GUIDELINES

FOR THE
CLINICAL
MANAGEMENT OF

THALASSAEMIA
2 REVISED EDITION
ND

Dedication

The authors dedicate this book to George, Ahmad, Giovanna, Nicos, Meigui, Sumitra, Christine,
Minh-Quan, Hamid, Pranee, Eduard, Karim, and all other patients with thalassaemia, who are not
with us any more but whose will and determination to live have inspired researchers and health
professionals across the world to promote scientific knowledge and quality care.

It is our fervent hope that this book will serve not only as a manual for promoting clinical
management, but also as a tool for improving communication and collaboration amongst all of
those, patients, parents, health professionals and others who are striving towards the same goal,
the establishment of effective control of thalassaemia and the promotion of equal access to
quality health care for every patient with Thalassaemia.

EDITORS AND AUTHORS:

Maria-Domenica Cappellini, MD Professor, Centro Anemie Congenite, Ospedale Maggiore
Policlinico IRCCS, University of Milan, Italy
Alan Cohen, MD Professor of Paediatrics, University of Pennsylvania, School of Medicine, USA
Androulla Eleftheriou, Ph.D. Ex-Director of the Virus Reference Laboratory, Ministry of Health
Cyprus, Executive Director - Thalassaemia International Federation
Antonio Piga, MD Professor, Dipartimento di Scienze Pediatriche e dellAdolescenza, Universita
degli Studi di Torino, Italy
John Porter, MD Professor, Department of Haematology, University College, London, UK
Ali Taher, MD Professor Medicine - Hematology & Oncology, Department of Internal Medicine,
American University of Beirut Medical Center, Beirut Lebanon

AUTHORS OF CHAPTERS:
Athanasios Aessopos, MD - Professor of Cardiology, First Department of Internal Medicine,
University of Athens - "Laiko" General Hospital, Athens, Greece
Emanuel Angelucci, MD - Professor of Haematology, U.O. Ematologia Ospedale Oncologico
"Armando Businco", Cagliari, Italy
Michael Antoniou, Ph.D. - Division of Medical & Molecular Genetics, GKT School of Medicine, Guy's
Hospital, London, UK
Ratna Chatterjee, MD Consultant/Senior Lecturer in Reproductive Health, University College
London, London, UK
Demetrios Farmakis, MD - First Department of Internal Medicine, University of Athens - "Laiko"
General Hospital, Athens, Greece.
Susan Perrine, MD - Director of Haemoglobinopathy/Thalassaemia Research Unit, Professor of
Paediatrics Medicine Pharmacology and Experimental Therapeutics Boston, Boston University
School of Medicine, Boston, Massachusetts, USA
Vicenzo De Sanctis, MD- Professor of Paediatric Endocrinology, Divisione Pediatrica Azienda,
Ospedaliera Archispedale S. Anna, Ferrara, Italy
Malcolm John Walker, MD - Consultant Cardiology Hatter Institute, Cecil Fleming House,
University College London Hospital, London, UK

CO-ORDINATING EDITOR:
Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA

CONTRIBUTORS:
Constantina Politis, MD Associate Professor, Director of the 3rd Reg. Blood Transfusion Centre,
'George Gennimatas' General Hospital, Athens, Greece
Ala Sharara, MD Professor, Director of Division of Gastroenterology- American University of
Beirut Medical CenterEndoscopy Unit, Beirut, Lebanon
Nicos Skordis, MD - Consultant of Paediatric Endocrinology, Department of Paediatrics,
Thalassaemia Centre, Makarios III Hospital, Ministry of Health Cyprus, Nicosia, Cyprus.
Ersi Voskaridou, MD - Director of the Thalassaemia Unit and WHO Collaborating Centre, Geniko
Laiko Nosokomio Athinon, Greece

ACKNOWLEDGEMENTS:
The Thalassaemia International Federation would like to express its most sincere appreciation and
gratitude to Dr. Helen Perry Editor, Dr Michael Angastiniotis - Thalassaemia International
Federation, Medical Advisor and Dr. Matheos Demetriades Thalassaemia International
Federation, Projects Coordinator for their invaluable contribution to the completion of the
book.

Contents
Foreword

Introduction

11

CHAPTER 1

14

Genetic Basis and Pathophysiology

CHAPTER 2

20

Blood Transfusion Therapy in -Thalassaemia Major

CHAPTER 3

33

Iron Overload

CHAPTER 4

64

Endocrine Complications In Thalassaemia Major

CHAPTER 5

70

Management of Fertility and Pregnancy in -thalassemia

CHAPTER 6

79

Diagnosis and Management of Osteoporosis in -thalasaemia

CHAPTER 7

83

The Management of Cardiac Complications in Thalassaemia Major

CHAPTER 8

92

The Liver in Thalassaemia

CHAPTER 9

106

Infections in Thalassaemia Major

CHAPTER 10

116

Splenectomy in -thalassaemia

CHAPTER 11

121

Thalassaemia Intermedia and HbE

CHAPTER 12

132

Stem Cell Transplantation

CHAPTER 13

136

Alternative Approaches to the Treatment of Thalassaemia

CHAPTER 14

139

Gene Therapy: Current Status and Future Prospects

CHAPTER 15

142

Psychological Support in Thalassaemia

CHAPTER 16

149

General Health Care and Lifestyle in Thalassaemia

CHAPTER 17

155

Organisation and Programming of a Thalassaemia Centre

CHAPTER 18

159

Outline of Diagnostic Dilemmas in Thalassaemia

References

170

Growth Charts

188

Index

192

About Thalassaemia International Federation

198

Foreword

The fight against thalassaemia has entered new and exciting territory, with major advances
dramatically improving patient care. At the forefront of that fight, the Thalassaemia International
Federation (TIF) remains true to its goal: to secure equal access to quality healthcare for every
patient with thalassaemia around the world. This book is a key tool in achieving that goal.
Written by some of the worlds leading authorities on haemoglobin disorders, this second revised
edition of Guidelines for the Clinical Management of Thalassaemia provides medical professionals
with a clear, comprehensive guide to the optimal treatment of thalassaemia, based on scientific
evidence, clinical studies and observations. The information provided here has been meticulously
compiled by experts fully aware of the many different circumstances in which medical personnel
strive to treat patients with thalassaemia. As such, it sets out to provide a full guide to the
treatment to which every patient everywhere is entitled, including access to sufficient quantities of
safe blood and iron chelation therapy, as well as offering a comprehensive assessment of
groundbreaking advances in chelation therapy, other treatment options and the long-awaited final
cure, including stem cell transplantation and gene therapy.
With the support of member associations, dedicated scientists and healthcare workers, patients,
families and friends, TIF focuses on three categories of projects, each contributing to the overall
goal of reaching its objectives and achieving its mission:
TIF projects aim to promote and support:
Awareness about thalassaemia, its prevention and its medical and other care;
Research focused on the continuous improvement of medical care and on realising a total cure
for thalassaemia, and;
Dissemination of the knowledge, experience and expertise of countries with successful control
programmes to countries in need.
TIFs activities in achieving the above include:
1. The establishment of new and promotion of existing national patient organisations;
2.

The development of a collaborative network of national and international

thalassaemia and other disease-specific patient organisations;
medical and scientific communities involved in the field;
research institutes and medical centres of excellence;
health-related organisations, and;
pharmaceutical industries

3. The coordination of or participation in national, regional and international projects contributing

to worldwide improvements in:
Epidemiology

 Medical and other care

Social integration and quality of life
Extending knowledge of the disease, its prevention and treatment to policy makers, health
professionals, patients and parents, and the community at large
Securing the rights of every patient for equal access to quality medical care, and
The safety and adequacy of blood
4. The establishment of programmes for the continuous education of health professionals,
patients and parents, and the community, including:
Organisation of local, national, regional European and international workshops, conferences,
seminars and meetings.
The preparation, publication, translation and free distribution of educational and awarenessraising material.
The recent launch of a unique e-MSc in Haemoglobinopathies, offered by University College
London (UCL) and part-funded by TIF, is just one example of the scope and ambition of TIFs
educational programme.

TIFs achievements are the result of voluntary, dedicated work by

scientists and medical professionals from around the world, without
which TIFs educational programme, one of its most important tools
for the dissemination of knowledge and experience, would never have
achieved the level of success it currently enjoys.
The authors and all other contributors that have made this book possible deserve particular
recognition for their work. The first edition of this book served for many years as the reference
text for the treatment of thalassaemia. We are confident that this second edition will make a
similar if not greater contribution to efforts to spread existing knowledge and the advances
achieved in the last seven years in the field of the clinical management of thalassaemia. Special
acknowledgement is also due to a number of other specialists, including Antonio Cao, Vilma
Gabutti, Renzo Galanello, Giuseppe Masera, Bernadette Modell, Annuziata di Palma, Calogero Vullo
and Beatrix Wonke, who led the way in the early, difficult years, when knowledge on this subject
was very limited. They are amongst the pioneers in the promotion of the clinical management of
thalassaemia and in the setting out of standards of care to which every patient is entitled.
The first edition of the Guidelines for the Clinical Management of Thalassaemia, published in 2000,
was the first of its kind to be produced at a time when specialists, patients and parents considered
its preparation essential, in view of the rapid achievements in the treatment of thalassaemia. This
new, fully updated, second edition is a timely response to the many further advances that have
been made since then.
As a response to the rapid medical advancements achieved after 2000 in the field of management
of thalassaemia, a new second edition of the Guidelines, Thalassaemia was published by TIF in

December 2007 offering an invaluable tool to medical staff involved in the treatment of
thalassaemia.
Only a year after its publication and distribution across the world, TIF ran out of stock and in order
to have a timely response to the needs of health professionals involved in the treatment of
thalassaemia, TIF in collaboration with the main authors and editors of the book have published
this second revised edition in December 2008.
Governments, National Health Authorities, Thalassaemia Centres and individual health professionals
in the field are strongly encouraged to follow the recommendations of the panel of experts as
presented in this book.

At the same time, it is extremely important that the prevention of

thalassaemia receives similar attention.
While outside the scope of this book, the prevention of thalassaemia remains a crucial objective for
TIF. Unless new births of affected children are prevented or minimized, even the best updated
treatment programmes will eventually collapse, unable to provide for an ever-increasing number of
patients. In this context, the development of national prevention programmes is at the heart of
TIFs activities. TIF, based on its long-time experience, can offer considerable support to countries,
including detailed advice on the structure of, and challenges to implementing, such programmes.
On behalf of the Board of Directors of TIF I would like to once again extend our deepest gratitude
to the experts who have dedicated work, time and effort in producing this second revised edition
of Guidelines to the Clinical Management of Thalassaemia. Last but by no means least, I would like
to express our most sincere appreciation to the Non-Communicable Diseases Genetics Department
of the World Health Organisation (WHO), with which TIF has been collaborating on an official basis
since 1996, and whose support and guidance in promoting our mission have been multi-faceted
and invaluable.

Panos Englezos
TIF President

10

Introduction

Haemoglobin (Hb) disorders are hereditary, genetic diseases consisting mainly of sickle cell
disease and the thalassaemias, which account for a great proportion of births affected by a
genetic disease.
The thalassaemias are a heterogeneous group of the haemoglobin disorders in which the
production of normal haemoglobin is partly or completely suppressed as a result of the
defective synthesis of one or more globin chains. Several types of thalassaemia have been
described and named according to the affected globin-chain, the most common types of clinical
importance being -, - and -thalassaemia.

Haemoglobin disorders are thought to have originated in countries

where malaria was or is endemicareas to which it was for many
years believed such disorders were confined.
Sub-Saharan Africa accounts for more than 70% of births affected by sickle cell disorders every
year, with the remainder occurring at various rates (from low to high) in other parts of the
world. Thalassaemia, including HbE, is more prevalent in the Mediterranean basin, the Middle
East, Southern and Eastern Asia, the South Pacific and South China, with reported carrier rates
ranging from 2% to 25%.
Although reliable data are still lacking for many regions of the world, recent data indicate that
about 7% of the worlds population is a carrier of a haemoglobin disorder, and that 300,000500,000 children are born each year with the severe homozygous states of these diseases.
(World Bank 2006, report of a joint WHO-March of Dime meeting 2006)
It is now well recognised that Hb disorders are not confined to any particular region, occurring
widely across the world and constituting a global public health problem. Hb disorders have
spread through the migration of populations from endemic areas to countries where their
prevalence in indigenous populations had been extremely low. Such countries include the USA,
Canada, Australia, South America, the United Kingdom and France, where migration occurred up
to a century ago and where large ethnic minority groups are now entering their fourth and even
fifth generation.
More recent migration movements from highly endemic countries have been to Northern and
Western Europe, where the prevalence of Hb disorders in the indigenous population is very low,
including Germany, Belgium, the Netherlands and, more recently, Scandinavia.
These changes have challenged health professionals and policy-makers throughout the region in
providing equitable access to quality services for the prevention and treatment of Hb disorders.
In some regions, such as Scandinavia, to which there is currently large-scale migration, the
proportion of births in at-risk groups is predictive of the future genetic make-up of the
population, as has been the case in some of the countries mentioned above, where large scale
migration from affected countries had occurred much earlier.

11

Carrier prevalence will clearly continue to rise in Northern and Western Europe, even in the
absence of further migration, as a result of reproduction and inter-community marriages, and
Hb disorders are likely to become the leading recessive disorder throughout the region, posing a
serious public health problem. Clearly, the earlier classification of endemic and non-endemic
countries for Hb disorders is no longer relevant. However, effectively addressing the control of
these disorders in these countries will require considerable work, financial backing and certainly
political commitment. The main difficulty is that the populations of these countries are not
homogeneous, as was the case in the Mediterranean countries where the earliest control
programmes were successfully established. Some countries in Europe, such as the United
Kingdom and France, have already accumulated considerable experience and knowledge in the
most cost-effective and practical ways of intervention to address this highly important public
health problem.
Recognition of the problem in Northern and Western Europe has raised concerns and stirred up
interest amongst national and EU health policy-makers who, in addition to and complementary
to the work of World Health Organisation (WHO), which was traditionally involved in the
promotion of control programmes for Hb disorders, have already taken significant steps in the
context of their agenda on rare diseases.
Unlike affected countries of the developing world, these countries already have strong health
care infrastructure and systems in place, and the resources and quality health services required.
The European countries need to address ethnic minorities, which are widely scattered
geographically, and to raise strong health professional and patient/parent awarenesstasks that
are essential in the promotion of effective control programmes.
Recent improvements in the resources and health care structures of Eastern European countries
such as Bulgaria and Romania have contributed to a greater recognition of the importance of
developing and implementing control systems for Hb disorders occurring in the indigenous
population, which in some regions can reach very high carrier levels.
Southern European countries with Hb disorders occurring in the indigenous population, albeit at
considerably lower prevalence rates, include Portugal and Spaincountries that are, however,
able to respond effectively to public health requirements and to adopt effective policies.
Low prevalence European countries where haemoglobinopathies have not yet penetrated to a
significant degree through migration include Poland, Hungary and the Czech Republic, although
these, along with Spain and Portugal, constitute potential targets for increasing migration.
Albania is a separate example, having higher prevalence rates of Hb disorders than the rest of
the Balkan countries in the indigenous population with carriers and affected individuals widely
scattered across the country. Although appropriate services are still largely underdeveloped,
significant progress has been achieved during the last few years, especially in the area of clinical
management. Unfortunately data on the epidemiology and status of control programmes in
Russia remains scanty.

12

In lower and middle-income countries on the other side of the world, where haemoglobin
disorders are most prevalent in the indigenous population, 50-80% of children with sickle cell
disease and a significant number of children with -thalassaemia die each yearundiagnosed or
misdiagnosed, sub-optimally treated or not treated at all.
There is an urgent need to bridge this wide gap until every patient in every part of the world has
equal access to quality medical care. An essential means of doing so is through global
collaboration on Hb disorders, enabling all countries to benefit from each others experience.
Health authorities need to recognise Hb disorders as a significant threat to public healthone
that deserves the development and implementation of national policies for treatment and
prevention. The instruments required to support such policies include:

Standards and guidelines for laboratory services

National guidelines for the management of thalassaemia
Epidemiological information and surveillance
Establishment of an educational programme for health
professionals, patients, parents and the community

It is evident that all countries would benefit from the sharing of experience and expertise. The
difficulties encountered in service development for haemoglobin disorders apply equally to many
other inherited disorders. Professionals and support groups alike would benefit from forming
wider partnerships with similar groups representing other disorders.
It is hoped that this book will offer valuablel information to all medical professionals involved in
the treatment of patients with thalassaemia. It includes updated information on new approaches
for more effective, safe and less laborious treatment, and an overview of the progress achieved
to date towards a total cure for thalassaemia, using methods such as gene therapy and stem cell
transplantation.
Until the final goal of a complete cure for thalassaemia is found, it is the obligation of national
health authorities and health professionals to provide, and the right of patients to receive, the
most complete and up-to-date systems of treatment available. We hope that these guidelines,
which constitute the authors consensus on the most effective treatment of -thalassaemia
major, will prove an indispensable tool for health professionals involved in this field.
Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA
TIF Executive Director
Coordinating Editor

13

Genetic Basis and

Pathophysiology

structure of the globin chains is coded by

genes contained in the DNA of chromosomes
16 (the gene cluster) and 11 (the gene
cluster). Flanking the structural genes, i.e. in
front (on the 5 side of the DNA sequence,
upstream) and following them (on the 3
side of the DNA sequence, downstream), lie
several nucleotide sequences which have a
regulatory role, i.e. they determine which
gene is to be turned on and which off, as
well as how efficient its expression will be. In
adult life, most of the globin synthesis occurs
in the erythroblasts in the bone marrow.
Haemoglobin must have the correct
structure and be trimmed in such a way that
the number of -chains precisely matches
that of the -chains. When the above
conditions are not met, the result is a
complete or partial defect in one or both
allelic globin genes.

Haemoglobin Types
Oxygen is transported from the lungs to the
tissues by a highly specialised protein
molecule, haemoglobin, which is located in
the red cells of the blood. Each red blood
cell contains approximately 300 million
molecules of this protein, totalling about 30
picograms in weight per cell. Each molecule
of haemoglobin is formed by two pairs of
identical sub-units, the globin chains, which
are named with letters of the Greek alphabet
and belong to two groups: the -globin
cluster, comprising the - and -globin
chains, and the -globin cluster, comprising
the globin chains , , and . The globin
chains appear sequentially during ontogeny
and, after pairing, form the following four
major types of haemoglobin:
a) embryonic haemoglobins, which are
detectable from the 3rd to the 10th
week of gestation and represent 22,
22 and 22 tetramers;
b) fetal haemoglobin (HbF 22), which
constitutes the predominant oxygen
carrier during pregnancy ;
c) adult haemoglobin (HbA 22), which
replaces HbF shortly after birth, and;
d) a minor adult component, HbA2 (22).

The Thalassaemias:
Definitions and
Worldwide
Distribution
The term thalassaemia refers
to a group of blood diseases
characterised by decreased
synthesis of one of the two
types of polypeptide chains (
or ) that form the normal adult
human haemoglobin molecule
(HbA, 22), resulting in
decreased filling of the red cells
with haemoglobin, and anaemia.

Under normal conditions, the red cells of the

adult human contain approximately 98% HbA,
2.0% HbA2 and traces of HbF.

Globin Genes and

Globin Synthesis
The globin chains have an extremely precise
structure, ensuring their prompt loading with
oxygen in the lung alveoli and its controlled
gradual delivery into the tissues. The precise

Depending on which of the genes the defect

occurs and the corresponding effect on the

14

alterations of their red cells, an increased

level of HbA2, and a low /- globin chain
ratio on biosynthesis, which is occasionally
associated with low normal or slightly
subnormal haemoglobin levels. Under normal
circumstances, the thalassaemia trait is not
related to any significant clinical effects,
mainly because the activity of the normal
gene on the allelic chromosome makes
enough stable globin. In contrast, inheritance
of two defective -globin genes results in a
wide spectrum of clinical conditions, ranging
from transfusion dependence (thalassaemia
major) to mild or moderate anaemia
(thalassaemia intermedia). Molecular studies
may reveal a large array of abnormalities
underlying the above phenotypes and may
assist in their identification.

production of globin chains, -thalassaemia

or -thalassaemia results. The present book
mainly addresses the latter group of
thalassaemias, which are now recognised to
occur widely across the world well beyond
the countries where these were originally
thought to be endemic i.e. countries around
the Mediterranean Basin, the Middle East,
Trans-Caucasus and India for - and the Far
East for -thalassaemia (see Figure 1).

-Thalassaemia
Phenotypic heterogeneity
As a rule, heterozygous carriers of thalassaemia (one affected allele), display a
low mean cellular haemoglobin (MCH), low
mean cell volume (MCV), mild morphological

CELL TYPE
SITE OF
ERYTHROPOIESIS

PERCENTAGE
OF TOTAL
GLOBIN
SYNTHESIS

Figure 1: Globin synthesis at various stages of embryonic and fetal development

15

below outlines the pathophysiology of thalassaemia and describes the chain of

events following globin chain imbalance and
the accumulation of excess -chains that is,
ineffective erythropoiesis leading to anaemia,
bone marrow expansion, skeletal deformities
and increased GI iron absorption.

Pathophysiology of
-thalassaemia
Advances in the management of thalassaemia
were achieved only after the pathophysiology
of the disease was elucidated and clearly
understood by the scientific and medical
community involved in the field. Figure 2

The degree of globin chain imbalance is

determined by the nature of the mutation of

PATHOPHYSIOLOGY OF -THALASSAEMIA MAJOR

Figure 2: Effects of excess production of free -globin chains

16

Table 1 includes the common types of

-thalassaemia mutations according to ethnic
distribution and severity. A more
comprehensive list of mutations can be
found on the internet at

the -gene. o refers to the complete

absence of production of -globin on the
affected allele. + refers to alleles with some
residual production of -globin (around 10%).
In ++ the reduction in -globin production is
very mild. More than 200 thalassaemic
mutations have been reported to date.

http://globin.cse.psu.edu/globin/html/huisman .

Population

-gene Mutation

Severity

Indian

-619 del

Mediterranean

-101

++

Black

-88

++

Mediterranean; African

-87

++

Japanese

-31

++

African

-29

++

Southeast Asian

-28

++

Black

-26

++

Mediterranean; Asian Indian

IVS1-nt1

Mediterranean; Asian Indian

IVS1-nt5

Mediterranean

S1-nt6

+/++

Mediterranean

IVS1-nt110

Chinese

IVS2-nt654

Mediterranean

IVS2-nt745

Mediterranean

codon 39

Mediterranean

codon 5

Mediterranean; African-American

codon 6

Southeast Asian

codons 41/42

African-American

AATAAA to AACAAA

++

Mediterranean

AATAAA to AATGAA

++

Mediterranean

Hb Knossos

++

Southeast Asian

HbE

++

Table 1: Common types of -thalassaemia, their severity and ethnic distribution

17

Beta structural
haemoglobin variants
relevant to
thalassaemia
management

are variable in severity ranging from those

characterising thalassaemia intermedia to
those described for severe transfusiondependent thalassaemia major. The reasons
for this variability have only partially been
defined, since patients with seemingly
identical genotypes present with clinical
manifestations very different in severity.

Haemoglobin E disorder is the most common

structural variant resembling thalassaemia
desorders (see relevant Chapter 11:
Thalassaemia Intermedia).
HbE results from a mutation (GA) at codon
26 of the -globin gene causing the
substitution of lysine for glutamic acid a
mutation that results in a qualitative and
quantitative -globin gene defect since it is
related to the activation of a cryptic splice
site at codon 24-25, leading to an alternative
splicing pathway. The overall result is the
production of reduced amounts of the
variant haemoglobin (HbE).

Hb Lepore is another structural

variant resulting from a fusion
of the and globin genes.
The homozygous state of Hb
Lepore can result in moderate
to severe transfusiondependent -thalassaemia
syndromes.
Haemoglobin S disorders: HbS, the most
common haemoglobin variant in the world,
results from a substitution of valine for
glutamic acid at position 6 of the -globin
chain. The interaction of -thalassaemia with
HbS results in a syndrome that most closely
resembles the sickling disorders, which
typically do not require lifelong transfusions
and are not consequently associated with
iron overload. As for thalassaemia, Guidelines
for the management of sickle cell disorders
have been formulated in recent years and a
useful web-site for more information is:
http://www.nhlbi.nih.gov/health/prof/blood/
sickle/sick-mt.htm.

HbE is the most common abnormal

haemoglobin in South East Asia, with a carrier
frequency of more than 50% in some
regions. It is also prevalent in parts of the
Indian subcontinent, including Bangladesh.
Heterozygotes for HbE are clinically normal
and manifest with 25-30% of HbE on
electrophoresis and with only minimal
changes in red blood cell indices.
Homozygotes for HbE are clinically silent and
may be only mildly anaemic. On microscopic
examination, the peripheral blood smear
demonstrates microcytosis with 20-80% of
target red cells, while Hb electrophoresis
shows 85-95% of HbE and 5-10% of HbF.

