulation
- Iron overload
Splenectomy
Iron chelation therapy
Central venous catheters
Stem cell transplantation
Disease related factorsTHERAPYDISEASE RELATED FACTORS
Ineffective erythropoiesis
Haemolysis
Anemia

22. Overwhelming post-splenectomy
infection (OPSI)
OPSI is a medical emergency.
 Following brief prodromal symptoms such as fever, shivering, myalgia,
vomiting, diarrhoea, and headache, septic shock develops in just a few hours,
with anuria, hypotension, hypoglycemia, and, commonly, disseminated
intravascular coagulation and massive adrenal gland hemorrhage (Waterhouse-
Friderichsen syndrome), progressing to multiorgan failure and death .
 The mortality rate is around 50 to 70% and most death occurs within the first
24 hours; only prompt diagnosis and immediate treatment can reduce mortality
.

23. Suspicion and approach to OPSI:
• Physicians must be aware of the potential life threatening infections in TDT
patients who underwent splenectomy and patients should be educated for seek
early care when fever develops.
• In patients at risk and with indicative symptoms, prompt initiation of empirical
antibiotics is essential. Intravenous infusion of third generation cephalosporin
(cefotaxime 2 g every 8 h or ceftriaxone 2 g every 12 h), combined with
gentamicin (5–7 mg/kg every 24 h) or ciprofloxacin (400 mg every 12 h) or
vancomycin (1–1.5 g every 12 h) .
• While waiting results of blood culture, bacteria can be visualised in gram
staining.
• A RT-PCR test for simultaneous identification of 3 main encapsulated bacteria
(S. pneumonia, H. influenza type B and N. meningitides) is available .

24. Endrocrine Disease
Endocrine abnormalities are among the most common complications of β-thalassaemia major
(TM).
Hypogonadism
Hypothyroidism
Short stature
Glycemic abnormalities
hypoparathyroidism

25. FERTILITY AND PREGNANCY
Iron overload in the pituitary is the main cause of infertility in females.
Successful pregnancy can be achieved in thalassaemia major though ovulation induction
because ovarian function is usually preserved.
Ovulation in females and spermatogenesis in males can be induced by exogenous
gonadotrophin therapy.
Management of infertility requires careful planning and preparation.
Induction of ovulation should only be undertaken by a specialist reproductive team.
Cont….

26. Several factors must be taken into consideration before encouraging women with
thalassaemia major to embark on pregnancy. These include
the degree of pre-existing cardiac impairment and of liver dysfunction
possibility of vertical transmission of viruses.
Pregnancy per se does not alter the natural history of thalassaemia – it is
safe,provided they have started early on proper treatment and have normal resting
cardiac function. If cardiac function deteriorates during pregnancy, deferoxamine may
be used cautiously after the first trimester.

27. Osteoporosis
• Osteoporosis: is defined as BMD T-score <-2.5 leading to higher risk of fracture.
• Osteopenia: is defined as BMD T-score between – 1 and – 2.5.
• Normal BMD: T-score > –1.0.
T-score is defined as the number of standard deviations (SD) that a patient’s
bone mass is above or below the mean peak bone mass for a 30-year-old healthy
woman.

28. Osteoporosis is a prominent cause of morbidity in patients with thalassaemia major; it is
present in approximately 40–50% of patients.
The pathogenesis includes
◦ genetic factors
◦ endocrine complications (mainly hypogonadism)
◦ iron overload
◦ bone marrow expansion
◦ vitamin deficiencies
◦ lack of physical activity

29. Management of Osteoporosis
Physical activity must always be encouraged.
Smoking should be discouraged.
Adequate calcium intake during skeleton development can increase bone mass in adult life and
in combination with administration of low doses of vitamin D may prevent bone loss and
fractures.
Early diagnosis and treatment of diabetes mellitus.
Adequate iron chelation may prevent iron toxicity in the bone and sufficient blood transfusions
may inhibit uncontrolled bone marrow expansion.
Hormonal replacement where it is needed.
Bisphosphonates should be given concomitantly with calcium and vitamin D and not for longer
than two years.

30. HAEMOPOIETIC STEM CELL TRANSPLANTATION
When considering the very significant combined costs of life-long blood transfusions,chelation
and the management of complications for optimal thalassaemia care, transplantation is certainly
a cost-effective option if adequate expertise exist, even in developing countries.
Haemopoietic stem cell transplantation should be offered to thalassaemia patients (and
families) at an early age, or before complications due to iron overload have developed if an HLA
identical sibling is available.