-thalassaemia
-thalassaemias are inherited disorders
characterised by reduced or suppressed
production of -globin chains. The human globin genes are duplicated and located in
the telomeric end of the short arm of
chromosome 16. -thalassaemia is caused

HbE/-thalassaemia constitutes the most

common combination of -thalassaemia with
a structural variant, most prevalent in South
East Asia. The related clinical manifestations

18

crisis, mainly in response to oxidant drugs

and infections.

most commonly by deletions of large DNA

fragments that involve one or both -globin
genes.
Silent carrier state: The presence of a single
-globin gene deletion results in the silent
carrier state occurring widely across the
world.

Other relevant structural variants include Hb

Constant Spring, characterised by ineffective
synthesis of a-globin chains, resulting from a
defect on the relevant gene that causes their
elongation. This mutation is found primarily
in Asia and its co-inheritance with the
deletion of two -genes results in a severe
form of HbH disease.

-thalassaemia trait is
characterised by the presence
of two residual functional agenes and is not related to any
serious clinical or laboratory
findings:

Hb Barts hydrops fetalis, the most severe

clinical manifestation of -thalassaemia, is
generally associated with the absence of all
four -globin genes and death in utero.
Absence of -globin genes in the cis
position on the same chromosome (thalassaemia) is common in South East Asia,
while it is rare in the Mediterranean area and
even rarer in Africa.

Mild anaemia and microcytosis.

Deletions or abnormalities of three globin
genes result in HbH disease, usually
characterised by a moderate haemolytic
anaemia, splenomegaly and acute haemolytic

With permition from the Source: March of Dimes: Global Report 2006

19

Blood Transfusion Therapy in

-Thalassaemia Major

relevant laws and taking into account

national needs, resources and prevalence of
infectious agents, should safeguard the
quality of blood transfusion services. Blood
donation practices, donor selection (e.g.,
through questionnaire) and product
screening constitute some of the most
important strategies that contribute to the
safety and adequacy of blood. For more
information on EU directives visit:
http://europa.eu.int and http://europa.eu.int
/consus/health/index_en.html.
On recommendations of the Council of
Europe visit http://www.coe.int, while on
WHO guidelines and American Standards visit
www.who.int/bloodsafety/gcbs/structure/en/
and http://www.aabb.org/content,
respectively. Other sites are also available
should the reader require to obtain more
information.

Goals of Blood
Transfusion Therapy
Appropriate goals of transfusion therapy and
optimal safety of transfused blood are the
key concepts in the protocol for routine
administration of red blood cells to patients
with thalassaemia. The major goals are:
Maintenance of red cell viability and
function during storage, to ensure
sufficient transport of oxygen;
Use of donor erythrocytes with a normal
recovery and half-life in the recipient;
Achievement of appropriate haemoglobin
level, and;
Avoidance of adverse reactions, including
transmission of infectious agents.

Quality and Adequacy

of Blood

Transfusion Therapy
in Thalassaemia

To safeguard the health of the

transfusion recipient, including
patients with thalassaemia,
blood should be obtained from
carefully selected regular
voluntary, non-remunerated
donors and should be collected,
processed, stored and
distributed, in the context of
dedicated, quality assured
national blood transfusion
centres.

This chapter will address five of the most

common questions related to the transfusion
therapy of patients with thalassaemia major:
(i)

When to initiate transfusion therapy and

whom to transfuse;
(ii) How blood is processed for effective
and safe transfusion therapy in
thalassaemia major;
(iii) Is there an optimal haemoglobin (Hb)
level for effective transfusion;
(iv) Do transfusion requirements affect the
success of iron chelation therapy;
(v) What are the most serious transfusion
related (TR) reactions (common and less
frequent);

Nationally developed legislation-based on EU,

Council of Europe, North American, World
Health Organisation (WHO) or other
international directives, recommendations or

20

For deciding whom to transfuse, the

following should be included in the
investigations:

Recommended blood
product

(i)

Patients with -thalassaemia

major should receive
leucoreduced packed red blood
cells with a minimum
haemoglobin content of 40g.

Confirmed laboratory diagnosis of

thalassaemia major;
(ii) Laboratory criteria:
Hb < 7g/dl on 2 occasions, > 2 weeks
apart (excluding all other contributory
causes such as infections) or
(iii) Laboratory and clinical criteria,
including:
- Hb > 7g/dl with:
- Facial changes
- Poor growth
- Fractures, and
- Extramedullary haematopoiesis

Reduction to 1 X 106 or less leucocytes per

unit (mean counts as low as 0.05 x 106 are
achievable) (Council of Europe, RE 2006) is
considered the critical threshold for
eliminating adverse reactions attributed to
contaminating white cells (see Table 1,
below) and for preventing platelet
alloimmunisation.

REACTIONS

CAUSATIVE AGENTS

Febrile non-haemolytic transfusion

HLA-antibodies in patients, cytokines

reactions (FNHTR)

produced by donor leucocytes

HLA- alloimmunisation of recipients

HLA antigens on donor leucocytes

Transfusion-transmitted infections

Cell-associated infectious agents

Graft-versus-Host-Disease (GVHD)

Donor T-lymphocytes

[Morell A, ZLB Central Laboratory Swiss Red Cross, Bern Switzerland, 2000.
Pathogen inactivation of labile blood products]
Table 1: Contaminating Leucocytes as pathogens: Some adverse effects of Leucocytes in labile blood products.

21

Methods for leucoreduction include:

immunoglobulin A (IgA) deficiency, in which

the recipients preformed antibody to IgA
may result in an anaphylactic reaction.
Washing usually does not result in adequate
leucocyte reduction and should not be used
as a substitute for leucoreduction. Instead,
washing should be used in conjunction with
filtration. In addition, washing of red cell
units may remove some erythrocytes from
the transfusion product, and it is therefore
valuable to monitor post-transfusion
haemoglobin levels to ensure attainment of
the targeted Hb level.

Pre-storage filtration of whole blood is

the preferred method for leucoreduction.
The delay in filtration (4-8 hours) may
allow some phagocytosis of bacteria (e.g.
Yersinia enterocolitica) (Buchholz, 1992).
This method of leucocyte removal offers
high efficiency filtration and provides
consistently low residual leucocytes in the
processed red cells and high red cell
recovery. Packed red cells are obtained
by centrifugation of the leucoreduced
whole blood.

Frozen (or cryopreserved) red cells is

the component derived from whole blood in
which red cells are frozen, preferably within 7
days of collection, using a cryopreservant
and stored at -60oC to -80oC or below, based
on the method used. These are used to
maintain a supply of rare donor units for
certain patients who have unusual red cell
antibodies or who are missing common red
cell antigens. The Council of Europe is
promoting an international network of rare
blood donor units and may be contacted as
follows:
Council of Europe Point I
F67075 Strasbourg Cedex
France
Tel: +33 3 88 41 2000
Fax: +33 3 88 41 2781
Email: point_i@coe.fr
Internet: www.coe.fr/index.asp

Pre-transfusion, laboratory filtration

refers to the filtration at the blood bank
laboratory of packed red cells, prepared
from donor whole blood.
Bedside filtration refers to the packed red
cell unit which is filtered at the bedside,
at the time of transfusion. This method,
although equally sensitive to those above,
may not allow optimal quality control
because the techniques used for bedside
filtration may be highly variable.

Blood products for

special patient
populations

Red cells obtained by donor

apheresis: This method whereby two units

Washed red cells may be beneficial for

patients with thalassaemia who have
repeated severe allergic transfusion
reactions. Saline washing of the donor
product removes plasma proteins that
constitute the target of antibodies in the
recipient. Other clinical states that may
require washed red cell products include

of red cells are collected from the same

donor for transfusion of one patient is
associated with reduction of donor exposures
and consequently to a decreased risk (i) of
transmission of infections, and (ii) of
developing alloimmunisation and other
transfusion related complications.

22

the additive solution a suitable osmotic

strength. Thus the introduction of additives
such as AS-1, AS-3, AS-5 (see Table 2b) has
permitted considerably longer storage of red
cells for up to 42 days.

Neocyte or young red cell transfusion

may modestly reduce blood requirements
(Spanos, 1996). However, patients are
exposed to a higher number of donors, with
a consequent increase in cost, risk of
transmission of infections, and risk of
developing alloantibodies.

The maximum duration of

storage (expiry date) as noted
on each unit varies with the
type of preparation
(concentration of cells, formula
of anticoagulant, use of additive
suspension fluid, etc) and
should be determined for each
type on the basis of achieving a
mean 24 hours post-transfusion
survival of no less than 75% of
the transfused red cells.

Storage of donor red

cell units
The anticoagulant preservative solutions used
in blood collection (see Table 2a) have been
developed to prevent coagulation and to
permit storage of red cells for a certain
period of time. All of these solutions contain
sodium citrate, citric acid and glucose, some
of them may also contain adenine, guanosine
and phosphate (e.g., CPD-A).

The haemoglobin oxygen release function

(which is extremely important in thalassaemia
major) is impaired during storage due to
progressive loss of 2, 3-biphosphoglycerate
(2, 3-BPG, previously known as 2, 3diphosphoglycerate, DPG). Although, the
storage time of whole blood in CPDA-1 for
example is 35 days (CoE Re 2006), after 10
days of storage all 2, 3 BPG is lost (CoE Re
2006). In the case of additives such as the
ones mentioned above (see Table 2b),
although storage times up to 42 days are
advocated and high levels of ATP are
maintained up to the 28th day of storage, 2,
3-BPG and P50 values may not be fully
maintained even for this length of time. In
addition, information about the red cell halflife in the recipient after prolonged storage
of donor blood is limited. Taking into
consideration all the above and in view of the
fact that in thalassaemia major, decreased
recovery and a shortened red cell half-life
may increase transfusion requirements and

When red cell concentrates are prepared, a

considerable part of the glucose and adenine
is removed with the plasma. If not
compensated for in other ways, sufficient
viability of the red cells can only be
maintained if the cells are not overconcentrated. Normal CPD-adenine red cell
concentrate should therefore not have a
haematocrit (Hct) above 0.70 on average
(CoE Re 2006). Newly developed additive
solutions, however, allow maintenance of red
cell viability even if more than 90% of the
plasma is removed, as they contain
considerably higher levels of the necessary
nutrients (see Table 2b). The use of glucose
and adenine is necessary for the
maintenance of red blood cell posttransfusion viability, phosphate may be used
to enhance glycolysis, and other substances
(e.g.; mannitol, citrate) may be used to
prevent in vitro haemolysis. Sodium chloride
or di-sodium phosphate may be used to give

23

as a consequence the rate of transfusional

iron loading. the current practice is to use
red cells stored in additive solutions for less
than two weeks, and in CPD-A for even less
days as fresh as possible. In patients with
cardiac disease and in small children,
particular attention should be paid to the

increased volume resulting from additive

solutions. In general, for all patients, the
lower haematocrit of red cell units containing
newer additive solutions should be taken into
consideration when calculating the annual
rate of transfusional iron loading (see Tables
2a & 2b).

ACD-A

CPD

CP2D

CPDA-1

Trisodium citrate

22.00

26.30

26.30

26.30

Citric acid

8.0

3.27

3.27

3.27

Dextrose

24.50

25.50

51.10

31.90

2.22

2.22

2.22

Monobasic sodium phosphate

Adenine

0.275

[Source: Brecker M, ed Technical Manul, 14TH ed Bethesda, MD: American Association of Blood
Banks, 2003: 162]
Table 2a: Content of anticoagulant-preservative solutions (g/L)

AS-1 (Adsol)

AS-3 (Nutricell)

AS-5 (Optisol)

Dextrose

2,200

1,100

900

Adenine

27

30

30

Monobasic sodium phosphate

276

Mannitol

750

525

Sodium Chloride

154.00

70.00

15.00

Sodium Citrate

588

Citric acid

42

[Source: Brecker M, ed Technical Manul, 14TH ed Bethesda, MD: American Association of Blood
Banks, 2003: 183]
Table 2b:Content of additive solutions (mg/100mL)

24

Compatibility testing

Development of one or more specific red cell

antibodies (alloimmunisation) is a common
complication of chronic transfusion therapy
(Spanos, 1990; Singer, 2000). Thus it is
important to monitor patients carefully for
the development of new antibodies and to
eliminate donors with the corresponding
antigens. Anti-E, anti-C and anti-Kell
alloantibodies are the most common.
However, 5-10% of patients present with
alloantibodies against rare erythrocyte
antigens or with warm or cold antibodies of
unidentified specificity.

If new antibodies appear, they must be

identified so that in future blood lacking
the corresponding antigen(s) can be
used. A complete and detailed record of
antigen typing, red cell antibodies and
transfusion reactions should be
maintained for each patient, and should
be readily available when and if the
patient is transfused at a different centre.
Transfusion of blood from first-degree
relatives should be avoided because of
the risk of developing antibodies that
might adversely affect the outcome of a
later stem cell transplant.

It is recommended that:

Before each transfusion it is

necessary to perform a full
crossmatch and screen for
new antibodies.

Before embarking on
transfusion therapy, patients
should have extended red cell
antigen typing that includes
at least C, c, E, e and Kell, in
order to help identify and
characterise antibodies in
case of later immunisation;

Transfusion
programmes
The recommended treatment
for thalassaemia major involves
lifelong regular blood
transfusions, usually
administered every two to five
weeks, to maintain the pretransfusion haemoglobin level
above 9-10.5 g/dl.

All patients with thalassaemia

should be transfused with
ABO and Rh(D) compatible
blood.

This transfusion regimen promotes normal

growth, allows normal physical activities,
adequately suppresses bone marrow activity
in most patients, and minimises transfusional
iron accumulation (Cazzola, 1995 and 1997).
A higher target pre-transfusion haemoglobin
level of 11-12 g/dl may be appropriate for
patients with heart disease or other medical

In addition, the use of blood that is also

matched for the C, E and Kell antigens is
highly recommended in order to avoid
alloimmunisation against these antigens.
Some centres use even more extended
antigen matching.

25

conditions and for those patients who do not

achieve adequate suppression of bone
marrow activity at the lower haemoglobin
level. Although shorter intervals between
transfusions may reduce overall blood
requirements, the choice of interval must
take into account other factors such as the
patients work/school schedule and other
lifestyle issues.

(Michail-Merianou, 1987; Spanos, 1990; see

Table 3). Presence of alloantibodies and
autoantibodies (see below) may severely
compromise transfusion therapy in patients
with thalassaemia intermedia, for example,
who receive their first transfusions in
adolescence or later.
Recommendations regarding the volume of
transfused red cells are complicated by the
use of different anticoagulant-preservatives
and additive solutions. For CPD-A units with a
haematocrit of approximately 75%, the
volume per transfusion is usually 10-15
ml/kg, administered over 3-4 hours. Units
with additive solutions may have lower
haematocrits in the range of 60-70%, and
consequently larger volumes with a higher
haematocrit level are needed to administer
the same red cell mass (see Table 4). For
most patients, it is usually easier to avoid
these differences in red cell concentration by
ordering a certain number of units (e.g. one
or two) rather than a particular volume of
blood. Younger children may require a
fraction of a unit to avoid under- or overtransfusion. Patients with cardiac failure or
very low initial haemoglobin levels should
receive smaller amounts of red cells at slower
rates of infusion.

The decision to initiate lifelong transfusion

therapy should be based on a definitive
diagnosis of -homozygous thalassaemia. This
diagnosis should take into account the
molecular defect, the severity of anaemia on
repeated measurements, the level of
ineffective erythropoiesis, and clinical criteria
such as failure to thrive or bone changes.
The initiation of regular transfusion therapy
for severe thalassaemia usually occurs in the
first two years of life. Some patients with
milder forms of thalassaemia who only need
sporadic transfusions in the first two decades
of life may later need regular transfusions
because of a falling haemoglobin level or the
development of serious complications (see
Chapter 11: Thalassaemia Intermedia and
HbE). The risk of alloimmunisation appears to
be greater in patients who begin transfusion
therapy after the first few years of life
Age at First Transfusion Alloimmunisation Rate
< 1 year old

7.7%

> 1 year old

27.9%

[Machail-Merianou et al, 1987]

Age at First Transfusion Alloimmunisation Rate

< 3 years old

20.9%

> 3 years old

47.5%

Table 3: Age and alloimmunisation in Thalassaemia

26

[Spanos et al, 1990]

Haematocrit of Donor Red Cells

Target
Increase in
Haemoglobin
Level

50%

60%

75%

80%

1 g/dl

4.2 ml/kg

3.5 ml/kg

2.8 ml/kg

2.6 ml/kg

2 g/dl

8.4 ml/kg

7.0 ml/kg

5.6 ml/kg

5.2 ml/kg

3 g/dl

12.6 ml/kg

10.5 ml/kg

8.4 ml/kg

7.8 ml/kg

4 g/dl

16.8 ml/kg

14.0 ml/kg

11.2 ml/kg 10.4 ml/kg

As an example, to raise the haemoglobin level by 4g/dl in a patient weighing 40kg and
receiving AS-1 blood with a haematocrit of 60% would require 560ml. This calculation
assumes a blood volume of 70ml/kg of body weight.

Table 4: Guidelines for choosing how much blood to transfuse

The post-transfusion Hb should

not be greater than 14-15g/dl
and should be monitored
occasionally to allow assessment
of the rate of fall in the
haemoglobin level between
transfusions in evaluating the
effects of changes in the
transfusion regimen, the degree
of hypersplenism, or
unexplained changes in
response to transfusion.

A careful record of transfused

blood should be maintained for
each patient, including the
volume or weight of the
administered units, the
haematocrit of the units or the
average haematocrit of units
with similar anticoagulantpreservative solutions, and the
patients weight. With this
information, it is possible to
calculate the annual blood
requirements as volume of
transfused blood and pure red
cells (haematocrit 100%) per kg
of body weight.

Although erythrocytapheresis, or automated

red cell exchange, has been shown to reduce
net blood requirements and thus the rate of
transfusional iron loading (Berdoukas, 1986;
Friedman, 2003], its use may be limited due
to a two- to three-fold increase in donor
blood utilisation, increased (i) costs, (ii) risk of
transmission of infections and (iii)
development of alloimmunisation.

The latter (RBC at 100% ht) when multiplied

with 1.08, the estimated amount of iron per
ml of RBC (see Chapter 3: Iron Load and Iron
Chelation) yields an approximate value for

27

the amount of transfusional iron that the

patient receives per kilogram of body weight
in a year. Figure 1 shows a detailed example
of how the daily rate of iron loading
(mg/kg/day) is calculated and Table 5 shows
the relationship between the annual
transfusion requirements and the daily rate
of iron loading at two common haematocrits

for donor blood. The rate of transfusional

iron loading may be very important in
choosing the appropriate dose of an iron
chelator. For example, the recommended
dose of the chelator deferasirox is based in
part on the daily or annual rate of
transfusional iron loading.

Patient weight: 40kg

Transfusion amount and schedule: 600ml every 4 weeks.
Average haematocrit of transfused red cells: 60%
Annual blood requirement: 13 transfusions x 600ml/40kg = 195ml/kg
Annual pure red cell requirement: 195ml/kg/yr x 60% (average haematocrit) = 117ml/kg/yr
Annual transfusional iron loading:
117ml/kg/yr of pure red cells x 1.08mg iron per ml pure red cells = 126mg iron
Daily transfusional iron loading: 126mg iron/yr/365 days = 0.34mg/kg

Figure 1: Calculation of annual blood requirements and transfusional iron loading.

Annual Blood
Requirement
(Haematocrit 60%)

Annual Blood
Requirement
(Haematocrit 75%)

100 150 ml/kg

80 120 ml/kg

150 200 ml/kg

Volume of
Pure RBCs/kg
(Haematocrit 100%)

Daily Iron
Loading

60 90 ml/kg

0.18 0.27 mg/kg

120 160 ml/kg

90 120 ml/kg

0.27 0.36 mg/kg

200 250 ml/kg

160 200 ml/kg

120 150 ml/kg

0.36 0.44 mg/kg

250 300 ml/kg

200 240 ml/kg

150 180 ml/kg

0.44 0.53 mg/kg

Table 5: Relationship between annual blood requirements and rate of daily iron loading.

28

Knowing the annual transfusion

requirements is also valuable in
identifying changes that may
constitute important evidence
of hypersplenism or accelerated
destruction of donor red cells.

Adverse reactions
Blood transfusion exposes the
patient to a variety of risks.
Thus, it is vital to continue to
improve blood safety and to
find ways of reducing
transfusion requirements and
the number of donor exposures.

Specific guidelines for consideration of

splenectomy in the presence of increasing
transfusion requirements are difficult to
establish because of a lack of information on
the haematocrit levels of the transfused
blood in earlier recommendations and
uncertainty with regard to long-term
consequences of splenectomy, including
sepsis and thrombosis. Moreover, the
decision to proceed to splenectomy must
take into consideration the individual
patients ability to control iron stores at a
given level of transfusional iron loading.
Nevertheless, as the annual transfusion
requirements rise above 200ml/kg/yr of pure
red cells, splenectomy should be considered
as a potential strategy to reduce the rate of
iron loading.

Adverse events (see Table 6) associated with

transfusion include:
Nonhaemolytic febrile transfusion
reactions: These were common in past
decades, but have been dramatically
reduced by leucoreduction, especially
pre-storage leucoreduction, which sharply
reduces cytokine accumulation and
leucocyte alloimmunisation. In the
absence of effective leucoreduction,
patients experiencing such reactions
should be given antipyretics before their
transfusions. Since fever may accompany
a haemolytic transfusion reaction or the
administration of a unit with bacterial

ACUTE

FREQUENCY

DELAYED

FREQUENCY

Haemolytic (Intravascular)

1/25,000

Alloimmune

1/100

Anaphylactic

1/50,000

Haemolytic (Extravascular)

1/ 2,500

Febrile non-haemolytic

1/100

Graft Vs Host Disease

Rare

Allergic (Urticarial)

1/100

TR Acute Lung Injury

1/10,000

Table 6: Broad categorisation of immune-mediated transfusion related (TR) reactions and reported
frequencies

29

adherence to standard protocols for

screening for antibodies and carrying out
the necessary full crossmatching of donor
units and (4) use of multiple patient
identifiers before transfusing the blood.
In many transfusion units, two staff
members check the identification of the
unit and the recipient prior to beginning
the transfusion.

contamination, these causes should

always be considered in a patient who
develops fever during administration of
red cells.
Allergic reactions are usually due to
plasma proteins and range from mild to
severe. Milder reactions include urticaria,
itching and flushing, and they are
generally mediated by IgE. More severe
reactions, such as stridor, bronchospasm,
hypotension or other symptoms of
anaphylaxis may occur, especially in
patients with IgA deficiency and anti-IgA
antibodies. Occasional mild allergic
reactions often can be prevented by the
use of antihistamines or corticosteroids
before transfusion. Recurrent allergic
reactions can be markedly reduced by
washing the red cells to remove the
plasma. Patients with IgA deficiency and
severe allergic reactions may require
blood from IgA -deficient donors.

If signs and symptoms suggest an acute

haemolytic reaction, the transfusion
should be stopped immediately and
intravenous fluids should be administered
to maintain intravascular volume.
Diuretics may help to preserve renal
function. Disseminated intravascular
coagulation (DIC) may require additional
measures such as heparin. The
identification of the patient and the
donor unit should be re-checked. The
blood bank should also be alerted to the
possibility of an undetected alloantibody.

Acute haemolytic reactions begin within

minutes or sometimes hours of beginning
a transfusion and are characterised by the
abrupt onset of fever, chills, lower back
pain, dyspnea, hemoglobinuria and shock.
These unusual reactions most commonly
arise from errors in patient identification
or blood typing and compatibility testing.
The risk of receiving the wrong blood is
greater for a patient with thalassaemia
who travels to another centre or is
admitted to a hospital not familiar with
his/her case and medical history.
Haemolytic reactions in these patients
can still be avoided by (1) the use of
optimal methods for identifying the
patients and labelling of the sample when
blood is obtained for crossmatch, (2)
proper linkage of the sample to the
donor unit in the blood bank, (3)

Delayed transfusion reactions usually

occur 5-14 days after transfusion and are
characterised by unexpected levels of
anaemia, as well as malaise and jaundice.
These reactions may be due to an
alloantibody that was not detectable at
the time of transfusion or to the
development of a new antibody. A
sample should be sent to the blood bank
to investigate the presence of a new
antibody and to repeat cross-matching of
the last administered unit(s).
Autoimmune haemolytic anaemia is a very
serious complication of transfusion
therapy that usually but not always
occurs in patients with alloantibodies.
Even red cells from seemingly compatible
units (i.e., those units that do not contain
the antigen to which there is a known
alloantibody) may demonstrate markedly

30

complication of transfusion.
Immunosuppressed patients are at
particular risk, but TI-GVHD may also
occur in immunocompetent recipients of
red cells from a haploidentical donor such
as a family member. TI-GVHD usually
occurs within 1-4 weeks of transfusion
and is characterised by fever, rash, liver
dysfunction, diarrhoea and pancytopenia
due to bone marrow failure. To reduce
the risk of TI-GVHD, donated blood from a
family member should be avoided or if
used should always be irradiated before
transfusion. Leucodepletion alone is
inadequate for the prevention of this
complication.

shortened survival, and the haemoglobin

concentration may fall well below the
usual pre-transfusion level. Destruction
both of the donors and the recipients
red cells occurs. The serologic evaluation
by the blood bank usually shows an
antibody that reacts with a wide range of
test cells and fails to show specificity for
a particular antigen. Steroids,
immunosuppressive drugs and
intravenous immunoglobulin are used for
the clinical management of this situation,
although they may give little benefit.
Some patients have also been treated
with rituximab, but the effectiveness of
its use in this situation is presently not
well defined. Autoimmune haemolytic
anaemia occurs more frequently in
patients who begin transfusion therapy
later in life (Rebulla, 1991), and should be
carefully considered before instituting
transfusion therapy for teenagers and
adults with thalassaemia intermedia.

Transfusion-associated circulatory
overload may occur in the presence of
recognised or unrecognised cardiac
dysfunction, or when the rate of
transfusion is inappropriately fast. Signs
and symptoms include dyspnoea and
tachycardia, and the chest radiograph
shows the classic findings of pulmonary
oedema. Treatment focuses on volume
reduction and cardiac support, as
required.

Transfusion-related acute lung injury

(TRALI) is a potentially severe
complication that is usually caused by
specific anti-neutrophil or anti-HLA
antibodies (Swanson, 2006). This
complication is characterised by
dyspnoea, tachycardia, fever and
hypotension during or within six hours of
transfusion. Hypoxemia is present and the
chest radiograph shows bilateral infiltrates
typical of pulmonary oedema although
there is no reason to suspect volume
overload. Management includes oxygen,
administration of steroids and diuretics,
and, when needed, assisted ventilation.

Transmission of infectious agents

including viruses, bacteria and parasites,
are a major risk in blood transfusion (see
Chapter 9: Infections in Thalassaemia
Major). Even in countries where residual
risk of transmission through blood of
clinically significant pathogens (HIV, HBV,
HCV and Syphilis) has been reduced to
minimal levels, problems continue to exist
or emerge because:
A limited range of known pathogens
is targeted in mandatory donor
screening (excludes HPV B-19, HCMV,
EBV, HAV, Yersinia enterolitica,
parasites, e.g., malaria);

Transfusion-induced graft versus host

disease (TI-GVHD) is caused by viable
lymphocytes in units of transfused red
cell. It is a rare but often fatal

31

 Transmission of viruses still occurs

(window period, sensitivity threshold
of tests);
The clinical significance of newly
identified infectious agents (HGV,
GBV-C, TTV, SEN-V, HSV6,7,8) is not
yet completely clarified and donors
are not screened for these agents;
Newly emerging infectious agents
(WNV, SARS, Avian Flu, prions),
constitute serious threats, and;
Absence of widely accepted tests for
bacteria (endogenous and exogenous)
and for parasitic protozoa associated,
for example, with Chagas disease,
toxoplasmosis and babesiosis.

In many regions of the developing world,

where thalassaemia is most prevalent,
continued transmission of hepatitis B,
hepatitis C and HIV underscores the
importance of promoting the quality of
national blood transfusion services, including
voluntary blood donations, careful donor
selection and screening, and public health
services provision of necessary
immunisation.

Summary Recommendations:
Careful donor selection and screening voluntary, regular non-remunerated blood
donation.
Confirm diagnosis of thalassaemia major.
Before initiation of transfusion therapy, confirm laboratory and clinical criteria.
Before first transfusion, extended red cell antigen typing of patients at least for C, E
and Kell.
At each transfusion, give ABO, Rh(D) compatible blood. Matching for C, E and Kell
antigen is recommended.
Before each transfusion, full cross-match and screen for new antibodies.
Keep record of red cell antibodies, transfusion reactions and annual transfusion
requirements for each patient.
Use leucoreduced packed red cells. Pre-storage filtration is recommended, but blood
bank pre-transfusion or bedside filtrations are acceptable alternatives.
Washed red cells for patients who have severe allergic reactions.
Use red cells stored in CPD-A, as fresh as possible (less than one week old) and in
additive solutions for less than 2 weeks.
Transfuse every 2-5 weeks, maintaining pre-transfusion Hb above 9-10.5 g/dl, but
higher levels (11-12 g/dl) may be necessary for patients with heart complications.
Keep post-transfusion Hb not higher than 14-15 g/dl.

32

Iron Overload

Iron overload occurs when iron intake is

increased over a sustained period of time,
either as a result of red blood cell
transfusions or increased absorption of iron
through the gastrointestinal tract (GI). Both
of these occur in thalassaemia, with blood
transfusion therapy being the major cause of
iron overload in thalassaemia major and
increased GI iron absorption being more
important in thalassaemia intermedia.

based on the assumption that

200 mg of iron is contained in
each donor unit.
Thus, irrespective of whether the blood used
is packed, semi-packed or diluted in additive
solution, if the whole unit is given, this will
approximate to 200 mg of iron intake.
According to the recommended transfusion
scheme for thalassaemia major, the
equivalent of 100200 ml of pure RBC per kg
per year are transfused (equivalent to 116232 mg of iron per kg body weight per year
or 0.32-0.64 mg/kg/day). Regular blood
transfusion therapy therefore increases iron
stores to many times the norm unless
chelation treatment is given.

In the absence of any

mechanism of the human body
to excrete excess iron, chelation
therapy is essential and
constitutes the second
important arm, besides
transfusion therapy, of the
clinical management of these
patients.

Increased gastro-intestinal absorption

of iron:
Normal intestinal iron absorption is about 1-2
mg/day. In patients with thalassaemia who
do not receive any transfusion, iron
absorption increases several-fold.

The Rate of Iron

Loading

It has been estimated that iron

absorption exceeds iron loss
when expansion of red cell
precursors in the bone marrow
exceeds five times that of
healthy individuals.

Blood transfusion:
Knowledge of the rate of iron loading from
transfusion to as high a level of accuracy as
possible will contribute significantly to the
formulation of chelation therapy appropriate
for each patient. Simple calculations, such as
those described in the Blood Transfusion
Chapter of this book, can provide the
treating physician with this information.

Transfusion regimens aimed at keeping the

pre-transfusion haemoglobin above 9 g/dl
have been shown to prevent such expansion
(Cazzola 1997). In individuals who are poorly
transfused, absorption rises to 3-5 mg/day or
more representing an additional loading of
1-2 grams of iron loading per year.

In case organisational or other

difficulties do not allow such
estimations, a rough
approximation can be made
33

Patients weight

20 kg

35 kg

50 kg

65 kg

Pure red cell volume (ml)

transfused yearly
(if 100-200 ml/kg/yr)

2,000-4,000

3,500-7,000

5,000-10,000 6,500-13,000

Yearly iron loading from

transfusion (g)

2.3-4.6

4.1-8.2

5.8 -11.6

7.5 -15.1

Daily iron loading from

transfusion (mg)

4.7 -9.5

11.1-22.2

15.9-31.8

20.6-41.5

Table 1: Examples of increase in iron stores from transfusion in the absence of chelation

Figure 1: A simplified scheme of iron turnover in healthy adults is shown above in bold arrows. The broken line
indicates the effect of transfusion on iron turnover, with an increased daily delivery of haem iron to
macrophages which leads to increased iron release rates from macrophages, saturation of transferrin
and the appearance of Non-Transferrin-Bound Iron (NTBI) in blood. This in turn causes increased iron
uptake by the liver and other parenchyma, such as the heart and endocrine glands.
(Adapted from Porter JB. Hematol Oncol Clin North Am. 2005;19:1-6)

(atoms or molecules with unpaired

electrons). These can damage lipid
membranes, organelles and DNA causing cell
death and the generation of fibrosis. In
health, iron is kept safe by binding to
molecules such as transferrin, but in iron
overload their capacity to bind iron is
exceeded both within cells and in the plasma
compartment. The resulting free iron
damages many tissues in the body and is
fatal unless treated by iron chelation therapy.

Toxicity from Iron

Overload
Mechanism of iron toxicity
Iron is highly reactive, easily alternating
between two states iron III and iron II in a
process which results in the gain and loss of
electrons, generating harmful free radicals

34

increase serum ferritin, while vitamin C

deficiency may depress it. A sudden and
unexpected rise in ferritin level should
prompt a search for hepatitis, other
infections or inflammatory conditions. In
thalassaemia intermedia, serum ferritin tends
to underestimate the degree of iron
overloading (Pootrakul 1981). Therefore
although there is a broad correlation
between serum ferritin level and liver iron,
the prediction of iron loading from serum
ferritin can be unreliable (Olivieri 1995).
Importantly, however, at least five studies
have shown an association between the
control of serum ferritin and prognosis
(Gabutti V and Piga A. 1996; Olivieri, N. et al
1994; Telfer PTl, 2000; Davis BA, et al. 2004;
Borgna-Pignatti, 2004). Studies have
identified a significantly lower risk of cardiac
disease and death in at least two-thirds of
cases where serum ferritin levels have been
maintained below 2,500 g/L (with
desferrioxamine) over a period of a decade
or more (Olivieri, 1994). Observations with
larger patient numbers show that
maintenance of an even lower serum ferritin
of 1,000 g/L may be associated with
additional advantages (Borgna-Pignatti, 2004)
(see Table 2).

Complications of iron overload

Untreated transfusional iron overload in
thalassaemia major is fatal in the second
decade of life, usually as a result of cardiac
complications (Zurlo 1989). Iron overload also
causes pituitary damage, leading to
hypogonadism and poor growth. Endocrine
complications, namely diabetes,
hypothyroidism and hypoparathyroidism, are
also seen. Liver disease with fibrosis and
eventually cirrhosis, particularly if
concomitant chronic hepatitis is present, is
also a serious complication. (These
complications are described in greater detail
in the relevant chapters of this book.)

Monitoring of Iron
Overload
Monitoring closely and assessing as accurately
as possible iron overload is essential in
establishing effective iron chelation regimes,
such as those mentioned in this chapter,
tailored to the individual patients specific
needs. However, some general principles of
monitoring iron overload apply to all
treatments:

Liver iron concentration (LIC)

Liver iron concentration is now regarded as
the reference standard for estimating body
iron loading and has been shown accurately
to predict total body iron stores (Angelucci,
2000), using the formula:

Serum ferritin
This is a relatively easy test to perform, well
established, generally correlating with body
iron stores and prognostically relevant in
thalassaemia major. Up to a value of about
3,000 g/L serum ferritin is secreted in an
iron-free form from macrophages, but above
this value increasing proportions of ironladen ferritin leaks from hepatocytes
(Worwood, 1980; Davis, 2004). Day-to-day
variations are particularly marked: high
degrees of iron loading, inflammation,
hepatitis and/or liver damage may falsely

Total body iron stores in mg/kg = 10.6 x the

LIC (in mg/g dry wt)
Normal LIC values are up to 1.8 mg/g dry wt,
with levels of up to 7 mg/g dry wt seen in
some non-thalassaemic populations without
apparent adverse effects.

35

Several studies link high Liver Iron Content

(LIC) (above 15-20 mg/g dry wt) to
worsening prognosis (Brittenham, 1993;

Telfer, 2000), liver fibrosis progression

(Angelucci, 1997) or liver function
abnormalities (Jensen, 2003).

Table 2: Measuring and interpreting serum ferritin

Advantages

Disadvantages

Easy to assess

Inexpensive

Repeat measures are useful for monitoring

chelation therapy
Positive correlation with morbidity and

mortality

In the absence of prior iron chelation

therapy, the risk of myocardial iron loading
increases with the number of blood units
transfused (Buja and Roberts, 1971; Jensen,
2003). However, more recent studies have
identified discordance between liver and
cardiac iron loading in some patients
receiving iron chelation: patients with
increased liver iron may have normal cardiac
iron stores, while patients with normal or
near normal liver iron may have increased

Indirect measurement of iron burden

Fluctuates in response to inflammation,
abnormal liver function, metabolic
deficiencies
Serial measurement required

cardiac iron. While the control of total body

iron over a period of years is important to
prognosis, liver iron concentrations are less
important than cardiac iron in determining
the immediate risk of heart failure. Thus,
while the long-term control of body iron is
important to prognosis, the risk for specific
organ damage to the liver or heart at any
given time is best assessed by measuring the
iron in the organ of interest.

36

LIC can also be measured accurately using a

method known as SQUID (supercoducting
quantum interference device). However, only
four such machines are currently available
worldwide: they are expensive to purchase
and maintain, and require dedicated trained
staff. Liver iron measured by SQUID has the
advantage of possessing a wide linear range
but each SQUID machine has to be
individually calibrated.

LIC determination should be considered, by

the treating physicians for those patients
whose serum ferritin levels deviate from
expected trends (i.e. those with suspected
co-existing hepatitis, or patients on chelation
regimens with variable or uncertain
responses), as this may reduce the risk of
giving either inadequate or excessive doses
of chelation therapy. Since the relationship
of serum ferritin to iron overload and iron
balance has not yet been established,
assessment of LIC may be particularly useful
when new chelating regimes are being used.

LIC can also now be measured using MRI

techniques, previously limited to a relatively
narrow linear range. One recently described
approach, is the R2 or Ferriscan technique
which appears to have acceptable linearity
and reproducibility over the range of clinical
interest (St Pierre TG, et al, 2005). The
technique demonstrates an average
sensitivity of >85% and specificity of >92%
up to an LIC of 15 mg/g dry wt, and has
been registered in the EU and US. For
calibration, the MRI machine must use a
Phantom supplied by the company, while the
data acquired is sent via internet for analysis
by dedicated Ferriscan software (payment
per scan analysed). A particular advantage of
this technique is that it can be applied with
little training, at any centre with a reasonably
up-to-date MRI machine (see Table 4).

Measurement of LIC can be done by chemical

determination on a liver biopsy sample
(fresh, fixed or from dewaxing of paraffinembedded material)(see Table3) or by noninvasive methods such as magnetic
biosusceptometry (SQUID) (Brittenham, 1993)
or magnetic resonance imaging (MRI)(see
Table 4). Biopsy is an invasive procedure, but
in experienced hands has a low complication
rate (Angelucci 1997). Inadequate sample
size (<1 mg/g dry weight, 4 mg wet wt or
about a 2.5 cm core length) or uneven
distribution of iron, particularly in the
presence of cirrhosis (Villeneuve 1996), may
give misleading results.

Table 3: Measuring LIC by liver biopsy

Advantages

Disadvantages

Invasive, painful procedure associated with

potentially serious complications
Risk of sampling error, especially in
patients with cirrhosis
Requires skilled physicians and
standardized laboratory techniques

Direct measurement of LIC

Validated reference standard
Quantitative, specific, and sensitive
Allows for measurement of non-heme
storage iron
Provides information on liver
histology/pathology
Positive correlation with morbidity and
mortality

37

myocardial T2* to <20 ms (implying

increased myocardial iron) is associated with
an increased chance of decreased LV
function (Anderson et al, 2001). For example,
patients with T2* values >20 ms have a very
low chance of decreased LVEF. T2* values of
10-20 ms indicate up to a 10% chance of
decreased LVEF; 8-10 ms indicates an 18%
chance; 6 ms indicates a 38% chance; and
T2* values of just 4 ms indicate a 70% chance
of decreased LVEF (Westwood, 2007). In
centres where such methodology is available,
the T2* value may identify patients at high
risk of developing a fall in LVEF before it
occurs permitting a more informed choice
regarding patients whose chelation
treatment should be intensified.

Heart function
Regular monitoring of left ventricular
ejection fraction (LVEF) has allowed
identification of a group of patients with
poor prognosis at high risk of subsequent
heart failure and death who responded well
to intensification of desferrioxamine (Davis et
al, 2004). Patients with a fall in ejection
fraction below reference values for the
method used have a 35-fold increased risk of
cardiac failure and death, with a median
interval to progression of 3.5 years allowing
time for intensification of chelation
treatment. Left ventricular function can be
quantified using MRI, MUGA or
echocardiography. The first two methods
have advantages over echocardiography in
that they are less operator-dependent and
therefore more easily adapted to longitudinal
monitoring.

The ability to estimate heart iron offers an

additional way to stratify risk, opening up a
new diagnostic window. However, factors
affecting the risk of developing heart failure
from myocardial iron overload are complex,
while T2* measures storage iron not in
itself directly toxic to cells. Factors that may
increase the availability of labile intracellular
iron to cause intracellular damage such as
myocarditis, or lack of continuous exposure
to intracellular chelation, may influence the

Myocardial iron estimation (T2* or

other measures)
Estimation of myocardial iron using MRI is
becoming increasingly available but requires
expertise in its use and standardisation.
The T2* value in tissues shortens as the iron
concentration increases. A shortening of

Table 4: MRI assessment of LIC

Advantages

Disadvantages

Assesses iron content throughout

the liver
Potentially widely available
Pathological status of liver and heart
can be assessed in parallel

Indirect measurement of LIC

Requires MRI imager with dedicated
imaging method

Liver iron levels can be assessed using a technique known as R2 (spin echo) MRI, which is a
validated and standardised method for measuring LIC
MRI=Magnetic Resonance Imaging

38

risk posed by excess heart iron, and explain

why only a proportion of people with short
T2* values show abnormal heart function at
any moment in time. Prospective data on the
relationship between myocardial T2* and
survival are still required. However, the
relationship between short T2* values
(<10ms) and the risk of heart dysfunction is
clear (see Table 5).

of which can redox cycle. One

way of measuring the NTBI
fraction that is labile and can
redox cycle is the labile plasma
iron assay (LPI assay). However,
although the measurement of
NTBI (or LPI) has proved a useful
tool for examining how
chelators interact with plasma
iron pools, its value as a guide
to routine treatment or
prognosis has yet to be
demonstrated.

Urinary iron estimation

Measurement of the urinary iron excretion
can assist in assessing the effect on iron
excretion of desferrioxamine (about half of
total iron excreted in urine) or deferiprone
(over 80% of iron excreted in urine).
However, the inherent variability in daily iron
excretion necessitates repeated
determinations. Faecal iron excretion
contributes an additional, but variable (30100%) to the amount of urinary iron
excretion, depending on the level of iron
stores, the dose of desferrioxamine and the
level of haemoglobin (Pippard 1982).

Other markers of oxidative damage

A wide variety of markers for oxidative
damage have been investigated.
Malondialdehyde (MDA) is increased in iron
overload, while a wide range of antioxidants
are depleted.

There has been interest in the

use of antioxidants or naturally
occurring products that contain
antioxidant properties, such as
Curcumin. However, until
controlled data are available
caution is advised in the use of
these, as the effects of
antioxidants in the presence of
iron can be unpredictable due
to redox cycling of iron
between the iron (II) and iron
(III) states.

Plasma non-transferrin bound iron

(NTBI)
In iron overload, transferrin, the normal
carrier of iron in plasma becomes saturated
leaving iron unbound i.e. Non-Transferrin
Bound Iron (or NTBI).
NTBI is cleared by different cells than
transferrin iron, and is mainly responsible for
the abnormal pattern of iron distribution in
transfusional iron overload. Because these
forms of iron rapidly reappear once iron
chelators are cleared from the blood, experts
suggest that the optimal treatment is 24hour chelation (Porter, 1996).

Other markers of organ dysfunction.

These are discussed more fully in other
chapters. However, iron overloaded patients
should be monitored for evidence of
hypoganadotrophic hypogonadism (growth
and sexual development and biochemical

NTBI consists of several chemical

entities, only some of which are
readily chelatable and only some

39

Iron appears to be removed more quickly

from some tissues, such as the liver, than
others for example, the heart.

markers of HH), diabetes mellitus (yearly GTT),

hypothyroidism and hypoparathyroidism.

Treatment of Iron
Overload

Increasing the dose of chelators given in an

attempt to speed up iron removal runs the
risk of increasing the toxicity of an iron
chelator, by chelating the iron needed for
normal tissue metabolism. The twin goals of
iron chelation in iron overloaded patients is
therefore to decrease tissue iron to safe
levels, while simultaneously making the iron
as safe as possible by binding the toxic iron
pools responsible for causing tissue damage.
Iron is constantly being turned over, either as
a result of the breakdown of red cells in
macrophages or the breakdown of ferritin
within cells. These same fractions are redoxactive and potentially harmful; the plasma
component of this iron (NTBI) is mainly
responsible for the iron loading of tissues.
As mentioned above, NTBI appears within
minutes of a chelator being cleared from the
body. Thus, in order to achieve the second
goal of chelation the minimisation of toxic
(labile) iron pools 24-hour chelation
coverage is the ideal, especially in heavily iron
loaded patients. Once low levels of iron have
been achieved, it is theoretically more
appropriate to reduce the dose of chelator
than to interrupt or decrease the frequency
of chelation.

Goals of iron chelation therapy

The primary goal of chelation

therapy is to maintain safe levels
of body iron at all times.
Unfortunately, once iron
overload has accumulated,
removal of storage iron is slow
and inefficient, because only a
small proportion of body iron is
available for chelation at any
given time.
Consequently, when an iron chelator is given,
only a small proportion of the drug binds
iron, before it is excreted or metabolised.
Once a patient is iron overloaded, it may take
months or years to reduce body storage iron
to safe levels, even with the most intensive
treatment. Chelation must therefore begin
soon after (2-3 years) the initiation of
transfusion therapy.

Table 5: MRI assessment of cardiac iron

Advantages

Disadvantages

Rapidly assesses iron content in

the septum of heart
Iron levels can be quantified reproducibly
Functional parameters can be examined
concurrently
Pathological status of liver and heart
can be assessed in parallel

Indirect measurement of cardiac iron

Requires MRI imager with dedicated
imaging method
Technically demanding
Methodology remains to be standardized
and validated

Cardiac iron levels can be rapidly and effectively assessed using a technique know as T2* (gradient echo) MRI, which is becoming the new standard method
MRI=Magnetic Resonance Imaging

40

Desferrioxamine
(Desferal or
deferoxamine)

approximately 14%. Iron excretion with

desferrioxamine increases with dose, with
body iron stores and in vitamin C deficient
patients with the addition of vitamin C.

Desferrioxamine has been in clinical use since

the 1970s and widely used as subcutaneous
infusions since about 1980. Provided that
treatment is 1) begun within 2-3 years of
beginning transfusion therapy, 2)
administered regularly and 3) administered in
adequate doses, desferrioxamine has a wellestablished impact on survival and on cardiac
and other complications of iron overload
described above (Brittenham, 1993; Gabutti
and Piga, 1996; Borgna-Pignatti, 2004).

Effects on serum ferritin

Clinical experience over a period of three
decades indicates that ferritin can be
controlled with desferrioxamine
monotherapy, and that maintaining serum
ferritin <2500 g/L with this drug is closely
linked to protection from heart disease and
to improved survival (Olivieri, 1994).

Evidence for the effectiveness of

desferrioxamine

However, the results of a formal

prospective study on the dose
required to stabilise or decrease
serum ferritin in large
populations have only recently
become available.

The main disadvantages of the

treatment are that it is costly
and that it must be
administered parenterally.

The study a prospective evaluation of

changes in ferritin levels and LIC as a function
of dose in 290 thalassaemia major patients
(Cappellini, 2006) demonstrated that a
mean daily dose of 42 mg/kg resulted in a
small decrease in serum ferritin of 364 g/L
at one year, whereas a mean daily dose of 51
mg/kg resulted in an average ferritin
decrease of approximately 1,000 g/L over
one year. Therefore, if the serum ferritin is
>2,500 g/l, a mean daily dose of at least 50
mg/kg/day is recommended (except in
children see below).