31. ALTERNATE AND NOVEL APPROACHES
At the current time, we would not recommend the use of HbF inducing agents or other
erythropoiesis stimulating agents outside the context of clinical trials.
If a patient is not showing appropriate responses to other therapies and they have a desire to
try another therapeutic agent, a trial of hydroxyurea may be useful.
We recommend that hydroxyurea be initiated at a dose of 15 mg/kg/day orally with blood
count monitoring every 4 weeks. We recommend dose escalation by 2.5 – 5 mg/kg/day every 8
weeks with close monitoring performed at 4 week intervals. We generally aim to determine a
maximum tolerated dose by ensuring that the absolute neutrophil count remains > 2.0 X 109/ L.
Clinical effectiveness can be assessed by measuring transfusion frequency in patients on regular
transfusions or by monitoring total haemoglobin levels in those who are intermittently or never
transfused.

33. PSYCHOLOGICAL SUPPORT
Patients with thalassaemia are vulnerable to experiencing psychological challenges.
Psychological well-being impacts on adherence to chelation treatment in Thalassaemia Major
and hence on survival.

35. Answer the question plz….
Healthcare professionals can provide confident and informed guidance to their patients.
Activities – sports – how far can I go?
Social life – dancing, smoking, and alcohol – what is allowed?
Education – can treatment and clinic visits interfere with the education program?
Can clinic times be adjusted to my needs?
Employment – what jobs can I accept? Is there employer prejudice?
Will I have absences?
Can I get married? Can I have children?
Can I support a family? For how long?
Can I have life insurance? Health insurance?
Will I be able to get a mortgage? Can I borrow?

36. Exercise and Participation in Sports
In general, physical and recreational activities should be encouraged, as this is an
important aspect of healthy and normal living, as well as a means towards social
integration.
Limitations in chronic disease must however be recognised. all existing studies have
concluded that there is exercise limitation in transfusion dependent thalassaemia
patients. Factors contributing to this limitation include the degree of anaemia, iron
overload affecting heart function - especially through vascular inflammation , and even
restrictive lung dysfunction
In general, pre-adolescent children are allowed to exercise without restrictions, if
treated according to accepted standards.
If athletic activity is contemplated, then ergometric tests must be included.

37. Education
The main limiting factor expressed by patients is the need to
interrupt educational sessions in order to meet clinic and transfusion
appointments, which are most often during working hours.

38. Employment
The United Nations Convention on the Rights of Persons with
Disabilities (United Nations 2007) clearly states in Article 27 that
state parties recognise the right of persons with disabilities to work
on an equal basis with others, prohibiting discrimination on the basis
of disability, assuring equal remuneration for work of equal value as
well as safe and healthy working conditions.

39. Marriage and Reproductive Life
The role of the treatment team in this respect is to ensure that from an early age
that, patients are seen by an endocrinologist to avoid hypogonadism as much as
possible and to initiate treatment early, so that any delay or absence in sexual
development is Avoided.

40. Nurtition
Zinc supplementation is usually delivered in the form of zincsulphate, although
other formulations are also available. The usual dose is 125mg 1-3 times daily,
although doses of 220mg 3 times daily have been quoted for haemoglobin
disorders.
Iron:Globally, many transfusion dependent patients do not receiveblood
transfusions before haemoglobin levels fall to 6 or 7 g/dl, and iron
absorptionmay rise up to 5 g/dl/day. In this group of patients in particular,
dietary restriction of iron is important. Taking black tea with meals may reduce
iron absorption, while foods rich in vitamin C will increase absorption.

41. Calcium and Vitamin D: Calcium and vitamin D are the most commonly
prescribed supplements for thalassaemia patients. Vitamin D and Calcium
supplementation is recommended for all patients at a dose of 2000IU/day.
Folic acid:Patients on high transfusion regimes rarely develop folate deficiency,
in contrast to those on low transfusion regimens. The possibility of providing
folic acid supplements at up to 1mg/day to all patients may be considered.

42. Vitamin E is a fat-soluble vitamin which is often deplete in thalassaemia
patients. A diet rich in foods that contain Vitamin E can be recommended, with
intake of foods including eggs, vegetable oils (e.g. olive oil, cornoil, safflower and
sunflower oil), nuts and cereals.
Vitamin C has antioxidant properties and can also be deplete in conditions in
which there are increased free iron radicals causing oxidative damage. However,
caution in recommending supplementation has been expressed due to the
following:
◦ Vitamin C is known to promote the absorption of dietary iron, and even
regularly transfused patients should control their intake of iron.
◦ Vitamin C increases labile iron and therefore contributes to iron toxicity.

43. L-carnitine may be beneficial at a dose of 50mg/kg/day, although caution should
be exercised in patients with thyroid dysfunction.
There is insufficient evidence on any long term benefits from wheat grass.
Silymarin at a dose of 140mg three times daily is recommended if liver
involvement is detected, and on consultation with a hepatologist.
Consumption of alcohol, tobacco and substance abuse should be avoided.