Mechanism of action and

pharmacology
Due to its molecular size, desferrioxamine is
poorly absorbed from the gut. The higher
the dose, the higher the proportion of iron
excreted in the faeces rather than the urine.
Iron excreted in the urine is derived from the
breakdown of red cells in macrophages,
whereas faecal iron is derived from iron
chelated within the liver (Hershko, 1979;
Pippard, 1982). Desferrioxamine has a short
plasma half-life (initial half-life 0.3h), being
eliminated rapidly in urine and bile. The
process of iron chelation ceases soon after
an infusion of desferrioxamine is complete.
The efficiency of desferrioxamine (measured
in terms of percent of dose excreted in the
iron bound form) administered at standard 812 hour intervals 5-7 days a week is

Effects on liver iron

Administered at least 5 times a week and in
sufficient doses, desferrioxamine is effective
in controlling liver iron and hence total body
iron stores (Brittenham, 1993). The
relationship between dose and change in LIC
was not examined systematically until
recently (Cappellini, 2006), in a study

41

establishing that a mean dose of 37 mg/kg

stabilised LIC for patients with baseline LIC
values of between 3 and 7 mg/g dry wt. For
patients with LIC values between 7 and 14
mg/g dry wt, a mean dose of 42 mg/kg
resulted in a small decrease of 1.9 mg/kg dry
wt. In patients with LIC values >14 mg/g dry
wt, a mean dose of 51 mg/kg resulted in LIC
decreases of an average of 6.4 mg/g dry wt.

Early intervention therefore for decreased LV

function is therefore recommended. Once
heart function has been improved, sustained
compliance is critical to outcome especially
while increase myocardial iron remains (Davis,
2004) .

Effects on heart iron (T2*)

Treatment with continuous

intravenous desferrioxamine has
been shown to improve
myocardial iron, even in the
most overloaded hearts, with

Thus a dose of 50 mg/kg at least 5 days a

week is recommended if a significant
decrease in LIC optimal levels (see above) is
required. It should be emphasised that these
are average changes and that the dose
required may increase or decrease depending
on transfusion requirement (Cohen, 2005).

average myocardial T2* values of <6 ms

(Anderson, 2004). The average rate of
improvement at this level of iron loading of
the heart is about 3 ms/year in severely
overloaded hearts: if improvement is linear it
would take several years to normalise the T2*
to >20 ms (Porter 2002).

Effects on heart function

Subcutaneous therapy has long been known
to improve asymptomatic cardiac disease
(Freeman, 1983; Wolfe, 1985; Aldouri et al,
1990). Since the introduction of
desferrioxamine, the incidence of ironinduced heart disease has fallen progressively
in cohorts of patients with a key factor
being the age of starting treatment
(Brittenham, 1994; Borgna-Pignatti, 2004).
Symptomatic heart disease can be reversed
by high dose intravenous treatment (Marcus,
1984; Cohen, 1989). The same results can be
obtained with excellent long-term prognosis
with lower doses (50-60 mg/kg/day see
below) and consequently less drug toxicity
using continuous dosing (Davis, 2000 and
2004). Continuous intravenous doses of 5060 mg/kg/day typically normalised LVEF in a
period of three months (Anderson LJ, et al.,
2004), significantly before liver or heart iron
stores had been normalised. However, if
advanced heart failure has developed before
treatment is intensified, the chances of
successful rescue are decreased.

In patients with baseline T2* values of

between 8-20 ms, subcutaneous treatment
at relatively low doses of 35 mg/kg showed
an average improvement in T2* of 1.8 ms
over one year (Pennell 2006). At a slightly
higher dose of 40-50 mg/kg, five days a
week, patients showed an improvement of 3
ms over one year (Porter et al, 2005).
Improvement in cardiac T2*, even at low,
intermittent doses, has been confirmed by
two prospective randomised studies (Pennell,
2006; Tanner, 2006).

Effects on morbidity
Regular subcutaneous therapy started before
the age of 10 years reduces the incidence of
hypogonadism (Bronspiegel-Weintrob, 1990),
as well as other endocrine disturbances,
including diabetes mellitus (Brittenham,
1993; Olivieri, 1994; Borga-Pignatti, 2004)

42

demonstrated by the improving survival in

patients born between the 1960s and the
present day (see Figure 3). Note that only
patients born after 1980 will have started
treatment at an early age, and that age of
starting treatment is a key factor in outcome
(Borgna-Pignatti, 2004; Brittenham, 1993;
Davis, 2004).

Effects on survival and complications

of iron overload
As mentioned previously, desferrioxamine
was first used to treat iron overload in
thalassaemia in the 1970s but was only
widely used by infusion after 1980. The
benefits of its regular use are clearly

Table 6: Decreasing complications in cohorts born after desferrioxamine was already available.

Birth 197074*

Birth 198084

Death at 20 years

5%

1%

Hypogonadism

64.5%

14.3%

Diabetes

15.5%

0.8%

Hypothyroidism

17.7%

4.9%

* IM, DFO introduced in 1975

SC, DFO introduced in 1980
In 1995, 121 patients switched to DFP (censored at the time)

Survival probability

Figure 3: Increasing probability of survival (% alive at ages shown) with desferrioxamine therapy for
thalassaemia, mainly as a result of decreased cardiac iron toxicity, in patient cohorts born
between 1960-64 and 1995-97 (Borgna-Pignatti, 2004)

Age (years)

43

infections such as Klebsiella may also be

exacerbated by continued treatment with
desferrioxamine.

Desferrioxamine needs to be
taken at least five times a week
in order to optimise survival
(Gabutti and Piga, 1996). Fatal
complications from iron
overload are also decreased if
body iron (as measured by liver
iron) is kept below certain levels
(Brittenham, 1993) (see below).

It is therefore recommended to cease

administration of desferrioxamine in anyone
with an unexplained fever, until the cause
has been identified and effective antibiotic
treatment begun. The decision as to when to
recommence treatment with desferrioxamine
requires clinical judgement and a careful
balancing of the potential risks and benefits.
For example, a patient with high cardiac iron
or poor heart function may be at high risk if
desferrioxamine is withheld during a septic
episode, outweighing the risks of infection
once antibiotics have been commenced.

Unwanted effects of
desferrioxamine
Local skin reactions, such as itching,
erythema, induration and mild to moderate
discomfort are common and may be due to
inadequate dilution of desferrioxamine.
Ulceration at the site of a recent infusion
results from an intradermal infusion of
desferrioxamine and should be addressed by
deeper placement of the needle in
subsequent infusions.

Severe allergy to desferrioxamine is a rare

event and can be treated by careful
desensitisation, carried out under close
medical supervision (Bosquet, 1983; Miller,
1981). Desensitisation is usually successful
but may need to be repeated. If
unsuccessful, an alternative chelator, such as
Deferiprone or Deferasirox (see below), may
be considered.

Infection with Yersinia enterocolitica is an

important risk associated with
desferrioxamine treatment (described in
detail in the Chapter 9: Infections in
Thalassaemia Major). Such an infection may
be difficult to diagnose. However, where
there is reasonable clinical suspicion of
infection, with Yersinia enterolitica treatment
with desferrioxamine should be temporarily
discontinued. Infection should be considered
in any patient with a febrile illness, especially
when associated with abdominal pain,
diarrhoea or joint pains, and should be
treated as a medical emergency.
Desferrioxamine can usually be reintroduced
once symptoms have subsided and a full
course of antibiotics completed. Other

Dose-related
complications
Administration of excessive dosage of
desferrioxamine may cause the following
complications in patients who are not heavily
iron loaded:

44

Hearing problems: High frequency

sensory neural loss, tinnitus and deafness
may occur when desferrioxamine is given
in high doses, particularly to young
children whose iron burden is low
(Olivieri, 1986), and when the therapeutic

essential in all children (see Chapter 4:

Endocrine Complications).

index is exceeded (>0.025) (Porter,

1989). Minor sensory neural deficit has
been reversible in some cases, but
significant hearing loss is usually
permanent. It is therefore advisable to
monitor audiometry yearly, bearing in
mind that audiometric changes due to
excessive desferrioxamine are usually
symmetrical; asymmetry suggests other
pathology.

Effects on the eye: These were first

noted when very high doses (>100
mg/kg/day) were given (Davies, 1983).
Symptoms may include night-blindness,
impaired colour vision, impaired visual
fields and reduced visual acuity. Severe
cases may show signs of retinitis
pigmentosa on fundoscopy, whereas
milder cases are only demonstrable with
electroretinography. The main risk factor
appears to be high dose (Olivieri, 1986)
but complications are also more likely in
patients who have diabetes (Arden, 1984)
or those receiving concomitant
phenothiazine treatment (Blake, 1985).
Treatment with desferrioxamine should
be temporarily suspended in patients who
develop complications, to be
reintroduced at lower doses once
investigations indicate resolution of the
problem.

Skeletal changes: These are more

common in cases of excessive dosage of
desferrioxamine where patients have a
low level of iron loading (De Virgillis,
1988; Olivieri, 1992; Gabutti, 1996).
Rickets-like bony lesions and genu valgum
may be seen in association with
metaphyseal changes, particularly in the
vertebrae, giving a disproportionately
short trunk. Radiographic features include
vertebral demineralisation and flatness of
vertebral bodies. Patients should be
regularly observed for such changes, as
they are irreversible.

Rare complications: Renal impairment

and interstitial pneumonitis have been
reported at very high doses of 10
mg/kg/h or more. In patients without
iron overload, desferrioxamine has
induced reversible coma when used with
a phenothiazine derivative (Blake, 1985).
Rapid intravenous injection, as may occur
during flushing of a line containing
desferrioxamine, must be avoided.

Recommended
standard therapy

Growth retardation: This may occur if

desferrioxamine is administered at too
high a dose. Another risk factor is a
young age of starting treatment (<3yrs)
(De Virgillis, 1988; Piga, 1988). Growth
velocity resumes rapidly when the dose is
reduced to <40 mg/kg day, while it does
not respond to hormonal treatment. It is
therefore recommended that doses do
not exceed 40 mg/kg until growth has
ceased. Regular monitoring of growth is

Standard dose and frequency

The standard recommended

method is slow subcutaneous
infusion over 8-12 hours of a
10% desferrioxamine solution,
using an infusion pump.
In general, average doses should not exceed
40 mg/kg until growth has ceased. The
standard dose is 20-40 mg/kg for children,

45

Liver iron concentration (by biopsy, SQUID or

MRI) has recently been advocated as a more
reliable alternative to serum ferritin (see
below). To avoid wasting a costly drug such
as desferrioxamine, the dose can be adjusted
to the nearest whole vial (500 mg or 2 g),
alternating dose volumes between the higher
and lower number of vials to achieve the
desired mean daily dose.

and up to 50-60 mg/kg for adults, as an 812-hour subcutaneous infusion for a

minimum of 6 nights a week. To achieve
negative iron balance in patients with
average transfusion requirements, a dose of
50 mg/kg/day at least 5 days a week is
required (Capellini, 2005). It is important that
patients with high degrees of iron loading or
at increased risk of cardiac complications
receive adequate doses.

When to start desferrioxamine

therapy

Use of desferrioxamine by
subcutaneous bolus

In thalassaemia major, this should start as

soon as transfusions have deposited enough
iron to cause tissue damage. This has not
been formally determined, but current
practice is to start after the first 10-20
transfusions or when the ferritin level rises
above 1,000g/l. If chelation therapy begins
before 3 years of age, particularly careful
monitoring of growth and bone development
is advised, along with reduced
desferrioxamine dosage. In thalassaemia
intermedia, the rate of iron loading is highly
variable and the relationship between serum
ferritin and body iron can be different from
that seen in thalassaemia major. If possible,
an estimation of liver iron is advisable before
starting treatment to see whether iron has
exceeded safe levels (see Figure 4).

If an infusion pump is not available or if 10hour infusions are not tolerated, bolus
subcutaneous treatment may be considered
if the patient is not at high risk of heart
disease. A randomised study has shown that
serum ferritin and liver iron can be controlled
equally effectively by giving an equivalent
total dose (45 mg/kg x 5 per week) either as
two subcutaneous boluses or as a nightly
10-hour subcutaneous infusion (Yarali, 2006).

Dose adjustment
At low ferritin levels, the dose of
desferrioxamine may need to be reduced and
desferrioxamine-related toxicities monitored
particularly carefully. Dose reductions can be
made using the therapeutic index (see Figure
4) (Porter, 1989):

Use of vitamin C: 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 desferrioxamine infusion so that
liberated iron is rapidly chelated. Where a
patient has just started on desferrioxamine
and it has been decided to administer
vitamin C, the vitamin supplement should
not be given until after several weeks
treatment.

Figure 4: Therapeutic Index

Therapeutic index =
mean daily dose (mg/kg)* / ferritin (g/l)
The aim is to keep the index < 0.025 at all
times
*mean daily dose = (actual dose received on each
infusion x doses per day/7)

Although a valuable tool in protecting the

patient from excess chelator, this index is not
a substitute for careful clinical monitoring.

46

Desferrioxamine use during

pregnancy: This is discussed in detail in the

Strength of infusion
The manufacturers of desferrioxamine
recommend that each 500 mg vial of the
drug is dissolved in at least 5 ml of water,
giving a 10% solution. Concentrations in
excess of this may increase the risk of local
reactions at the site of infusion.

relevant Chapter 5: Management of Fertility

and Pregnancy in -thalassaemia), but
Desferrioxamine is not generally
recommended unless the risk of cardiac
disease in the mother without chelation
treatment is high.

Site of infusion
Care must be taken to avoid inserting
needles near important vessels, nerves or
organs. The abdomen is generally the best
place. However because of local reactions
such as erythema, swelling and induration, it
is often necessary to rotate the sites used
for injection (see Figure 5). Some patients
find that the skin over the deltoid or the
lateral aspect of the thigh provides useful
additional or alternative sites.

Practical issues with

subcutaneous
infusion
Because regular use of desferrioxamine is
critical to a good outcome, every effort
should be made with each individual to help
him or her to find the most convenient way
to infuse the drug.

Figure 5: Rotation of infusion sites

Figure 6: Insertion of needles for desferrioxamine

infusion

47

Compliance requires a sustained and secure

relationship between doctor, patient and
parents, and regular discussion and support
are keys to maximising compliance. The
reasons for poor compliance are varied. In
some cases, parents cannot sanction the
daily ordeal of chelation therapy for their
child. In others, compliance may only
become a problem when a child reaches
adolescence. Sometimes a previously good
complier may become less compliant when
other life events or stresses become a
burden (see Chapter 15: Psychosocial
Support). Helping a patient to take control or
self-manage is often a useful approach of
long-term benefit (see TIFs book on
Compliance to Iron Chelation Therapy with
Desferrioxamine).

Type of needle
The best needle to use will depend on the
individual. Many patients are happy with
butterfly needles of 25 gauge or smaller,
which are inserted at an angle of about 45
degrees to the skin surface. The needle tip
should move freely when the needle is
waggled. Other patients prefer needles that
are inserted vertically through the skin and
are fixed with an adhesive tape attached to
the needle (see Figure 6). Patient preference
is highly variable and clinicians should explore
the best type of needle for each patient in
order to maximise compliance.

Type of infuser
There are many types of infusers now
available. Newer devices, including balloon
pumps, are smaller, lighter, and quieter than
their predecessors. For patients who find
dissolving, mixing and drawing up
desferrioxamine a problem, pre-filled syringes
or balloons may be useful. Some pumps are
designed to monitor compliance.

Monitoring compliance
There is no perfect way to measure
compliance. One successful approach may be
to give patients a calendar, in which each
infusion of desferrioxamine is noted down
during the treatment. Some pumps can log
usage. Another approach has been to keep a
record of empty vials returned to the
provider of the desferrioxamine.

Local reactions
Persistent local reactions may be reduced by
varying the injection sites, lowering the
strength of infusion or, in severe cases, by
adding 5-10 mg of hydrocortisone to the
infusion mixture.

Rescue therapy with continuous

infusions
In high risk cases, continuous infusion of
desferrioxamine is potentially more beneficial
than periodic infusions because it reduces
the exposure to toxic free iron (NTBI), which
returns to pre-treatment levels within
minutes of stopping a continuous
intravenous infusion (Porter, 1996). The
route of administration is not critical,
provided that as close to 24-hour exposure
to chelation is achieved. Intensification of
treatment through continuous, 24-hour
intravenous administration of
desferrioxamine via an implanted intravenous

Supporting compliance

It is clear that compliance with

therapy determines prognosis.
However, desferrioxamine treatment is
troublesome and time-consuming, and can
be painful. Practical approaches to
maximising compliance by decreasing local
reactions and providing the most convenient
pump system have been discussed above.
Especially important, however, is support
from family and the health care team.

48

delivery system (e.g. Port-a-cath) (Davis,

2000) or subcutaneously (Davis, 2004) has
been shown to normalise heart function,
reverse heart failure, improve myocardial T2*
(Anderson, 2002) and lead to long-term
survival, provided treatment is maintained. In
non-high risk cases, options such as
encouraging the patient to improve
compliance or an increase in dose should be
explored before moving to 24-hour
treatment.

Suggested dosing
A dose of at least 50 mg/kg/day and not
exceeding 60 mg/kg/day is recommended as
a 24-hour infusion (Davis, 2000 and 2004).
Higher doses have been used by some
clinicians however DFO is not licensed at
these doses and the risk of retinopathy
increases. Addition of vitamin C is
recommended only when acute heart
dysfunction has settled, which usually occurs
by three months of continuous treatment
(Anderson, 2004). As ferritin falls, the dose
but preferably not the duration of treatment
can be reduced, in line with the therapeutic
index (see above).

Consideration for intensive therapy

Intensification should be considered in the
following cases:
severe iron overload
- persistently very high ferritin values*
- liver iron > 15 mg/g dry weight *

Management of in-dwelling
intravenous lines
Infection and thrombosis of the catheter
may occur. Careful aseptic procedures must
be followed in order to prevent possible
infection by Staphylococcus epidermidis and
aureus, which when established are difficult
to eradicate and often removal of the
infusion system becomes necessary. The risk
of thrombosis and infection is likely to be
greater in centres that do not have regular
experience in the use of long-term indwelling lines. Use of prophylactic
anticoagulation is advised as line-thrombosis
is relatively common in thalassaemia major
(Davis, 2000). As development of a
thrombosis can occur at the tip of the
catheter, it is advisable, if possible to avoid
placing the tip in the right atrium.

significant cardiac disease^:

- significant cardiac dysrhythmias
- evidence of failing left ventricular
function
- evidence of very severe heart iron
loading (T2*<6 ms)
prior to pregnancy or bone marrow
transplantation, when rapid reversal of
iron loading may be desirable
* If the only abnormalities are high ferritin or LIC, it would
be usual to try to increase the dosing (for example, to 5060 mg/kg) or the duration or the frequency of
subcutaneous infusions.

When cardiac disease is present, 24-hour

intensive therapy(or combination therapy
with desferrioxamine and deferiprone-see
below) is necessary and simple increments in
conventional 8-12-hour dosing are not
recommended.

Intravenous desferrioxamine with

blood transfusion
This has been used as a supplement to
conventional therapy (e.g. 1 g over 4 hours
piggy-backed into the infusion line), but its
contribution to iron balance is very limited.
Special attention must be given to avoiding

49

accidental boluses due to desferrioxamine

collecting in the dead space of the infusion
line. Co-administration of desferrioxamine
and blood can lead to errors in interpreting
side effects such as acute fever, rashes,
anaphylaxis and hypotension during blood
transfusion. Desferrioxamine should never be
added directly into the blood unit.

Effects on serum ferritin

Four prospective randomised trials compare
the effects of deferiprone on serum ferritin
at baseline and at follow-up (Maggio, 2002;
Gomber, 2004; Pennell, 2006; Ha, 2006).
Pooled analysis shows a statistically significant
decrease in serum ferritin at six months in
favour of desferrioxamine (Gomber, 2004;
Ha, 2006), with no difference between the
two drugs at 12 months (Maggio, 2002;
Pennell, 2006). There are numerous nonrandomised cohort studies demonstrating a
lowering of serum ferritin at doses of 75
mg/kg/day administered in three doses. The
effect on serum ferritin at this dose appears
greater at higher baseline ferritin values. In
these studies significant decreases in serum
ferritin are seen in patients with baseline
values above 2,500 g/L (Al-Refaie et al.,
1992; Agarwal, 1992; Oliveiri, 1995) but not
with values below 2,500 g/L (Olivieri,1995;
Hoffbrand,1998; Cohen, 2000).

Deferiprone
(Ferriprox, Kelfer,
L1)
Deferiprone is an orally absorbed iron
chelator that began clinical trials in the UK in
the 1980. It was first licensed for use in
thalassaemia in India, followed by the
European Union and other countries outside
the US and Canada, in the late 1990s.

Pharmacology

Effects on liver iron

Three molecules of deferiprone are required

to bind one iron atom, and the efficiency of
iron binding decreases with falling
concentrations of iron or of chelator. The
drug is rapidly metabolised and inactivated in
the liver by glucuronidation of one of its iron
binding sites (Kontoghiorghes, 1998). At
currently used doses, about 6% of the drug
binds iron before it is excreted or
metabolised (6% efficiency) (Aydinok, 2005).
Unlike desferrioxamine, iron excretion is
almost exclusively in the urine.

Four trials that measure change in liver iron

concentration (LIC) from baseline after a
period of treatment with deferiprone
compared with desferrioxamine are available
(Olivieri, 1997a; Maggio, 2002; Pennell, 2006;
Ha, 2006). One study showed increases in LIC
at 33 months of 5 mg/g dry wt with
deferiprone (n=18) and 1 mg/g dry wt with
desferrioxamine (n=18) (Olivieri, 1997). A
second study showed an average decrease in
LIC at 30 months with both deferiprone
(n=21) and desferrioxamine (n=15) (Maggio,
2002). A third study found decreases in LIC at
one year of 0.93 mg/g dry wt with
deferiprone (n=27) and 1.54 mg/g dry wt
with desferrioxamine (n=30) (Pennell, 2006).

Evidence of effectiveness of
deferiprone
There are considerable accumulated
publications about the effects of
deferiprone. Most of these have not been
randomised controlled trials, making
comparison with desferrioxamine difficult.

50

Another study reported decreases in LIC at six

months with both deferiprone (6.6 mg/g dry
wt, n=6) and desferrioxamine (2.9mg/g dry
wt, n= 7) (Ha, 2006). In a non-randomised
prospective study, using Deferiprone, LIC
increased from baseline by 28% at two years
and by 68% at three years of treatment
(Fischer, 2003). In other studies where only
single biopsies were performed after several
years of Deferiprone treatment, LIC has been
found to be above 15 mg/g dry wt in
variable proportions of patients: 11% (Del
Vecchio, 2002), 18% (Tondhury, 1998) and
58% (Hoffbrand et al, 1998).

was reported for either drug (Maggio, 2002).

A recent study using a new technique
multislice, multiecho T2* demonstrated
improved T2* values in the Deferiprone
group compared to the Desferrioxamine
group (Pepe, 2006).

Effects on survival and complications

of cardiac disease
In six randomised prospective comparisons
with desferrioxamine, mortality was not
reported as an outcome measure while in a
seventh, one death reported in the
Deferiprone arm, but not in the
Desferrioxamine arm was considered as due
to cardiac complications (Ha, 2006). In a
retrospective cohort analysis of patients
treated with deferiprone or desferrioxamine,
no deaths were reported (n=157) in the
Deferiprone arm in contrast to the
desferrioxamine-treated patients (BorgnaPignatti, 2006a), although some caution was
expressed by the authors with regard to the
interpretation of these results. In this analysis
the author noted that there were no cardiac
events in 750 patient years of exposure to
Deferiprone in more than 150 patients.

Effects on heart function

One prospective one-year study found that in
patients with normal left ventricular ejection
fraction, deferiprone given at high doses (92
mg/kg) improved heart function (Pennell,
2006). In another randomised study over one
year, no difference in LVEF or other
measures of LV function was seen with either
deferiprone at 75 mg/kg/day or
desferrioxamine (Maggio, 2002). A
prospective study of the effects of
deferiprone monotherapy on patients with
abnormal LVEF or symptomatic heart disease
has not been reported.

Compliance with deferiprone

One study comparing compliance with
deferiprone and desferrioxamine found rates
of 95% and 72% respectively (Olivieri, 1990),
while another found 94% and 93%
respectively (Pennell, 2006).

Effects on heart iron

The effect of deferiprone monotherapy on
heart iron has been reported in two
prospective studies. One study found
significant improvement in T2* after one year
at 92 mg/kg of deferiprone daily. Patients
with starting T2* values of between 8 and 20
ms showed an average increase from 13 ms
to 16.5 ms in the deferiprone group, and
13.3 to 14.4 ms in the desferrioxamine group
(Pennell, 2006). In another randomised
study, of deferiprone and desferrioxamine
administered at standard doses over one
year, no change in heart iron estimated by T2

Two important points to be taken into

consideration are (i) compliance with any
treatment tends to be higher in studies than
in routine use, and (ii) although compliance
with oral treatment is expected to be better,
it cannot be taken for granted requiring, as
in the use of Desferrioxamine, constant
supervision and patient support.

51

reintroduced, and the use of GM

CSF should be considered in the
case of agranulocytosis; offlabel use of the drug should be
avoided.

Unwanted effects
with deferiprone
Neutropenia, agranulocytosis and
thrombocytopenia

Gastrointestinal symptoms

The most serious and potentially fatal adverse

effect of deferiprone is agranulocytosis
(absolute neutrophil count, or ANC*,
<500/mm3). The condition may occur with
thrombocytopenia, but also isolated
thrombocytopenia has occasionally been
reported. Onset of agranulocytosis is variable,
from a few months to nine years. In a
prospective trial where weekly neutrophil
counts were undertaken and where
deferiprone was discontinued when the ANC
was <1,500/mm3, agranulocytosis developed
in 0.2/100 patient years and milder forms of
neutropenia (ANC 500-1500/mm3) occurred
in about 2.8/100 patient years (Cohen, 2000
and 2003). Recently, 46 cases of
agranulocytosis, were reported, in Europe
with nine related deaths (Swedish Orphan,
safety alert, 2006). Five of these cases were
in patients who had been prescribed the
drug for an unspecified off label indication,
and several were not receiving weekly blood
count monitoring. Swedish Orphan has
subsequently issued the following
recommendations on the use of deferiprone:

Nausea and change in appetite (loss or gain)

occur in 3-24% of patients (Ceci 2002; Cohen
et al, 2000).

Effects on liver
Variable fluctuation in liver enzymes has been
reported. About a quarter of patients show
ALT fluctuation of twice the normal upper
limit (Cohen, 2000). One prospective
randomised study showed no significant endof-study changes in liver enzymes with
deferiprone or desferrioxamine (Pennell,
2006). An observational report of fibrosis
after treatment for three or more years
(Olivieri, 1998) has not been supported by
other reports (Tondury, 1998; Hoffbrand,
1998; Wanless, 2002). A relevant prospective
randomised study investigating the
progression to fibrosis, using Deferiprone for
one year, showed no difference as compared
with Desferrioxamine, over the same period
and no difference in baseline and end-oftreatment liver function tests (Maggio, 2002).

Arthropathy

ANC* should be monitored

every week or more frequently
if there are signs of infection;
concomitant treatment that
could affect the white cell
count should be avoided; if
severe neutropenia or
agranulocytosis develop, the
drug should be stopped and not

The frequency of arthropathy varies greatly

between studies, from as low as 4.5% at one
year (Cohen, 2000) to 15% after four years
(Cohen, 2003) in a predominantly European
patient group, and as high as 33-40% in a
study of patients in India (Agarwal et al,
1992; Choudhry et al, 2004). It is not yet
clear whether these differences reflect
environmental or genetic differences, or
differences in iron overload between
populations at the start of treatment.

* ANC: absolute neutrophil count

52

Symptoms range from mild non-progressive

arthropathy, typically in the knees,
controllable with non-steroidal antiinflammatory drugs to (more rarely) severe
erosive arthropathy that may progress even
after treatment is stopped. Cases involving
other joints, such as wrists, ankles and
elbows, and avascular necrosis of the hips,
have also been described.

As a result of the various

unwanted effects, 20-30% of
patients are unable to sustain
long-term treatment with
deferiprone (Hoffbrand, 1998).
Frequency of adverse events
compared with desferrioxamine
Adverse effects have been reported in four
randomised studies comparing deferiprone
with desferrioxamine. One trial has reported
data that allows comparison of the
probability of an adverse event with
deferiprone and desferrioxamine (Maggio,
2002), establishing a statistically significant
two-fold difference between deferiprone
(34%) and desferrioxamine (15%), but no
difference between temporary or permanent
treatment withdrawal.

Treatment should be stopped

where joint symptoms continue
despite a reduction in
deferiprone dose and are not
controlled by non-steroidal antiinflammatory drugs.
Neurological effects
Neurological complications are very rare and
have been typically associated with
unintentional overdosing. Rare neurological
effects have included cognitive effects,
nystagmus, walking disorders, ataxia, dystonia
and impaired psychomotor skills. These
effects appear to improve on cessation of
treatment.

Pregnancy
Deferiprone is teratogenic in animals and
must never be given to patients attempting
to conceive. Until more is known, potentially
fertile sexually active women and men taking
deferiprone must use contraception.
Deferiprone should not be used in pregnant
women.

Effects on eye and ear

There have been isolated reports of loss of
vision (central scotoma). One study reported
continued audiometric deterioration after
switching from desferrioxamine to
deferiprone (Chiodo, 1997). It is therefore
advisable to monitor for CNS, audiometric
and visual function in patients on regimes
containing deferiprone.

Recommended treatment regimens

with deferiprone
According to the official European licensing
Agency (EMEA*), Deferiprone could be used
as a second line drug, for removing iron in
patients who are unable to use
Desferrioxamine or in whom DFO therapy has
proven ineffective.

Other effects
Zinc deficiency during deferiprone therapy
has also been observed in some patients,
especially those with diabetes.

Standard dosing and frequency

The daily dose of deferiprone that has been
evaluated most thoroughly is 75 mg/kg/day,
given in three doses. In the EU, the drug is
* EMEA:

53

European Agency for the Evaluation of Medicinal

Products

monitoring of the blood count throughout

treatment.

licensed for doses up to 100mg/kg/day but

formal safety studies of this dose are limited.
The standard dose of 75mg/kg/day
administered in three separate doses is
therefore recommended.

Combined
Desferrioxamine and
Deferiprone

Dose escalation with deferiprone.

Doses of 100mg/kg/day have been given in
at least one prospective study (Pennell,
2006), with no increase in side-effects
reported. High dose monotherapy with
deferiprone has not yet been prospectively
evaluated for safety and effectiveness for
patients with abnormal heart function, and
combination therapy with deferiprone and
desferrioxamine (see below) or intensive
therapy with desferrioxamine as a 24-hour
infusion should be recommended for this
group of patients.

A variety of regimens involving combinations

of deferiprone and desferrioxamine have
been used by clinicians, either in the context
of a formal trial or on an ad hoc basis, usually
when monotherapy with desferrioxamine or
deferiprone has failed to control iron
overload or its effects.

Pharmacology
In principle, chelators can be given at the
same time as each other (simultaneously) or
following one another (sequentially). There is
considerable variation in the way in which
sequential treatment can and has been
administered. Some investigators have used
the term alternating therapy to describe the
use of two drugs administered on alternate
days, reserving the term sequential therapy
for when desferrioxamine is given at night
and deferiprone during the day. In practice
regimes may involve a component of
sequential and alternating therapy, such as
when desferrioxamine is given three times a
week (alternate nights) and deferiprone
every day. Most regimes have tended to give
deferiprone daily, at standard doses,
combined with varying frequency and dosing
of desferrioxamine.

Age of commencement
Although there have been some
retrospective reports of its use in children,
the safety and efficacy of this drug has not
been formally evaluated in children under 10
years of age.

Use of vitamin C
The effect of vitamin C on iron excretion
with deferiprone is not clear and is thus not
recommended.

Safety monitoring
Weekly blood counts are necessary
throughout treatment so that a falling white
cell count can be detected early and
treatment stopped before overwhelming
sepsis develops. If severe neutropenia or
agranulocytosis develops, re-challenge is
contra-indicated. Recent reports of eight
deaths from agranulocytosis in patients
treated in Europe, cited above, only
emphasise the importance of scrupulous

The pharmacology of combinations of

chelators may be fundamentally different
depending on whether the drugs are present
in cells or plasma at the same time. By giving
desferrioxamine at night and deferiprone by

54

day (sequentially), 24-hour exposure to iron

chelation can be achieved (similar to that
achieved with 24-hour desferrioxamine
infusion or once daily deferasirox. (For more
on deferasirox (Exjade), see below). This has
the theoretical advantage of 24-hour
protection from labile (redox active) iron
(Cabantchik, 2005). If the drugs are given at
the same time (simultaneously), they may
interact in a process that involves the
shuttling of iron, which may lead to
additional chelation of iron from cells or
plasma and so improved iron removal.
However, there is also a possibility of
chelation from metalloenzymes, leading to
increased drug-related toxicity.

achieved with two nights of desferrioxamine

plus seven days of deferiprone at 75 mg/kg
(n=14). Another randomised study, involving
30 patients and three different treatments
(Gomber et al, 2004), found that the
decrease in serum ferritin was greatest with
five nights of desferrioxamine, albeit not
significantly different from that achieved
with a combined treatment of
desferrioxamine two nights a week plus
deferiprone seven days a week. A third
randomised study, involving 60 patients
(Galanello, 2006), found no difference in the
level of decrease in serum ferritin in patients
randomised to combined treatment (two
days desferrioxamine at 33 mg/kg + seven
days deferiprone at 75 mg/kg) or to
desferrioxamine five nights a week at 33
mg/kg.

In short, the simultaneous use of these drugs

has not been tested formally in large enough
patient groups to allow firm, evidence-based
recommendations about efficacy and safety.

Taken together, these studies suggest that

serum ferritin can be controlled with a
relatively small dose of desferrioxamine given
twice a week, when combined with
deferiprone at standard doses (75
mg/kg/day). In a more recent randomised
study of 65 patients (Tanner, 2007), serum
ferritin was decreased more by combined
treatment (desferrioxamine five days a week
plus deferiprone seven days a week) than
with standard desferrioxamine monotherapy
(40 mg/kg five times a week).

However, data from several prospective

studies indicate that sequential (or
alternating) use of these chelators can be
used to achieve control of iron overload and
improvement in heart iron measurements.

Evidence of efficacy
of combined
treatments

Effects of sequential use on liver iron

One randomised study, assessing the effects
on liver iron of combined treatment
compared to desferrioxamine monotherapy
(n=60), found LIC of <7 mg/g dry wt at
baseline a figure maintained, on average, in
both arms of the study (Galanello, 2006).
Another prospective randomised study,
comparing the effect of desferrioxamine
monotherapy administered subcutaneously
five times a week with that of deferiprone

Effects of sequential use on serum

ferritin
Four randomised studies have compared
levels of serum ferritin in patients using
combined treatments with those under other
treatment regimes. One study (Mourad et al,
2003) found the decrease in serum ferritin
achieved with five days of desferrioxamine
monotherapy (n=11) to be similar to that

55

(T2* 8-20 ms), myocardial T2* changes with

combined deferiprone 75 mg/kg seven days
a week plus desferrioxamine five days a week
were compared with patients on standard
desferrioxamine five times a week (Tanner,
2007). T2* improved in both groups but was
significantly greater (6 ms) with combined
treatment than with desferrioxamine
monotherapy (3 ms). In an observational
study, the T2 of the heart improved with
combined therapy (Kattamis, 2006).

administered daily at 75 mg/kg daily or

deferiprone at 75 mg/kg daily, plus twiceweekly desferrioxamine, found that the
decrease in liver iron was highest in the
desferrioxamine monotherapy group and
lowest in the deferiprone monotherapy
group, with sequential combination
treatment showing an intermediate effect
(Aydinok, 2005). A further randomised study,
comparing deferiprone plus desferrioxamine
five times a week with desferrioxamine
monotherapy five times a week (n=65),
found that an improvement in liver T2* (as a
surrogate measure of LIC) was greater in the
combination arm (Tanner, 2007).

Safety of combined treatment

Formal safety data on combined treatment
are limited. A meta-analysis of the incidence
of agranulocytosis with combined regimes
compared with deferiprone monotherapy
suggests that the risk may be increased
several-fold, although the number of
patients that qualify for evaluation is small
(Macklin, IND submission to FDA, 2004). The
increased incidence appeared to occur
mostly in those regimes where the drugs
were administered simultaneously. In a
recently reported prospective study, one
case of agranulocytosis and two of
neutropenia were seen at one year in the
combination arm, including 32 patients
(Tanner, 2007), while no increase in
arthropathy was observed in the same group
of patients.

Effects of sequential use on heart

function
In the above-mentioned randomised
controlled study of 65 patients (Tanner,
2007), with baseline LVEF >56% changes in
LVEF improved by approximately 2.5% in the
combination arm and 0.5% in the
desferrioxamine monotherapy arm. Two
observational studies have also reported
changes in heart function under combined
treatment. In 79 patients treated with a
variable desferrioxamine regimen plus
deferiprone at 75 mg/kg seven days a week
for a variable time, there was an
improvement in LVEF measured by
echocardiography (Origa, 2005). In an
observational study of 42 patients with
sequential use of treatment over three to
four years (deferiprone 75 mg/kg/day plus
desferrioxamine two to six days a week), the
LV shortening fraction improved (Kattamis,
2006).

Conclusions and possible treatment

regimens

The above-mentioned studies

suggest that some combined
regimens can control iron
overload in the liver and heart
where monotherapy is not
having the desired effects. In
general, if a patient is not doing

Effects of sequential use on cardiac

iron
In a randomised controlled study of 65
patients with moderate heart iron loading

56

provides 24-hour chelation from labile

plasma iron (Nisbet-Brown, 2003; Galanello,
2003). The efficiency of chelation is 28%,
over a wide range of doses and levels of iron
loading.

well with monotherapy,

combined treatment offers an
additional approach (as does
intensive therapy with at least
50 mg/kg/day of
desferrioxamine for as many
hours a day as is practicable-see
above). For patients with very
high levels of heart iron or
cardiac dysfunction, 24-hour
treatment with desferrioxamine
and daily therapy with
deferiprone should be strongly
considered.

Evidence of effectiveness of
deferasirox
Deferasirox has undergone preclinical and
clinical evaluation that has included largescale prospective randomised studies
involving over 1,000 patients, to assess
safety, efficacy and the dose response
effects of treatment. At this time, evidence
of effectiveness is confined to serum ferritin
and liver iron.

Dose effect on serum ferritin

A dose-dependent effect on serum ferritin
has been observed in several studies
(Cappellini, 2006; Piga, 2006). A prospective
randomised study comparing the effects of
deferasirox in 296 thalassaemia major
patients with that of desferrioxamine in 290
patients found that 20 mg/kg daily of
deferasirox stabilised serum ferritin close to
2,000 g/L. At 30 mg/kg, serum ferritin was
reduced, with an average fall of 1,249 g/L
over one year (Cappellini, 2006). Longer-term
analysis of ferritin trends shows that the
proportion of patients with ferritin values
<1,000 g/L and less than 2,500g/L is
decreasing progressively with time (Porter,
2006).

Deferasirox (Exjade)
Deferasirox was developed by Novartis as a
once-daily, oral monotherapy for the
treatment of transfusional iron overload. The
drug has been licensed as first-line
monotherapy for thalassaemia major in over
70 countries worldwide, including the US
(2005) and the EU (2006). The average follow
up in large-scale prospective trials at the time
of writing is three years.

Pharmacology
This is an orally absorbed iron chelator, with
two molecules binding each iron atom. The
tablet is dissolved in water (or apple juice)
using a non-metallic stirrer, and consumed as
a drink once daily, preferably before a meal.
Metabolic iron balance studies show iron to
be excreted almost entirely in the faeces,
with less than 0.1% of the drug eliminated in
urine (Nisbet-Brown, 2003). Metabolism
occurs predominantly by glucuronidation in
the liver. Due to the long plasma half-life
(nine to 11 hours), once-daily administration

Dose effect on liver iron and iron

balance
In the same prospective study, iron balance
was achieved at 20 mg/kg/day, with mean
LIC constant over one year (Cappellini, 2006).
Negative iron balance was achieved at 30
mg/kg/day, while mean LIC fell by 8.9 mg/g
dry wt (equivalent to a decrease in body iron

57

of 94 mg/kg body weight) over one year.

These are average trends and a closer
analysis shows that the blood transfusion rate
influences the response to treatment
(Cohen, 2005). Thus for patients in the high
or low transfusion category (see Table 7), the
average dose required to achieve iron
balance is accordingly adjusted up or down
from 20mg/kg/day (Cohen, 2005). Some
patients will still fail to achieve negative iron
balance at a daily dose of 30 mg/kg/day of
deferasirox, and studies are currently
underway to assess the effectiveness and
safety of higher doses.

and estimated heart iron were not evaluated

formally as part of the drug registration
process, and formal prospective studies on
both heart function and heart iron are now
in progress. Retrospective analysis of effects
on myocardial T2* after one year and two
years of treatment suggests that this
measure can be improved in a significant
proportion of patients with pre-existing
abnormal T2* values (Porter, 2005). Patients
with normal LVEF showed no change in this
measure over one year (Porter, 2005).

Unwanted effects
with deferasirox

A more moderate reduction in LIC occurred

in children under six years old, despite the
administration of an average dose of 21.9
mg/kg in this subgroup. However, these
patients had the highest mean transfusional
iron intake.

Gastrointestinal effects
Gastrointestinal disturbances typically mild
and transient occurred in 15% of patients
and included abdominal pain, nausea and
vomiting, diarrhoea and constipation, lasting
a median of less than eight days. These

Effects on heart iron and heart

function
The effects of deferasirox on heart function

Transfusion rate

% of patients

LIC change*

LIC change*

so transfused

at 20mg/kg

at 30mg/kg

Low (<0.3 mg/kg/day)

24%

-4

-.9.5

Intermediate (0.3-0.5 mg/kg/day)

59%

-2

-9.0

High (>0.5 mg/kg/day)

17%

+1.8

-4.0

*in mg/g dry wt

Table 7: Relation of transfusion rates with LIC.

58

symptoms rarely required dose adjustment or

discontinuation.

Effects on the liver

Overall a decrease in ALT* was seen, which
paralleled improvements in LIC (Deugnier,
2005). Two patients out of 296 developed
elevated ALT values greater than twice the
ULN while receiving deferasirox for one year,
which the investigator reported as related to
the administration of the drug.

Skin rashes
These occurred in (11%) of patients and were
typically pruritic, maculopapular and
generalised, but occasionally confined to
palms and soles of the feet. A rash typically
developed within two weeks of starting
treatment. A minority of patients required
permanent discontinuation of therapy, and
mild rashes often resolved without dose
modification.

Other effects
No agranulocytosis, arthropathy or growth
failure was associated with deferasirox
administration. Comparing 296 patients who
received deferasirox in a one-year
prospective randomised study with 290
patients receiving desferrioxamine, deafness,
neurosensory deafness or hypoacusis were
reported as adverse events in eight patients
on deferasirox and seven in desferrioxamine.
Cataracts or lenticular opacities were
reported as adverse events in two patients
on deferasirox and five on desferrioxamine
(Cappellini, 2006).

Increase in serum creatinine

An increase in serum creatinine 30% on at
least two consecutive readings was observed
in 38% of patients receiving deferasirox, most
frequently at doses of 20 mg/kg and 30
mg/kg (Cappellini, 2006). These increases
were sometimes transient and generally
within the normal range, never exceeding
two times the upper limit of normal (ULN),
and were more frequent in the population of
patients having the most dramatic decrease
in LIC and serum ferritin. In the randomised
study, a dose reduction of 33-50% was
planned if at least two consecutive increases
in serum creatinine were >33% above
baseline. As the creatinine spontaneously
normalised in a number of cases, dose
reductions were instituted in only 13%. In
about 25% of those cases, the creatinine
then returned to baseline, while in the rest it
remained stable or fluctuated between
baseline and the maximum increase observed
prior to dose reduction. With follow up of a
median of three years at the time of writing,
no evidence of progressive renal dysfunction
has been reported where the above doses
and modifications are used. Further work on
the mechanism of creatinine increases is
being undertaken.

Convenience and impact on quality of

life
Studies comparing satisfaction and
convenience of DFS with DFO in thalassaemia
major show a significant and sustained
preference for DFS (Cappellini, 2006). Total
withdrawals in deferasirox-treated patients
were 6% at one year compared with 4% with
desferrioxamine (Cappellini, 2005). This
compares with a dropout rate of 15% at one
year with deferiprone (Cohen, 2000). Based
on thalassaemia patient reported preferences
for DFS and DFO, published compliance data
with DFO and the probability of complications
from iron overload in relation to compliance
with DFO, the cost effectiveness per qualityadjusted life year (QALY) gained is 4.1 per
patient for DFO and 8.1 per patient for
deferasirox.
* ALT: Alanine L-Aminotransferase

59

Recommended
treatment regimens
with deferasirox

The drug also appears to be palatable to

children at this young age. On the basis of
present knowledge, the criteria for starting
treatment (ferritin level, age, number of
transfusions) do not differ from those of
desferrioxamine.

Recommended dosing

Other indications and

contraindications

The drug is taken orally as a suspension in

water, once daily, preferably before a meal. A
starting dose of 20 mg/kg is recommended
for thalassaemia major patients who have
received 10-20 transfusion episodes and
currently receive standard transfusion at
rates of 0.3-0.5 mg of iron/kg/day. In those
patients in whom there is a higher rate of
iron intake from transfusion (>0.5
mg/kg/day) or in patients with pre-existing
high levels of iron loading, where a decrease
in iron loading is clinically desirable, 30
mg/kg/day is recommended. For patients
with a low rate of iron loading (<0.3
mg/kg/day), a dose of 10-15 mg/kg may be
sufficient to control iron loading.

Deferasirox is contraindicated in patients with

renal failure or significant renal dysfunction.
For patients with evidence of significant
heart dysfunction (e.g. LVEF below reference
range) there is very limited clinical experience
and treatment cannot be recommended at
this time for patients with heart failure or
poor LV function. The combined use of
deferasirox with other iron chelators has also
not been formally assessed and therefore
cannot be recommended at this time. The
drug should not be used in pregnant women.

Experience of use in patients

with pre-existing renal disease
(baseline creatinine outside
reference range) is insufficient
at this time to recommend its
use. As the median follow up in
large-scale studies is three years
at this time, vigilance in
monitoring for possible longterm effects is still advisable.

Age of commencement
Prospectively randomised studies of
deferasirox in children as young as two years
of age have been carried out (Cappellini,
2006; Galanello, 2006).

A fall in LIC was seen across all

age groups analysed, with no
age-related adverse effects: in
particular, no adverse effects on
growth, sexual development or
bones were seen (Piga, 2006).

60

Summary of Iron Overload and its treatment:

1.08 mg of iron in 1ml of pure red cells (HCT = 100%);
Rate of iron loading: volume of RBC x 1.08 (annual transfusion requirements x
donor Hct = volume of RBC). On average 200mg iron/donor unit;
Recommended transfusion 100-200 ml/kg/year is equivalent to 116-232 mg
iron/kg/year or 0.32-0.64 mg/kg/day;
Serum ferritin broadly related to body iron. When high, the following should be
considered:
(i) iron overload;
(ii) inflammation;
(iii) hepatitis; and/or
(iv) liver damage.
When serum ferritin is low, the following should be considered:
(i) low body iron;
(ii) vitamin C deficiency.
In thalassaemia intermedia, ferritin underestimates the degree of iron overload.
Ferritin levels related to low risk are below 2,500 mg/l, preferably below 1,000
mg/l;
Ranges of LIC reflecting levels of RISK:Very low risk = <1.8 mg/g dry weight
Low to moderate risk = 1.8 - 7 mg/g dry weight;
Moderately high to high risk = 7 - 15 mg/g dry weight;
Very high risk = > 15 mg/g dry weight;
Total body iron stores = 10.6 x LIC (mg/g dry weight);
LIC is measured by:
a) Liver biopsy indicated if ferritin levels deviate from expected trends, if coexistent hepatitis and if uncertain response to chelation;
b) SQUID not universally available;
c) MRI R2.
Cardiac iron reflected by heart function tests and measured by MRI T2*;
Urinary iron used to monitor desferrioxamine or deferiprone dose effects.
Variability in daily excretion, and
NTBI and LPI not yet routinely used.

61

Desferrioxamine:
Initiate treatment after first 10-20 transfusions or ferritin level above 1,000 g/l;
If before 3 years of age monitoring of growth and bone development is
recommended;
Therapeutic index = mean daily dose (mg/kg) (Mean daily dose = actual dose of each
infusion x doses/7 days) /ferritin (mg/l). Keep index < 0.025 at all times;
Standard treatment: a) Slow subcutaneous infusion over 8-12 hours, b) 10%
desferrioxamine solution (5 ml water for each 500 mg vial), and c) infusion pump
(several types available);
Standard dose: a) children 20-40 mg/kg (not exceeding 40 mg/kg, until growth has
ceased), and b) adults 50-60 mg/kg. Infuse 8-12 hours 6 nights minimum per week;
Alternative route: subcutaneous bolus two S.C. boluses/day to a total daily dose of 45
mg/kg;
Vitamin C-dose limited to 2-3 mg/kg/day given orally at the time of infusion;
Pregnancy desferrioxamine can be used in pregnancy. It should be interrupted during
the first trimester and can be used in the second and third trimesters, in selected
cases;
Intensive chelation with desferrioxamine continuous 24-hourly infusions IV or SC.
Indications:
a) Persistently high serum ferritin;
b) LIC > 15 mg/g dry weight;
c) Significant heart disease, and;
d) Prior to pregnancy or bone marrow transplantation
Dose: 50 mg/kg/day (up to 60 mg/kg/day)
In-dwelling catheters: danger of infection and thrombosis.

62

Deferiprone:
Standard dose: 75 mg/kg/day in 3 divided dose (up to 100 mg/kg/day, but as yet
not enough information);
Children above 10 years of age;
Vitamin C concomitant treatment not recommended;
Weekly blood counts (more frequently if signs of infection);
Pregnancy stop treatment. It is recommended that sexually active patients should
use contraception;

COMBINATION THERAPY. In patients for whom monotherapy with desferrioxamine or

deferiprone is not controlling body levels of iron or myocardial iron or in the presence
of significant heart disease, combined regimes offer an alternative that can reduce iron
levels in both the liver and heart. No recommendations as to which is the more
effective combination can be made at present.
CAUTION: agranulocytosis may be more frequent in combination therapy, especially in
simultaneous use.

Deferasirox:
Recommended dose:
Starting dose 20 mg/kg/day. After 10-20 transfusions (iron intake (0.3-0.5
mg/kg/day);
If pre-existing iron overload (or iron intake > 0.5 mg/kg/day), the dose of 30
mg/kg/day is recommended. For patients with low rate of iron loading (<0.3
mg/kg/day), lower doses may be sufficient to control iron loading; some patients will
still fail to achieve negative iron balance at a daily dose of 30mg/kg/day of
deferasirox, and studies are currently underway to assess the effectiveness and
safety of higher doses;
Administration: Tablet dissolved in water (or apple juice), using a non-metallic stirrer.
Taken once a day before a meal.
Continuous Monitoring
Use in children > 2 (FDA) and >6 (EMEA) years of age
Contraindicated in renal failure or significant renal dysfunction;
Cannot be given during pregnancy

63

Endocrine Complications
In Thalassaemia Major

Endocrine abnormalities are among the

common complications of thalassaemia.
Despite early establishment of appropriate
chelation therapy, problems such as delayed
sexual maturation and impaired fertility may
persist. Determining the prevalence of
endocrine complications is difficult because
of differences in the age of first exposure to
chelation therapy, and the continuing
improvement in survival in well-chelated
patients.
The growth rates and endocrine
complications of a sample of 3,817
thalassaemia patients in 29 countries are
reported in Table 1 (De Sanctis, 2004).

contributing factors to stunted growth in

patients with thalassaemia may include
chronic anaemia, transfusional iron overload,
hypersplenism and chelation toxicity
(DeSanctis, 1991). Other contributing factors
include hypothyroidism, hypogonadism,
growth hormone deficiency/insufficiency,
zinc deficiency, chronic liver disease, undernutrition and psychosocial stress.

Diagnosis and investigations

Diagnosis requires careful clinical evaluation
to establish:
slow growth rates: growth velocity
expressed in cm/year, below 1SD for age
and sex (based on growth velocity charts)
short stature: height below the 3rd
centile for sex and age (based on national
growth charts) (see Appendix A)
signs of other pituitary hormone
deficiencies (e.g., gonadotrophins)
other possible causes of retarded growth.

Growth
Growth retardation is common in
thalassaemia major. Patterns of growth are
relatively normal until the age of 9-10 years
when growth velocity begins to slow. Key

Short stature
Primary hypothyroidism
Insulin-dependent diabetes mellitus
Impaired glucose tolerance
Hypoparathyroidism
Hypogonadism
Growth hormone
deficiency/insufficiency

males
females
males
females
males
females
males
females
males
females
males
females
males
females

Based on a sample of 3,817 thalassaemia patients in 29 countries

Table 1: Growth and endocrine complications in thalassaemia

64

Number of patients
664
513
60
64
75
46
109
136
40
125
353
243
53
148

%
31.1
30.5
2.8
3.8
3.5
2.7
5.1
8
6.5
7.4
43.3
37.7
7.1
8.8

patients with thalassaemia receiving irregular

transfusion, as well as in those regularly using
desferrioxamine. In peri-pubertal patients,
hypogonadism should be carefully
investigated before starting growth hormone
treatment which may result in decreased
insulin sensitivity and abnormal glucose
tolerance (de Sanctis, 1999).

Investigation of a child with

thalassaemia who has stunted growth
is generally similar to that of a child
without thalassaemia.
Evaluation of short stature/retarded growth.

The first step in the

investigation of short stature or
retarded growth is the regular
(six-monthly intervals) and
accurate measurement of
standing and sitting height,
pubertal staging (Tanner 1962)
and bone age, including
examination of metaphyses.
Interpretation of absolute
height must take into account
the height of the parents.

Oral zinc sulphate supplementation should be

given to patients with proven zinc deficiency.

Delayed puberty and

hypogonadism
Delayed puberty and
hypogonadism are the most
obvious clinical consequences of
iron overload.

Additional endocrine studies that may be

helpful include thyroid function tests (FT4,
TSH), assessment of levels of sex hormones,
growth hormone (GF) secretion, zinc,
calcium, alkaline phosphatase, urine analysis,
and investigation of glucose tolerance.
Possibly useful tests include: Insulin Growth
Factor-I (IGF 1) and Insulin Growth Factor
Binding Protein-3 (IGFBP-3). The secretion of
GH is normal in the majority of patients with
thalassaemia. However, an investigation of
transglutaminase antibodies is also essential,
to exclude celiac disease.

Delayed puberty is defined as the complete

lack of pubertal development in girls by the
age of 13, and in boys by the age of 14.
Hypogonadism is defined in boys as the
absence of testicular enlargement (less than
4 ml), and in girls as the absence of breast
development by the age of 16 (de Sanctis,
1995).
Arrested puberty is a relatively common
complication in moderately or grossly iron
overloaded patients with thalassaemia, and is
characterised by a lack of pubertal
progression over a year or more. In such
cases, the testicular size remains 6-8 ml, and
breast size at B3 (see Table 2). In such cases
annual growth velocity is either markedly
reduced or completely absent (de Sanctis,
1995).

It is important to bear in mind

that desferrioxamine toxicity is
an important cause of delayed
growth (see Chapter on Iron
load and Iron Chelation)
Treatment
Anaemia, folate deficiency and hypersplenism
are traditional causes of poor growth in

65

Penile development
P1: Prepubertal

Breast development
B1: Prepubertal

Growth of pubic hair

PH1: Prepubertal

P2: Early puberty

(enlargement of scrotum and
testes, 4-5 ml, little or no
enlargement of penis)

B2: Early puberty

(breast bud stage)

PH2: Early puberty

(sparse growth)

P3: Mid-puberty
(enlargement of penis and
further growth of testes,
8-12 ml, and scrotum)

B3: Mid-puberty
(breast and areolar
enlargement)

PH3: Mid-puberty
(hair extends over
the pubic junction)

P4: Advanced puberty

(enlargement of penis in
length and breadth. Increased
pigmentation of scrotal skin
and enlargement of testicles,
15-25 ml)

B4: Advanced puberty

(areola and nipple project
separately from the
contour of the breast)

PH4: Advanced puberty

(hair corresponds to adult
growth but less extensive)

P5: Adult

B5: Adult
PH5: Adult
(Fully developed breast,
the areola no longer projects
separately from the breast
contour)

Table 2: Pubertal assessment according to Tanner

Most women with thalassaemia major present

primary amenorrhoea, with secondary
amenorrhoea developing over time,
particularly in poorly chelated patients.
Ovarian function in such cases is generally
normal but gonadotrophin response to
Gonadotrophin-Releasing-Hormone (Gn-RH) is
low compared to patients with normal
menstrual cycles.

Investigations

Routine biochemical analysis

Bone age (X-ray of wrist and hand)
Thyroid function (TSH and FT4)
Hypothalamic-pituitary-gonadal function:
Gonadotrophin-Releasing-Hormone (Gn-

RH), stimulation test for Luteinizing

Hormone (LH) and Follicle Stimulating
Hormone (FSH)
Sex steroids (serum testosterone, serum
17- Estradiol)
Pelvic ultrasound to assess ovarian and
uterine size
Transglutaminase antibodies
In selected cases, Growth Hormone (GH)
stimulation test
In selected cases, Insulin Growth Factor-I
(IGF-I), Insulin Growth Factor Binding
Protein-3 (IGFBP-3), plasma zinc

Treatment

The treatment of delayed or

arrested puberty and of
66

It is important that the treatment of pubertal

disorders is treated on a patient-by-patient
basis, taking account of the complexity of
the issues involved and the many associated
complications.

hypogonadotrophic
hypogonadism depends on
factors such as age, severity of
iron overload, damage to the
hypothalamo-pituitary-gonadal
axis, chronic liver disease, and
the presence of psychological
problems resulting from
hypogonadism. Collaboration
between endocrinologists and
other doctors is critical.

Hypothyroidism
This may occur in severely anaemic and/or
iron overloaded patients, usually appearing in
the second decade of life. The condition is
uncommon in optimally treated patients (de
Sanctis, 1995; Sabato, 1983).

For girls, therapy may begin with the oral

administration of ethinyl estradiol (2.5-5 g
daily) for six months, followed by hormonal
reassessment. If spontaneous puberty does
not occur within six months after the end of
treatment, oral oestrogen is re-introduced in
gradually increasing dosages (ethinyl estradiol
from 5-10 g daily) for another 12 months. If
breakthrough uterine bleeding does not
occur, low oestrogen-progesterone hormone
replacement is the recommended treatment.

Signs and symptoms

Pre-clinical hypothyroidism is asymptomatic.
In mild and overt hypothyroidism, symptoms
such as growth retardation, decreased
activity, above normal weight, constipation,
reduced school performance, cardiac failure
and pericardial effusion may be encountered.
The incidence of hypothyroidism is slightly
higher in females. Typically, the thyroid gland
is not palpable, thyroid antibodies are
negative and thyroid ultrasonography shows
an irregular echo pattern with thickening of
the thyroid capsule.

For delayed puberty in males, low dosages of

intramuscular depot-testosterone esters
(25mg) are given monthly for six months,
followed by hormonal re-assessment. In
patients with hypogonadotrophic
hypogonadism, treatment at a dose of 50
mg per month can be continued until growth
rates wane. The fully virilising dose is 75-100
mg of depot-testosterone esters every 10
days, administered intramuscularly. The same
effects can be achieved with topical
testosterone gel.

Annual investigation of thyroid function is

recommended, beginning at the age of 12
years. Free T4 and TSH are the key
investigations, and their interpretation, along
with TRH test and TSH response, are shown in
Table 3. Bone age may be helpful in
evaluating hypothyroidism. The majority of
patients have primary thyroid dysfunction.
Secondary hypothyroidism caused by ironmediated damage of the pituitary gland
occurs very rarely.

For pubertal arrest, the treatment consists of

testosterone esters or topical testosterone
gel, administered as for the treatment of
delayed puberty and hypogonadotropic
hypogonadism.

67

Hypo-thyroidism

Serum FT 4

Serum TSH

TSH Response
to TRH
Increased

Subclinical

Normal

Mild
Overt

Marginally low
Low

Marginally
increased
(TSH: 4.5-8mIU/l)
Elevated
Exaggerated
Elevated
Exaggerated

Treatment
Observation

L-thyroxin
L-thyroxin

KEY: FT4-free thyroxine; TSH-thyroid stimulating hormone; TRH-thyrotrophin-releasing hormone (adapted

from Evered, 1973)
Table 3: Hypothyroidism and its treatment

Abnormal thyroid function may be reversible

at an early stage through intensive chelation,
and good compliance.

The pathogenesis resembles type-2 diabetes,

with differences in the age of onset (it may
start early in the second decade of life) and
slow progression of disturbances in glucose
metabolism and insulin secretion.

Treatment depends upon the severity of

organ failure. Sub-clinical hypothyroidism
requires regular medical follow-up and
intensive iron chelation therapy.

The type of glycaemia may be classified as

diabetic, borderline or normal.

Treatment

Diabetic type: Fasting Plasma Glucose

(FPG) 7.0 mmol/l (126 mg/dl) and/or
plasma glucose 2 hours after 75 g
glucose load (2hPG) is 11.1mmol/l (200
mg/dl). A casual Plasma Glucose (PG)
11.1 mmol/l (200 mg/dl) also indicates
diabetic type. The persistence of diabetic
type indicates that a subject has
diabetes.
Normal type: FPG <6.1 mmol/l (110
mg/dl) and 2hPG <7.8 mmol/l (140
mg/dl).
Borderline type: includes those who are
neither diabetic nor normal types,
according to cut-off values for venous PG
measurements.

In patients with mild or overt

hypothyroidism, L-thyroxine is given.

Impaired
carbohydrate
metabolism
Impaired glucose tolerance and
diabetes mellitus may be the
consequence of -cell
destruction secondary to iron
overload, chronic liver disease,
viral infection and/or genetic
factors.

Diabetes in thalassaemia is rarely complicated

by ketoacidosis.

68

after the age of 16 (de Sanctis, 1995). The

majority of patients show a mild form of the
disease accompanied by paraesthesia. More
severe cases may demonstrate tetany,
seizures or cardiac failure.

Investigations
Oral Glucose Tolerance Test (OGTT) should be
performed annually from the age of puberty.
For children, a dose of 1.75 g/kg (to a
maximum of 75 g) is used for OGTT.

Investigations should begin from the age of

16 and should include serum calcium, serum
phosphate and phosphate balance. In cases
with low serum calcium and high phosphate
levels, parathyroid hormone should also be
evaluated. Parathormone may be normal or
low, with low readings for 1,25
dihydroxycholecalciferol (vitamin D).

Treatment
Impaired glucose tolerance may be
improved by a strict diabetic diet, weight
reduction, where applicable, and possibly
intensive iron chelation therapy
In symptomatic patients, insulin
treatment is normally required but
metabolic control may be difficult to
achieve
Where hyperinsulinism is insufficiently
managed by diet alone, acarbose may be
a useful first-line therapy for glycaemic
control
The role of oral hypoglycaemic agents
remains to be fully determined

Bone radiology shows osteoporosis and

malformations.

Treatment
Oral administration of vitamin D or one of
its analogues. Some patients require high
doses of vitamin D to normalise their
serum calcium levels. This should be
carefully monitored, as hypercalcaemia is
a common complication of this
treatment.
Calcitriol, 0.25-1.0 g, twice daily, is
usually sufficient to normalise plasma
calcium and phosphate levels. Weekly
blood tests are required at the start of
treatment, followed by quarterly plasma
and daily urinary calcium and phosphate
measurements.
In patients with persistently high serum
phosphate levels, a phosphate binder
(other than aluminium) may be
considered.
Tetany and cardiac failure due to severe
hypocalcaemia require intravenous
administration of calcium, under careful
cardiac monitoring, followed by oral
vitamin D.

Monitoring diabetes and its

complications
Blood glucose (daily or on alternate days)
Ketones check if blood sugar is above
250 mg/dl
Fructosamine estimation is more helpful
than glycosylated haemoglobin levels
Urinary glucose is influenced by increased
renal glucose threshold
Renal function (serum creatinine)
Serum lipids (cholesterol: HDL, LDL,
triglycerides)
Urinary protein
Evaluation of retinopathy

Hypoparathyroidism
Hypocalcaemia, due to hypoparathyroidism,
is a recognised late complication of iron
overload and/or anaemia and usually begins

69

Management of Fertility and

Pregnancy in -thalassemia

gonadal axis (Chatterjee and Katz, 2000;

Skordis, Christou et al, 1998). Also, the
management during pregnancy are different
in that TI patients have an increased
thrombotic risk and need transfusion during
pregnancy (Nassar, 2006), whereas TMs, in
addition to complications specific to iron
overload, also face the risk of thromboembolism, particularly those with
splenectomy and autoimmune antibodies.

Advances in the primary care of thalassaemia major (HbTh) by optimal blood

transfusion and chelation therapy have
improved patient survival into adulthood. At
the same time, patients quality of life has
also increased significantly, and the
expectation of having a familyan important
dimension of quality of lifeis consequently
an important aspiration for many.
Although spontaneous fertility can occur in
well-chelated and -transfused patients with
spontaneous puberty, the majority are
infertile due to hypogonadotrophic
hypogonadism (HH) consequent to
transfusional haemosiderosis (Chatterjee and
Katz, 2000) and need Assisted Reproductive
Techniques (ART).

Management of
fertility
Although 80-90% of patients have HH,
gonadal function is usually intact in the
majority of patients, indicating that fertility is
usually salvageable, i.e. ovulation in females
and spermatogenesis in males can be
induced by exogenous gonadotrophin
therapy, bypassing the H-P axis. However,
other endocrine disorders, namely diabetes
and hypothyroidism, may also influence the
outcome of fertility treatment and need to
be corrected by standard care. Successful
spontaneous pregnancies, as well those
resulting from the induction of
gametogenesis, have been documented in
HbTh females and males (Aessopos et al,
1999).

Planned pregnancy is essential

both in spontaneous and ART
conceptions, as HbTh
pregnancies are high risk for the
mother and the baby. However,
these risks can be minimised
through pre-pregnancy
counselling with the
haematologist, the reproductive
medicine specialist, the
cardiologist and the
obstetrician, in conjunction with
the specialist nurse.

Management of infertility requires a

thorough work-up, including pre-pregnancy
counselling of the couple (see below).
Fertility assessment of patients with
thalassaemia should also include evaluation
of the partner according to standard criteria
(see http://www.rcog.org.uk). The fertility
options are dependent on two factors (a)
partners carrier status and (b) site of
damage to the H-P-G axis.

The management of patients of thalassaemia

intermedia (TI) is similar to that of
thalassaemia major (TM), with minor
modifications. Older patients with
thalassaemia major usually have
hypogonadotrophic hypogonadism and are
unlikely to conceive spontaneously, whereas
patients with thalassaemia intermedia are
potentially fertile with intact pituitary-

70

H-P damage, when gonadotrophins are

pulsatile. But majority of patients with HH are
apulsatile with functional gonads, and are
therefore likely to benefit from HMG/HCG
therapy with 80% success rate. Patients with
endometrial damage respond better to IVF
programmes.
Induction of ovulation should only be
undertaken by a specialist reproductive team,
according to Human Fertilisation and
Embryology Authority (HFEA) guidelines
(Deech, 1998 review). Patients should be
counselled regarding risk of hyperstimulation syndrome, multiple pregnancy,
ectopic pregnancy and miscarriage. The risk
of hyper-stimulation and multiple births can
be minimised by vigilant monitoring of the
induced cycle, followed up through, vaginal
ultrasound scans. For such procedures, it is
important to obtain the consent both and
imperative of the patients and involved
clinicians and carefully documented notes
should be kept throughout. The regime to be
followed will be dependent on the teams
local protocol (See Figure 1 for an
established protocol).

If both partners are homozygous for thalassaemia, use of donor gametes,

preferably donor sperm is the ideal option, as
sperm can be more easily available from
sperm banks, whereas the use of donor eggs
is technically more complicated with an
unpredictable success rate (Deech, 1998
review). If the partner is heterozygous, then
Pre-implantation Genetic Diagnosis (PGD) is
another option, where diagnosis can be
made prior to conception. This method may
be more acceptable to certain communities
with religious beliefs against termination of
affected pregnancy. Lastly, in patients with
severe organ damage or where both partners
have HbTh, another option may be adoption,
where there is good family support.

Methods for
induction of
ovulation
Induction of ovulation with pulsatile GnRH
infusion is only possible at the early stage of
FIGURE1

71

patients. The induction process must be

undertaken according to HFEA guidelines,
with an emphasis on consent and counselling
(Deech, 1998 review) (See Figure 2 for an
established protocol).

Key points in induction of ovulation:

Careful monitoring of the cycle by serial
vaginal ultrasound scans
DFO should be continued until HCG is
injected/biochemical pregnancy is
confirmed
Luteal support with progesterone may be
required
After a maximum of six cycles, reassess
and refer for IVF

However, the recent advent of

micromanipulation techniques such as intracytoplasmic sperm injection (ICSI) has
improved conception rates, even in oligoasthenospermic patients. Therefore, sperm
should be cryopreserved in all subjects unless
azoospermic, to better preserved fertility and
so the chance of conception. However, our
recent literature on sperm DNA damage in
HbTH (Perera, Pizzey et al, 2002) males raises
anxiety about mutagenic risks in these
individuals, especially after ICSI, where natural
protective barrier against gamete selection
during fertilisation is lost.

Induction of
spermatogenesis
The induction of spermatogenesis in male
patients with thalassaemia is more difficult
that the induction of ovulation in their
female counterparts, with a success rate of
10-15% in moderate to severely iron loaded

FIGURE 2

INDUCTION OF SPERMATOGENESIS
Baseline testosterone and semen analysis
HCG 2000 units twice-weekly for 6 months
Monitor testosterone level
Repeat semen analysis-no sperm
Continue HCG with combined HMG 75 units three times weekly
for additional 6 months
If semen analysis is satisfactory

SAVE

If azoospermia persists, stop treatment

72

Pre-pregnancy
counselling

before encouraging women with

thalassaemia major to embark on pregnancy:
cardiac impairment, liver dysfunction and the
vertical transmission of viruses.

Before embarking on fertility treatment, it is

important that patients and their partners
attend pre-pregnancy counselling, which has
a three-fold purpose (a) evaluation of
eligibility, (b) physicians to review
medications involved and (c) physician/s,
patient and partner to discuss the risks
associated with induced fertility and
pregnancy.

1. The most important is cardiac function

because cardiac complications remain the
leading cause of death in both transfused
and untransfused patients. The cardiac
load is increased during pregnancy by at
least 25-30% due to increased heart rate
and stroke volume. This, along with iron
load, has a real potential for premature
death from cardiac failure. Therefore it is
prudent that all patients with TM should
have cardiac assessment by ECHO (Left
ventricular ejection fraction >65%;
fractional shortening >30%), by ECG, both
at rest and with exercise, and by 24 hr
tapes to check for rhythm disorders. If LV
dysfunction can be demonstrated in
patients under stressful conditions or if
significant arrhythmias have occurred,
then women should be strongly advised
against planning pregnancies (Hui et al,

Evaluation of
eligibility (Figure 3)
Each patient should be assessed regarding
suitability to embark on pregnancy with
optimum outcome both for the mother and
the fetus. There are at least 3 important
factors that must be seriously considered

Figure 3

EVALUATION OF ELIGIBILITY FOR PREGNANCY

Heart: ECG, Echo, MRI
Liver: LFT, ultrasound, biopsy
Endocrine: diabetes, thyroid, parathyroid and
Risk of thrombo-embolism: thrombophilia screen
Viral infections: HBV, HCV, HIV, rubella
Bone health: Vitamin D, calcium, DEXA, x-ray
Iron overload: ferritin, liver and heart Fe
Ascertain hemoglobinopathy status of partner
Optimise lifestyle issues (smoking, etc).

73

Diagnosis and Management of

Osteoporosis in -thalassaemia). Patients
should also be screened for diabetes,
thyroid function, and acquired red cell
antibody. Both partners should be
screened for haemoglobinopathy.

2002). Most of the non-invasive cardiac

investigations are relatively insensitive for
detecting early cardiac loading. Modified
MRI has recently been developed using
gradient T2* measurements to quantify
iron levels, and can accurately relate
these to LV dimensions assessed using
the same technique (Anderson et al,
2001). If the facility exists, cardiac MRI
should be performed and the aim should
be to have T2* closer to 20 ms.

Review of
medications

2. Liver function should be evaluated by

biochemical test while iron overload
status by liver biopsy and MRI. Liver
biopsy can also provide information on
fibrosis and cirrhosis.

(Figure 4)

This is a good opportunity to review

medications and to give advice to patients
regarding diet, smoking and alcohol, and to
commence supplements of folic acid, calcium
and vitamin D. Patients on oral chelators
(deferasirox or deferiprone) are
recommended to switch to desferrioxamine
prior to induction of
ovulation/spermatogenesis (Singer and
Vichinsky, 1999). Hormone replacement
therapy should also be stopped at least 4-6
weeks prior to induction of gametogenesis.
Bisphosphonate is contraindicated during
pregnancy and breast-feeding, as both are
states of considerable negative calcium
balance. It is therefore prudent to ensure
adequate calcium and vitamin D intake
before and throughout pregnancy. Other
medications that should be discontinued at
least six months prior to fertility treatment
include interferon, ribovarin and hydroxy
urea. Hypothyroid patients receiving thyroid
replacement therapy should receive
increased doses, to ensure they are
euthyroid. Hyperthyroidism is rare in patients
with thalassaemia. However, if a patient is
receiving an anti-thyroid drug such as
carbimazole, this should be replaced by
propyl thiouracil.

3. All patients should be screen for HIV,

Hepatitis B, Hepatitis C and rubella. The
opportunity should not be missed to
ensure rubella immunity prior to
pregnancy. If the patient is HIV positive
and wishes to have a family, she should
be advised of the usual recommendations
for care which include appropriate
antiviral agents, delivery by CS and the
avoidance of breast feeding to reduce
the risk of vertical transmission to <5%
(RCOG clinical Green Top Guidelines,
2004). As regards Hepatitis C-positive
cases, these women should be given a
course of antiviral agents to attain
Hepatitis C RNA negative status.
4. Before embarking on pregnancy, it is also
important to establish bone heath by Xray of spine and DEXA scan of hip and
spines (BMD score) and correction of
osteoporosis/osteopenia by institution of
appropriate therapy (see Chapter 6:

74

Figure 4

REVIEW OF MEDICATIONS PRIOR TO PREGNANCY

Stop HRT
Stop interferon, ribovarin, hydroxy urea
Stop bisphosphonates six months prior to fertility treatment
Switch from warfarin to heparin
Switch from oral hypoglycaemic to insulin
Switch from oral iron chelation to DFO
Review thyroid medication
Give calcium and vitamin D supplements
Start folic acid supplement to prevent neural tube defect

pregnancy. Serum ferritin is likely to alter by

10%, despite increase in frequency of blood
transfusion (Aessopos, 1999; Tuck, 1998;
Daskalakis, 1998; Butwick, 2005). The aim
during pregnancy is to maintain pretransfusion haemoglobin concentration
above 10g/dL (Aessopos, 1999).

Risks associated with

pregnancy (Figure 5)
All patients should be made aware that
pregnancy per se does not alter the natural
history of thalassaemia. If pregnancy is
managed in a multidisciplinary setting, the
foetal outcome is usually favourable with a
slight increase in incidence of growth
restriction (Aessopos, 1999; Ansari, 2006;
Tuck, 1998). It has been shown that the risks
of pregnancy-specific complications such as
ante-partum haemorrhage and pre-eclampsia
in thalassaemia are similar to the background
population. It has also been shown that DFO
is not required during pregnancy in patients
that are not iron overloaded and that have
adequate cardiac function prior to

Management of
pregnancy (Figure 6)
Once pregnancy is confirmed, the patient
should be managed in a multidisciplinary
team consisting of obstetrician, midwife,
physician, haematologist and anaesthetist.
The patient should be made aware that
although pregnancy is high risk, the outcome
is usually favourable (Aessopos, 1999).

75

Figure 5

Risks associated with pregnancy

Pregnancy does not alter the natural history of the disease
Requires intense/vigilant monitoring
Cardiac complications
Risk of pregnancy-specific complications same as background population
Risk of miscarriage same as background population
Risk of foetal malformation: no increase
Risk of foetal growth restriction: two-fold increase
Preterm labour risk: two-fold increase
Risk of transmission to the fetus/baby of Hepatitis B/C, HIV
Risk of iso-immunisation
Risk of pre-maturity and growth restriction is increased in multiple births

from mid-trimester (Nassar, 2006; Eldor and

Rachmilewitz, 2002). Although there is a
predisposition to venous thrombosis in postsplenectomy patients, no reports of
thrombotic episodes have been reported in
the literature (Tuck, 1998; Daskalakis, 1998).
Folate demand in pregnancy is normally
increased and this may be relevant in
patients with thalassaemia due to bone
overactivity. Regular folic acid
supplementation is recommended in mothers
with thalassaemia major to prevent
superimposed megaloblastic anaemia,
although this has only been demonstrated
individuals with -thalassaemia minor
(carriers) (Leung, 1989). If cardiac function
deteriorates during pregnancy, DFO may be
used, with caution, as evidence regarding

The main risk to the mother is

cardiac complications, which
can be minimised by ensuring
optimal cardiac function before
embarking on pregnancy.
The key points include evaluation of cardiac
function by ECHO, and of liver and thyroid
functions, in each trimester. All patients
should be screened for gestational diabetes
at 16 weeks and, if normal, this should be
repeated again at 28 weeks. Serial ultrasound
scans from 24-26 weeks onwards must be
undertaken to monitor foetal growth. In
selected cases, particularly those with
thalassaemia intermedia, thromboprophylaxis
by low molecular weight heparin is required

76

After delivery, DFO can be recommenced but

not oral chelating agents. Breastfeeding
should be encouraged in all cases except in
those who are HIV and/or hepatitis C RNApositive and/or HBsAg positive because of
the risk of transmission via breast milk.

teratogenicity of DFO is equivocal (Singer and

Vichinsky, 1999). As regards the newer oral
chelating agents, data on fetotoxicity are
lacking. However, the manufacturers
product information for DFO includes risk of
skeletal anomalies in animal pregnancies.
Although there are currently no reports
regarding human foetal anomaly from DFO,
patients should be informed about this prior
to its use during pregnancy.

All patients should be counselled regarding

contraception. Intrauterine devices should be
avoided because of risk of infection. Taking
oestrogen-containing birth control pill is also
not advisable because of the risk of
thrombo-embolism (Orr, 1967). In most
cases, progesterone-only pill or barrier
methods are usually appropriate. Male
patients with hypogonadotrophic
hypogonadism are not fertile spontaneously
and therefore contraception is not required.
Calcium and vitamin D supplements should
be continued during breast-feeding, however
bisphosphonate therapy for osteoporosis
should only be resumed after cessation of
breastfeeding.

As regards the management of labour, if

pregnancy is non-complicated, one could
await the spontaneous onset of labour. But,
similar to reported data, it is the authors
experience that 80% of women with
thalassaemia will require caesarean section
(CS) because of higher frequency of
cephalopelvic disproportion, largely due to
short stature and skeletal deformity in this
cohort, combined with normal foetal growth.
It is desirable to use epidural anaesthesia for
CS wherever feasible, to avoid the risk of
difficult intubation associated with general
anaesthesias due to severe maxillo-facial
deformity in TM patients (Orr, 1967).
Although most skeletal deformities are largely
prevented by regular transfusion, spinal
abnormalities associated with TM are relevant
to regional blockade. Osteoporosis and
scoliosis are common in TM, despite
transfusion therapy (Borgna-Pignatti, 2006b).
Patients with osteoporosis usually have
vertebral bodies with reduced height and the
segmental position of the conus may be
lower than predicted (Borgna-Pignatti,
2006b). It is therefore important to correct
osteoporosis prenatally by hormone
replacement (and premidronate therapy),
where required, to increase bone density so
that spinal anaesthesia at CS becomes
feasible.

77

Figure 6

Key points for pregnancy care

Check cardiac, liver and thyroid function once each trimester
Screen for gestational diabetes
Increase frequency of blood transfusion to maintain pre-transfusion Hb
above 10 g/dL
Serial ultrasound scans to monitor fetal growth
Higher incidence of caesarean section
Encourage breastfeeding unless HIV positive and/or CV RNA and/or
HBsAg positive
Resume DFO after delivery
Discuss contraception, where appropriate
POP, barrier method
Avoid intrauterine device and oestrogen-containing preparations
Resume bisphosphonate after breastfeeding has ceased

78

Diagnosis and
Management of
Osteoporosis in -thalasaemia

Osteoporosis is a skeletal disease

characterised by low bone mass and micro
architectural deterioration with a resulting
increase in bone fragility and hence
susceptibility to fracture (Sambrook, 2006).
With increased life expectancy, osteopeniaosteoporosis syndrome (OOS) is a major
cause of bone pain of hip and spine and
fragility fractures especially of the lumbar
spine which may be found in 70-80% adult
patients with -thalassaemia world-wide,
accounting for significant bone morbidity
(Chatterjee, 2001).

2003; Lasco, 2001). The diminished

osteoblast function with reduced osteocalcin
(Morabito, 2004) is accompanied by a
comparable or even greater increase in
osteoclast activity through
RANK/RANKL/osteoprotegerin pathway as the
final, dominant mediator (Voskaridou, 2003).

Diagnosis and
investigations
(Figure 1 and Figure 2)

Aetiology and
pathogenesis

The commonest presentation is bone pain

and backache with or without past history of
fractures. Patients may also be asymptomatic
in 20% cases.

Several studies have shown reduced bone

mass in osteoporotic patients with
thalassaemia (Chatterjee, 2000; BorgnaPignatti 2006b; Chan, 2002; Morabito, 2004;
Voskaridou, 2003) but the underlying
pathogenesis is still speculative. The causes
of OOS in thalassaemia syndromes are
multifactorial (Chatterjee, 2000), and include
marrow expansion secondary to ineffective
erythropoiesis (Borgna-Pignatti, 2006),
anaemia , transfusional haemosiderosis
(Borgna-Pignatti 2006) , delayed puberty
(Chatterjee, 2000), use of deferioxamine
(Voskaridou, 2003) or oral chelation agents
for iron overload (Chan, 2002), multiple
endocrinopathies such as
hypogonadothrophic hypogonadism or
primary hypogonadism (Chatterjee, 2000),
low IGF1 (Lasco, 2002), low vitamin D levels
due to aberrant vitamin D-PTH axis (BorgnaPignatti, 2006). Genetic factors, for instance,
polymorphism of the VDR gene and COL 1
gene seem to play an important role in the
development of low bone mass (BorgnaPignatti, 2006; Morabito, 2004; Voskaridou,

(A) DEXA Scan

The diagnosis is best confirmed by bone
mineral density (DEXA) according to WHO
criteria (Figure 1). Although bone mineral
density remains the best available noninvasive assessment of bone strength in
routine clinical practice, many other skeletal
characteristics also contribute to bone
strength (Mahachoklertwattana 2003). These
include bone macro architecture (shape and
geometry), bone micro architecture (both
trabecular and cortical), matrix and mineral
composition, as well as the degree of
mineralisation, micro damage accumulation,
and the rate of bone turnover, which can
affect the structural and material properties
of bone which are complicated and difficult
to assess in routine clinical practice
(Sambrook, 2006).

79

Figure1

World Health Organisation (WHO) criteria for diagnosis of OOS

Osteoporosis
BMD > 2.5 SD below the young normal mean (T score) or
Standard deviations in relation to patients age (Z score)
Osteopenia
BMD >1.5-2.5 SD below the young normal mean (T score)

Figure 2

List of investigations
Bone profile-serum Ca, PO4, 25(0H) vitamin D, PTH 24h urinary calcium.
Endocrine profile FSH, LH, E2/T, TFT
Liver function test
Spinal X-ray
DEXA-Spine-hip, radius, ulna-annually
Markers of iron overload

(B) Biochemical
(D)MRI

All patients must have endocrine and bone

profile including 25 (OH) vitamin D3, PTH,
calcium, phosphate, liver function tests,
(alkaline phosphate, ALT, bilirubin, albumin)
FSH, LH, testosterone and oestradiol assays
(Chatterjee, 2001; Chatterjee, 2000).

MRI of spine, if available, must be undertaken

to determine extramedullary haematopoiesis,
specially in TI patients and also to check for
degenerative changes, skeletal dysplasia and
disc prolapse.

(C) Radiology

(E) Assessment of iron load and

chelation therapy (see Chapter 3: Iron

AP and lateral X-ray of the spine is important

to rule out fractures even in asymptomatic
patients who may have micro fractures.

Overload).

80

(2) Calcimimetics
Vitamin D deficiency must be corrected
(oral dose of 1000-1500 IU/day) and
calcium supplementation (500 mg-1G
orally/day) (Sambrook, 2006).

MANAGEMENT
Principles of management of OOS are the
same as other patients with osteoporosis due
to other conditions (Sambrook et al, 2006).
The aim is to improve BMD score and
prevent/reduce future risk or fracture
with/without offering pain relief in
thalassaemia patients. General guidelines
include assessment of other drugs, lifestyle
issues, exercise and diet.

(3) Anti-resorption agents

Bisphosphonates represent the biggest
advance in the treatment of osteoporosis
in the past decade in non-thalassaemic
patients (Sambrook, 2006), with results of
clinical trials showing reductions in the
risk of vertebral fractures (4050%) and
non-vertebral fractures (2040%),
including hip fractures. Bisphosphonates,
the potent inhibitors of osteoclast
function, can be used as second line
therapy in TM patients (non-responders
or poor responders) and those without
hypogonadism (TI) with encouraging
results.
Route of administration and dose: They
can be given as pamidronate 1-2 mg/kg
body weight once a month as IV infusion
for 3-5 years (Chatterjee, 2001), orally as
alendronate 70 mg orally per week
(Borgna-Pignatti, 2006b) or zolandronic
acid twothree times per year
(Mahachoklertwattana 2006).
Daily alendronate and risedronate have
reduced the risk of single and multiple
spine fractures, asymptomatic
(morphometric) and symptomatic spine
fractures in women with bone mineral
density T scores of less than -2.5 and one
or more prevalent spine fractures
(Borgna-Pignatti 2006b). Despite their
impressive anti-fracture efficacy, several
issues are now arising with respect to
bisphosphonates including the risk of jaw
osteosclerosis in long-term users (BorgnaPignatti 2006b).

(A) Therapeutic Options (Figure 3)

Controversy exists regarding the best
therapeutic option for osteopeniaosteoporosis. It is likely that the factors
contributing to OOS in thalassemia intermedia
(TI), while overlapped with those of
thalassaemia major (TM) have a different
emphasis with intramedullary expansion
being more important and hypogonadism
less important than in TM. The choice of
therapy depends on the age of the patient,
the type of thalassaemia including
transfusion dependence, symptoms and
severity of clinical presentation, the past
history of type and number of fractures,
previous therapy, presence of risk factors of
nephrocalcinosis, associated hypogonadism,
hyperparathyroidism. An ideal therapy should
be safe and effective, able to correct the
specific defect of bone remodelling unit,
strengthen the bone and offer symptomatic
relief.
(1) Sex steroid replacement therapy
In symptomatic or asymptomatic TM
patients with proven OOS (DEXA scan) and
hypogonadism, it is logical to correct
hypogonadism first by sex hormone
replacement therapy for at least two
years (Chatterjee, 2001; Chatterjee, 2000;
Lasco, 2001; Carmina, 2004).

81

(4) Combination therapy

Combination of pamidronate to HRT
regime in TM has been used with
successful results (Chattergee et al,
2001).

treatment for >5 years is not recommended

as it may induce osteosclerosis, specially of
the jaw (Borgna-Pignatti, 2006) and may
even aggravate the existing problem.
Biochemical correction of hypogonadism
must be confirmed from optimal peak and
trough sex steroid levels. Caution must be
exercised in prescribing vitamin D
replacement therapy patients with risk of
nephrocalcinosis and bisphosphonate is also
given in caution (Borgna-Pignatti 2006).
Patients on thyroxine and corticosteroid
replacement therapy must be monitored
carefully as excess replacement can
aggravate osteoporosis.

(B) Monitoring of Treatment

Treatment should be monitored with
biochemical parameters (bone and sex
steroid profile) and annual DEXA scan of
spine and femoral neck to determine the T
scores. A rise of 1-2% per year is expected in
the femoral neck with or without change in
femoral scores (Mahaklertwattana et al,
2003). After 3 years of pamidronate, usually
the BMD effect plateaus. Also long-term

Figure 3

Recommendations
Diet and exercise
Vitamin D and calcium supplementation
Sex hormones replacement in HH-HRT
Anti-resorption agents-Bisphosphonate
Combination therapy-Bisphosphonate+HRT

82

The Management
of Cardiac Complications in
Thalassaemia Major

The quality and duration of life of

transfusion-dependent patients with
thalassaemia has been transformed over the
last few years, with their life expectancy
increasing well into the third decade and
beyond, with a good quality of life (Olivieri
1995; Zurlo 1989).

prompt intervention.
Ideally, a quantitative assessment of the
degree of myocardial iron overload is
required in order to identify those patients at
risk of developing heart complications as well
as, importantly, those where the risk may be
minimal. Establishing the best treatment
protocols requires co-operation between the
treating physician and cardiologists
experienced in dealing with
cardiomyopathies.

Nevertheless, cardiac symptoms and

premature death from cardiac causes are still
major problems.

Iron related heart complications

are the leading cause of death
and one of the main causes of
morbidity.

Clinical
manifestations
Patients with considerable iron
overload of the heart may
remain free of symptoms. Once
myocardial dysfunction
develops, discernible symptoms
are related to the degree of
ventricular impairment. Subtle
early signs may be confused
with the effects of the
underlying condition.

In the absence of effective iron chelation

therapy, many patients sustain iron-induced
myocardial damage resulting in cardiac
failure, cardiac arrhythmia, progressive
congestive cardiac failure or sudden death
(Brittenham,1994).

Even after significant effects on

heart muscle, however,
including symptoms of heart
failure, aggressive iron chelation
can restore myocardial function
to normality.

For example, breathlessness during exercise

may be attributed to anaemia. In more
advanced stages of heart failure, clinical
presentations are equivalent to those seen
with any severe heart muscle disease and
may include dyspnoea, peripheral oedema,
hepatic congestion and severe exercise
limitation. Signs and symptoms of right heart
failure may predominate, but bi-ventricular
involvement is the norm. The development
of the signs of classical heart failure implies
advanced disease with a poor prognosis, until
the acute situation is resolved.
As mentioned above, an important

The unique capacity of the heart to recover

from the effects of iron overload only
emphasises the importance of early
detection and, ideally, prevention; once overt
heart failure is manifest, acute survival may
be as low as 50%.

The regular assessment of

cardiac status helps physicians
to recognise the early stages of
heart disease and allows for

83

distinguishing feature of heart failure due to

iron overload is the capacity of heart
function to make a complete recovery with
appropriate chelation therapya fact that
may not be widely appreciated by physicians
and cardiologists unaccustomed to dealing
with patients with thalassaemia. It must be
emphasised that the patient may require
support of failing circulation for a period of
several weeks in order to achieve a full
recovery.

Treatment is directed towards the relief of

iron overload, with a secondary strategy of
symptomatic treatment of the documented
arrhythmia.

Symptoms of palpitations are common in

patients with thalassaemia, and are a
frequent cause for anxietyboth for patients
and their physicians. In brief, the prognostic
implications of arrhythmia are related to the
degree of myocardial iron-overload and any
associated myocardial dysfunction. Thus in
the case of a non-iron overloaded patient,
the development of an arrhythmia such as
atrial fibrillation (AF) deserves simple
investigation and possible pharmacological
treatment, but does not necessarily imply an
adverse outcome. The same arrhythmia in a
heavily iron overloaded heart, particularly if
cardiac dysfunction is present, may be the
harbinger of severe decompensation and
requires immediate response and probable
hospitalisation.

Patients frequently present with epigastric

pain due to liver congestion, diminution in
exercise capacity and also dyspnoea and
cough.

Chest pain is uncommon in thalassaemia, but

may accompany intercurrent illnesses
including pericarditis or myocarditis. The
frequency of these complications appears to
differ between countries, being rare in the
UK but more prevalent elsewhere.

Clinical examination
A thorough medical history and physical
examination are required for a basic
cardiological assessment, which should also
include: 12-lead electrocardiogram and a
detailed echocardiogram, undertaken
according to published guidelines. Where
available, cardiac magnetic resonance
imaging (CMR), used to quantitatively
estimate cardiac iron overload, has become
an invaluable tool in the estimation of clinical
risk for the development of heart
complications in thalassaemia. Additional
tests may also be valuable for the detailed
assessment of individual clinical problems,
such as the investigation of cardiac
arrhythmia (Holter or 24-hour ECG) or
functional assessment by exercise tests.

Palpitations must therefore be investigated

and treated in the context of the patient as a
whole. Ectopic activity, usually supraventricular but occasionally ventricular, can
produce symptoms requiring prophylactic
drug treatment (often with beta-blockers),
especially as these transient events can
trigger more sustained arrhythmias,
particularly AF. Arrhythmias that produce
symptoms of haemodynamic compromise
(dizziness, syncope or pre-syncope) pose a
significant clinical risk and are associated with
significant myocardial iron-overload.

Electrocardiogram
The electrocardiogram is frequently
abnormal, but changes are typically nonspecific. These changes commonly include
depolarisation changes in the T-waves and ST
segments of the anterior chest leads, and
sometimes a preponderance of right
ventricular voltages. Occasionally P-waves are

84

right and left heart dimensions, biventricular

function (left ventricular fractional
shortening and ejection fraction), estimated
intracardiac pressures (pulmonary artery
pressure, systolic and mean) and Doppler
analysis of intra-cardiac flows. Longitudinal
follow-up assessments should be carried out
at approximately the same time in the
patients transfusion cycle, to minimise
variability of clinical parameters.

also affected, suggesting bi-atrial

enlargement. Conduction disturbance in the
forms of bundle branch block may be seen
but higher degrees of conduction
disturbance are rare. When new ECG
abnormalities appear during follow-up,
further investigation is required in order to
detect the cause.

Ambulatory monitoring of ECG

The standard method for detecting and
investigating cardiac arrhythmia is via Holter
ECG recording for 24 or more hours. There
are now many types of recorders suited to
the detection of intermittent cardiac
arrhythmia.

Examination by echocardiography of the

ventricular response to exercise may also be
useful, highlighting individuals with subclinical disease in whom the ejection fraction
fails to rise, or even falls, in response to
exertion or simulated exercise using i.v.
dobutamine.

Exercise ECG
Exercise testing, by treadmill or cycle
ergometer, may be of value in identifying
patients at risk for cardiac arrhythmias or for
assessing functional capacity. Adequacy of
treatment of cardiac disease can also be
gauged by exercise test performance.

Radioisotope studies: The use of MUGA

(Multiple Uptake Gated Acquisition) to
determine the overall left-ventricular ejection
fraction is an outmoded technique (both in
requiring the use of radioactive isotopes and
its high cost). Greater accuracy can be
achieved by monitoring resting ejection
fraction and the response to a reproducible
stress, in order to establish whether the
ejection fraction can rise from its basal level.

An exercise test with gas-exchange

evaluation allows verification of: VO2 peak
(maximal O2 utilisation at the peak of the
stress) and VO2 AT (anaerobic threshold),
which are parameters closely related to the
functional status and prognosis of patients
with left-ventricular dysfunction.

Cardiac Magnetic Resonance Imaging

(CMR)

The CMR scan provides a

combination of morphological,
functional information on the
heart as well asuniquely
quantitative estimates of tissue
iron overload.

Echocardiography
Echocardiography is widely available,
relatively inexpensive and easy to perform. A
large number of parameters can be obtained
from the cardiac ultrasound investigation but
even the simplest measurements of chamber
size can provide immediate and valuable data
on cardiac status and clinical progress, as
long as they are obtained by a skilled
practitioner following a standardised
protocol. A minimum data set should include:

As a result, CMR is rapidly becoming the tool

of choice in the clinical assessment of
patients with thalassaemia and is hampered
only by the limitation in access to
appropriate scanners in some parts of the

85

measures, along with particular cardiological

interventions. Such measures might include:

world. Scan times have been progressively

reduced with modern protocols and very few
patients are unable to tolerate the procedure
due to claustrophobia.

Maintenance of pre-transfusional
haemoglobin level close to 9-10.5 g/dl in
patients without heart disease, and 1011 g/dl in patients with heart disease;
Regular iron-chelation therapy and, for
patients with high iron loads or cardiac
disease, constant infusion regimens (s.c.
or i.v.); consideration of combined
chelation regimes using parenteral and
oral chelators simultaneously.
Surveillance and adequate management
of other causes of heart failure such as
hypothyroidism, hypoparathyroidism,
renal dysfunction, coincidental valve or
structural heart disease, vitamin C
deficiency. Avoidance of unhealthy life
styles, including smoking, lack of physical
exercise and excess alcohol consumption.

Cardiological management protocols

The frequency of cardiological assessments
described above depends on the age of the
patient and a clinical assessment of the likely
risk of significant myocardial iron overload, or
awareness of high total body iron burden.
Well-chelated patients: first assessment at
puberty, with repeat examinations yearly.
The timing of a first CMR is not
determined but should probably wait
until the time of greatest actuarial risk,
i.e. late teens to early 20s.
Asymptomatic patients with any evidence
of cardiac impairment: every three to six
months. An initial CMR will give evidence
of specific myocardial iron burden, which
may then be followed by repeat
examinations at six to 12 months to
ensure treatment strategies are
associated with a fall in heart iron
content (rise in CMR T2* parameter
towards 20 msec).
Patients with symptoms of cardiac
impairment: weekly to every one to four
months, depending on clinical condition.
An immediate CMR will help guide
management while subsequent scans
provide an indication of response to
treatment.

Monitoring cardiac function can be a useful

guide to a patients overall prospects.
Impaired myocardial function may require
specific cardiac treatment, but it also calls
attention to the immediate need for much
stricter adherence to chelation protocol or
the initiation of a more intensive chelation
programme, in order to prevent an
inexorable progression to severe cardiac
failure.

Specific Cardiological Care

The essence of treatment of

cardiac disease should be
aggressive chelation therapy to
rapidly counteract iron toxicity
and progressively remove
excessive iron deposits (Davis
and Porter 2000).

Overall Management
Strategy
The therapeutic strategy to diminish the risk
of heart complications in patients with
thalassaemia involves a number of general

(see Chapter 3: Iron Overload for details on

86

fibrillation.

designing an appropriate chelation

programme under these conditions).

Diuretics are the mainstay in producing

symptomatic improvement in those
individuals who develop pulmonary
congestion or signs of right-sided heart
failure. Loop diuretics such as Frusemide and
Bumetanide will produce a reduction in
circulating volume, which may considerably
decrease pre-load. These diuretics should
therefore be used with caution in patients
with thalassaemia. The tendency for patients
with thalassaemia to have restrictive
physiology, with diastolic heart failure, means
that the reduction in pre-load due to a loop
diuretic can produce a sudden fall in cardiac
output. These effects may precipitate prerenal failure. To restate, loop diuretics should
be used cautiously and mainly in the late
stages of disease.

Over recent years there has been a trend

towards treating patients with thalassaemia
exhibiting mild ventricular dysfunction with
agents known to improve myocardial
function in other forms of cardiomyopathy.
Treatment of myocardial dysfunction is best
undertaken using angiotensin converting
enzyme inhibitors (ACE inhibitors). In
controlled trials, these agents have been
shown to reduce mortality in patients
without thalassaemia established
cardiomyopathy and to reduce the rate of
appearance of heart failure in those with
asymptomatic left-ventricular dysfunction.
These results are very promising, and while
their extension to heart failure in
thalassaemia remains conjectural, it is widely
applied in clinical practice. The usual
precautions for initiating treatment in
patients who are well hydrated and starting
at low doses are recommended. The dose
should be increased to the maximum
tolerated, limited by hypotension in patients
with thalassaemia. Certain patients are unable
to tolerate ACE inhibitors due to the
development of chronic cough. These
individuals should be treated with
angiotensin II receptor antagonists, such as
losartan. Even though support for this drug
in cardiac failure is not strong at present, the
haemodynamic profile approximates that of
ACE inhibitors.

Recent evidence supports the use of

spironolactone as adjunctive treatment in
non-thalassaemic patients with cardiac
failure. This and related agents reduce
potassium depletion induced by loop
diuretics and counteract hyperaldosteronism.
Potassium sparing agents can be used with
ACE inhibitors, but require careful monitoring
of electrolytes.
When dealing with severe congestive cardiac
failure in hospital, it is advantageous to use
constant intravenous infusions of loop
diuretics. This aids careful titration of the
doses of diuretic on an hour-to-hour basis,
according to urine output, thus avoiding the
dangerous situation of massive diuresis,
volume depletion, fall in cardiac output and
worsening of renal function that can follow
large i.v. bolus doses of loop diuretics.
Inotropic support may be indicated in severe
cases.
Managing such patients can be aided by

Digoxin should not be used in the early

stages of cardiomyopathy but may have a
role as an inotropic agent in patients with
cardiac dilatation accompanied by low blood
pressure. Digoxin has a very specific role in
the maintenance of reasonable ventricular
rates in patients with established atrial

87

treatment of AF.

utilising biochemical markers of heart failure

(BNP or pro-N-terminal BNP). Values are high
in decompensated heart failure and fall in
response to treatment. Data support delaying
hospital discharge in decompensated heart
failure until BNP levels have reverted to
normal.

Amiodarone has a very wide spectrum of

effectiveness against supraventricular and
ventricular arrhythmias and produces a
survival benefit in non-thalassaemic
individuals with life-threatening ventricular
dysrhythmias. However, Amiodarone does
have an enormous potential for side effects,
one of whichdisturbances of thyroid
functionis of particular relevance in
patients with thalassaemia.

Anti-arrhythmic agents: In many

instances, the use of drugs to treat relatively
benign but symptomatic arrhythmias may
produce greater morbidity and mortality than
in untreated individuals. The decision to treat
arrhythmias in patients with thalassaemia
must therefore be carefully considered,
bearing in mind that iron toxicity is the
primary cause of this complication. Intensive
chelation treatment has been demonstrated
to reduce arrhythmias. In the majority of
instances, the arrhythmias are
supraventricular, although ventricular
tachycardia may occur in seriously ill
individuals. The development of arrhythmia
may be associated with a deteriorating
ventricular function, and can be improved by
addressing the latter problem. Overall,
arrhythmias require very careful assessment.
For most supraventricular arrhythmias,
reassurance of the patient is generally
appropriate, whereas patients with
ventricular arrhythmias require urgent
attention to address associated high
myocardial iron load, via
intensified chelation.

The role of other drugs, such as calciumantagonists and class I antiarrhythmic agents,
has yet to be established. Generally, these
agents should be avoided, since they all have
a tendency to produce negative inotropic
effect. Their use has not been widespread,
since arrhythmias tend to be associated with
more severe levels of myocardial impairment.
Without more formal study, the use of such
drugs cannot yet be recommended for the
treatment of patients with thalassaemia.
Cardioversion should be considered in
patients who fail to respond to iron chelation
therapy and pharmacological intervention. In
the situation of acute heart failure,
cardioversion from AF to normal rhythm
should be considered early on, as reestablishing synchronised cardiac conduction
improves cardiac failure.

Anti-coagulation: All patients with in

dwelling central venous lines require formal
anti-coagulation with warfarin or other
suitable Coumadin derivatives, to prevent the
potentially life-threatening complication of
intra-atrial thrombus formation with
embolisation and the development of
pulmonary hypertension. Patients in AF also
should be considered for anti-coagulation, if
only as a temporary measure prior to

Beta-blocking agents can also be used to

control many arrhythmias, and are indicated
in patients with stabilised heart failure as
they improve the medium- to long-term
prognosis. Dosages should be low at first
with careful slow upward titration over days
and weeks. In heart failure, Carvidelol and
Bisoprolol have a special role, while Sotalol
may have advantages for the prophylactic

88

with or without symptoms:

intensification of iron chelation: i.v.
desferrioxamine (24 hours x 7
days/week); consider combination
treatment with oral deferiprone and s/c
desferrioxamine
slow blood transfusion with diuretics
specific cardiac medications:
ACE inhibitors, or ARII blockers where
ACE not tolerated
beta-blockers: carefully introduce
once acute heart failure stabilised;
bisoprolol or carvidelol remain first
choice
diuretics, for the symptomatic relief
of fluid overload; use sparingly whilst
monitoring renal function;
spironolactone should be introduced if
possible
digitalis, if in atrial fibrillation,
Warfarin: if central line in situ, or if in AF

cardioversion.

Heart transplant: A few patients have

undergone heart transplant for severe,
irreversible cardiac damage, and this
procedure has also been combined with liver
transplant (Olivieri, 1994). The outcome of
transplant in patients with thalassaemia
needs to be carefully studied to determine
the effectiveness of this approach. The
presence of iron-induced damage to other
organs may adversely affect the outcome of
heart transplant. If surgery is successful,
intensive chelation therapy is still required to
remove iron from other organs and to
prevent iron accumulation in the
transplanted heart.

Summary
A) For asymptomatic patients with a normal
heart and no myocardial iron content by
CMR (or, where no CMR is available,
patients with proven good chelation
records and an absence of iron-related
complications):
encourage continuation of current,
effective chelation
encourage maintenance of a healthy
lifestyle

Conclusion
The prospects for patients with thalassaemia
have improved with a greater understanding
of the disease and with better, individualised
regimes of management. Close co-operation
between the medical disciplines is called for.
At the same time, the fundamental
treatment aim remains to provide regular,
effective iron chelation, in forms that
encourage patients to comply with
treatmenttreatment that must be allied to
more precise definition of tissue-specific iron
loads, so that patient and physician alike have
a better idea of individualised risk.

B) For patients with increased cardiac iron

content (measured by CMR) but normal
cardiac function (or, where no CMR is
available, those with iron related
complications and/or a poor chelation
history):
intensification of iron chelation: s.c. or
i.v. desferrioxamine (24 hours x 7
days/week); consider combination
treatment with oral deferiprone and s/c
desferrioxamine
as for group A
C) For patients with cardiac impairment,

89

in TI. According to this study, moderate to

severe PHT was observed only in TI patients
with a prevalence of 23%. Systolic left
ventricular dysfunction, in contrast, was
present only in TM cases with a prevalence of
8%. Heart failure was observed in 3% of TI
patients and 4% of TM ones.

The prevalence,
pathophysiology,
diagnosis and
management of
pulmonary
hypertension in
-thalassemia

In terms of pathophysiology, it seems that

PHT in -thalassemia results from a rather
complex combination of mechanisms, which
lead to the increase of both cardiac output
and pulmonary vascular resistance. Chronic
tissue hypoxia and chronic hemolysis are
believed to hold the central pathogenetic
role, while individual mechanisms involved
include the prolonged anemic state, the
increased percentage of hemoglobin F, the
hepatic abnormalities, the presence of a
hypercoagulabilable state, the thalassemiarelated elastic tissue defects, and the
coexistent endothelial dysfunction (Aessopos,
2007).

Cardiac involvement represents the primary

cause of mortality in both thalassemia major
(TM) and thalassemia intermedia (TI). In this
context, pulmonary hypertension (PHT) is
part of the cardiopulmonary complications of
the disease (Aessopos, 2005).
Pulmonary hypertension was initially
documented in a small group of 7 TI patients
with right heart failure (Aessopos, 1995). In a
subsequent study (Aessopos, 2001) of a large
110-patient series, age-related PHT was
found in nearly 60% of cases followed by
right heart failure in 5% of patients. It should
be noted that all those patients had
preserved left ventricular systolic function
and normal pulmonary capillary wedge
pressure. Thus, following those observations
PHT is currently considered to be the primary
cause of heart failure in TI patients.

The diagnosis of PHT in patients with

thalassaemia may be performed simply and
non invasively using transthoracic Doppler
echocardiography (Aessopos, 2000). It has
been shown that a peak systolic tricuspid
pressure gradient in the presence of tricuspid
regurgitation higher than 30 mmHg is
indicative of the presence of pulmonary
hypertension. A follow-up strategy with
clinical examination of the cardiovascular
system, electrocardiography, chest X-ray and
echocardiography, performed on an annual
basis, or in shorter intervals if clinically
indicated, should be applied in every patient
with thalassaemia. A close collaboration
between attending physicians, hematologists
and cardiologists is required in this context.
Although both forms of the disease share a
common molecular background, the diverse
severity of the genetic defect and of the

In what concerns the development of PHT in

TM, a recent study (Aessopos, 2007)
compared cardiac disease between two large
aged-matched groups of TM (n=131) and TI
(n=74) patients, both treated uniformly in
the currently accepted manner, namely
regular transfusion and chelation therapy in
TM and absence of any particular treatment

90

resulting clinical phenotype impose a

different therapeutic approach. The currently
applied regular lifelong therapy in TM
patients eliminates chronic hypoxia and thus
prevents the development of PHT. On the
other hand, the absence of systematic
treatment in TI leads to a cascade of
reactions that compensate for chronic
anemia but at the same time allow the
development of PHT. The accumulated
experience indicates that a large number of
TI patients, if not the majority of them,
should be considered for regular transfusion
and chelation therapy (Aessopos, 2007). Two
crucial points that remain to be clarified are
the patient selection criteria and the timing
of treatment onset. Until research data
becomes available, the judgement should be
based on individual clinical and laboratory
assessment of patients. The applied
treatment, once started, should definetely
aim at prevention and not palliation of
anaemia-induced complications.

91

The Liver
in Thalassaemia

overload (HIC in mg/g dry weight x 10.6 =

whole body iron store in mg/kg) (Angelucci,
2000). Non-invasive techniques used to
assess hepatic iron include computed
tomography, biomagnetic liver
susceptometry (SQUID) and magnetic
resonance imaging (MRI). Of these, relaxation
rates R2 (1/T2) and R2* (1/T2*) measured by
MRI appear to be the most promising and
accurate (Wood, 2005).

Under normal circumstances, about one-third

of storage iron (ferritin and haemosiderin) in
the body is found in the liver. Approximately
98% of hepatic iron is found in hepatocytes,
which make up 80% of total liver mass; the
remaining 1.5-2% of total liver iron is found
in reticuloendothelial cells, endothelial cells,
bile ductular cells and fibroblasts. Iron that
enters the cell in excess of that required
accumulates in the major storage forms of
iron, ferritin, and haemosiderin. Progressive
accumulation of storage iron is associated
with cellular toxicity, although the specific
pathophysiologic mechanisms for
hepatocytes injury and liver fibrosis are not
entirely understood. These include lipid
peroxidation of organelle membranes,
increased lysosomal fragility and decreased
mitochondrial oxidative metabolism. Iron also
has a direct effect on collagen synthesis
and/or degradation, and alterations in
microsomal enzymes.

Hepatic iron stores are closely

correlated with cumulative
transfusional iron load and have
been used as a marker for the
effectiveness of chelation
therapy and prognosis. An
increase in hepatic iron is
associated with an increased risk
of impaired glucose tolerance,
diabetes mellitus, cardiac
disease and death.

The liver plays a central role in iron

homeostasis. In addition to iron released
from transfused red cells, an enhanced rate
of gastrointestinal iron absorption has been
suggested. This excess iron is initially
confined to the Kupffer cells but when
transfusion requirements produce massive
iron overload, spillover to hepatic
parenchyma cells quickly occurs, with the risk
of late development of fibrosis and cirrhosis.
In patients with -thalassaemia, in absence of
co-factors, the threshold hepatic iron
concentration for the development of
fibrosis is about 16 mg/g dry weight liver
(Angelucci, 2002). Clinical studies suggest a
relationship between hepatic iron
concentration and the development of ironinduced hepatotoxicity.

Hepatitis C Virus
(HCV)
This RNA virus was first characterised in 1989,
having previously been termed non-A non-B
hepatitis. The majority of HCV isolates studied
so far can be divided into six major groups,
designated genotypes 1-6, with subdivisions
in each (subtype a, b, c, etc.). Antibodies
that develop after infection are not
protective but rather are indicative of
current or past infection. Active infection is
diagnosed by the presence of circulating HCV
RNA in blood (Sharara, 1996)

Hepatic iron concentration (HIC) is the gold

standard for the measurement of body iron

92

Reversibility: The reversibility of advanced

fibrosis and even early cirrhosis (Child A
compensated or well-compensated*) has
been documented in thalassaemia once
causes of liver injury (iron overload and HCV
infection are removed) (Muretto, 2002).

Preventative measures to
minimise the risk of posttransfusional hepatitis C include
careful selection of voluntary
donors and appropriate blood
donor screening.

End-stage liver disease: should lead to

consideration of liver transplantation.
Hepatitis C is currently the commonest
reason for liver transplantation worldwide.
Recurrent hepatitis C infection occurs in >
90% of cases after transplant but is usually
mild. Long-term survival after liver
transplantation for hepatitis C is similar to
that for other diagnoses, averaging 65% after
5 years (Gane, 1996).

Natural history and

complications of
infection
Acute infection: generally benign, with
>80% asymptomatic. Anicteric Fulminant
Hepatitis is very rare.

Hepatocellular carcinoma (HCC):

Chronic infection: develops in 70-80% of

develops in 1-5% of infected individuals after

20 years, particularly after the development
of cirrhosis, increasing by 1-4% each year
thereafter (Colombo, 1991). Prevention and
early detection of HCC are more effective
than attempted cure. Cirrhosis patients
should undergo a regular six-monthly
screening programme, including liver
ultrasound examination and alpha-fetoprotein check, for the early detection of
hepatocellular carcinoma.

cases, leading to chronic liver disease.

However, the clinical outcome is highly
variable, for reasons that are not completely
understood. Determinants of disease severity
or chronicity as well as response to therapy
include age at acquisition, as well as hostspecific (e.g. immunity) and virus-specific
(e.g. genotype) factors and, most important,
co-morbidities.

Cirrhosis: develops in a variable percentage

of HCV-infected patients, ranging from < 5%
in young, healthy people, to approximately
25-35% of cases of patients with relevant comorbidities. Age and co-morbidities appear
to be the most important factors affecting
the risk of developing cirrhosis. Cirrhosis
usually takes as long as two to three decades
to develop from the time of acquisition. Fiveyear survival in patients with compensated
cirrhosis is 91%, with a 79% rate of 10-year
survival. When cirrhosis is decompensated
however, 5-year survival falls to just 50%.

Extra-hepatic manifestations of HCV

infection include porphyria cutanea tarda,
essential mixed cryoglobulinemia,
glomerulonephritis, autoimmune thyroidits
and vasculitis (Sharara, 1996).

* Liver cirrhosis is divided to 3 stages following the

Child-Pugh score, Score 5-6 (Score A) is
characterised by: No ascites, Bilirubin < 2mg/dl,
Albumin>3.5g/dl. INR <1.7, no encephalopathy.
Therefore, Child-Pugh stage A can be defined as
well compensated disease.

93

to guide decisions on therapy and anticipate

complications (Angelucci, 1995).

Special features of
hepatitis C in
thalassaemia major

Treatment
This is a rapidly changing field and the
treatment of hepatitis in patients with
thalassaemia should therefore be undertaken
in close collaboration with a specialist in liver
disease.

The severity of chronic hepatitis C in patients

with thalassaemia may be greater because of
concomitant iron overload, other concurrent
viral infections (HBV, HIV) and possible
infection with mixed hepatitis C genotypes. It
has been demonstrated that iron and HCV
infection are independent but mutually
reinforcing risk factors for the development
of liver fibrosis and cirrhosis, with a reciprocal
multiplicative effect (Angelucci, 2002). It
appears therefore that patients with
thalassaemia, particularly those with poor
control of iron overload, face an increased
risk of developing cirrhosis.

Similar to non-thalassaemia patients,

treatment of HCV in patients with
thalassaemia is aimed at eradication of the
virus, improvement in liver histology,
reduction of the risk of liver cirrhosis and
hepatocellular carcinoma.

Selection of patients for therapy

Patients diagnosed with acute HCV infection
and persistently positive serum HCV RNA
after 12 weeks of exposure or diagnosis
should receive treatment (Sharara, 2006).

Diagnosis and
monitoring

Initiation of treatment in chronic hepatitis C

has traditionally been based on one or more
of the following:
confirmed presence of HCV-RNA
moderate to high serum ALT levels
abnormal liver histology

Antibody testing
This is most valuable for screening blood and
blood products and as initial testing in
patients with chronic unexplained elevation
in serum transaminases or those suspected
of having chronic liver disease. Confirmatory
testing is done using HCV RNA detection by
polymerase chain reaction (PCR), the current
standard for the confirmation of viremia.
Ascertaining the genotype and quantity of
HCV RNA in serum is useful only in
determining the type and duration of
treatment (see below).

Encouraging results for the treatment of HCV

in thalassaemia, combined with the abovementioned risks of greater severity of chronic
hepatitis C in such patients, means that the
presence of serum HCV-RNA alone is
sufficient to consider treatment in patients
with thalassaemia, where the patient has no
other contraindications to treatment or other
significant co-morbidities.

Liver biopsy in thalassaemia major

Liver biopsy prior to treatment is helpful in
determining the extent of liver damage and

Response to treatment
Depending on HCV genotype and viral load,

94

 High baseline HCV-RNA level and the

absence of its early decay (4-12 weeks)
upon initiation of treatment
HCV genotypes 1 or 4
Presence of bridging fibrosis or cirrhosis
Co-existence of other viruses (HBV, HIV)

40-80% of patients with chronic hepatitis C

will respond to the current standard
treatment of pegylated interferon and
ribavirin. Response is defined on the basis of
a negative highly sensitive qualitative HCV
RNA PCR assay, carried out 24 weeks after
completion of therapy.

Controversial in this specific setting is the

role of iron overload.

Patient responses are classified as follows:

Early viral response (EVR): defined as
an undetectable HCV RNA or a > 2-log
reduction in viral load after 12 weeks of
treatment
Response at end of treatment
(ETR): defined as absence of HCV-RNA at
the end of treatment
Sustained viral response (SVR):
absence of HCV-RNA > 6 months after
concluding treatment. This is in practice
equivalent to viral eradication of HCV
Non-responders: lack of significant
decline (defined as > 2-log reduction
from baseline) in HCV RNA after 12 weeks
of therapy
Relapsers: re-emergence of HCV-RNA
after a satisfactory end of treatment
response

Since no baseline factor is specifically

predictive of treatment success or failure,
withholding therapy on the basis of factors
suggesting a poor response is unwarranted.
Because of the possible role of iron overload
in reducing the likelihood of successful
treatment of hepatitis C and for general,
well-known clinical reasons, effective
chelation therapy should be strongly
considered before initiation of antiviral
therapy in patients with bad control of
transfusional iron.

Treatment regimens
The gold standard is combination therapy
with pegylated interferon and ribavirin. An
example of an algorithm used for Hepatitis C
managament is presented in Figure 1.

Monitoring response
Depending on HCV viral genotype, the
current recommendation is to measure the
biochemical (serum ALT) and virological (HCVRNA) response after 4 to 12 weeks of
therapy, and to continue therapy for an
additional 12 to 24 weeks in patients with
undetectable HCV-RNA. Because serum ALT
may be raised for other reasons in patients
with thalassaemia (iron overload,
concomitant infections), monitoring response
is based on viral HCV RNA.

Type of interferon: Pegylated interferon

-2a or -2 given subcutaneously once
weekly
Duration: 24 to 48 weeks, depending on
genotype

Side effects: Typical side effects in most

patients include flu-like symptoms, insomnia,
and cognitive and mood changes, especially
in the first two weeks after starting
interferon. Dose-dependent neutropenia and
thrombocytopenia commonly occur during

Prediction of poor response

Negative predictors in all patients with
hepatitis C are:

95

Figure 1

96

In thalassaemia major this may be associated

with a more marked haemolysis and a 30%
increase in transfusion requirement, which
requires careful adjustment of the
transfusion interval and intensification of iron
chelation therapy (Li, 2002; Inati, 2005).

interferon therapy. Particular attention

should be paid to this complication in
patients with thalassaemia and
hypersplenism. Since both deferiprone and
interferon may cause neutropenia, there are
theoretical risks associated with their
combined use, and this combination should
be initiated with caution and under careful
monitoring. Hypothyroidism is an important
complication of interferon treatment.

It is important to note that dose-reduction of

ribavirin is associated with an inferior
sustained viral response and it is hence
recommended that transfusion-chelation
requirements be adjusted to compensate for
ribavirin-associated haemolysis rather than
altering the recommended ribavirin dose
(Inati, 2005).

Some patients have experienced

exacerbation of local reactions at the site of
desferrioxamine infusion during interferon
treatment. Heart failure has been seen in a
few patients with thalassaemia receiving
interferon, and special care should be given
if prescribing interferon for patients with
pre-existing heart disease.

Treatment duration and viral load

monitoring: Depends primarily on the HCV
genotype. For genotypes 1 or 4, treatment is
administered for 48 weeks provided there is
a positive early viral response (EVR) at 12
weeks. In the absence of EVR, treatment is
usually discontinued and further treatment
options considered.

Monitoring for side effects: Close

monitoring for hypothyroidism is mandatory
in patients receiving interferon, and testing
for thyroid function and the presence of
anti-thyroid antibodies should precede
initiation of therapy. Regular monitoring of
blood counts is also necessary, to identify
neutropenia or thrombocytopenia. Cessation
of therapy should be considered if the
absolute neutrophil count falls below 1,000.

This approach has been validated in patients

with thalassaemia where an SVR of 64% is
seen in patients infected with genotype 1
and 4 and who have exhibited an
undetectable HCV RNA at 12 weeks of
treatment (Inati, 2005). For genotypes 2 or
3, treatment is limited to 24 weeks. Given the
high rate of SVR for genotypes 2 and 3,
approaching 80%, a 12-week determination
of viral load is not usually necessary.

Ribavirin is a nucleoside (guanosine)

analogue, well absorbed orally, and typically
given in doses of 800-1200mg/d. Alone, it
has limited antiviral activity in hepatitis C but
in combination therapy with interferon has
been shown to significantly increase
sustained response rates compared to
interferon alone.

Treatment options for nonresponders

These have not been firmly established and
are currently considered experimental. An
expedited second treatment option may
need to be considered in patients with
advanced fibrosis on liver biopsy.

Side effects: Haemolysis occurs in most

patients without thalassaemia, with a
decrease in haemoglobin of 10-20% from
baseline levels.

97

Management of special patient

populations

HBsAg, and other public health

measures, have led to a
significant reduction in
hepatitis B infections in most
countries of Europe and North
America, as well as other parts
of the world. Hepatitis B
nevertheless remains a
formidable medical problem,
mainly in developing
countries.

Consultation with a physician experienced in

the management of liver disease is especially
important in the clinical management of the
following patient populations:
Children
Patients with cirrhosis
Immunosuppressed patients
Pregnant patients
Patients with acute hepatitis C

Prevention
There is currently no vaccine or
immunoglobulin to prevent hepatitis C. The
following recommendations are made to
reduce the risk of non-parenteral
transmission:

Current HBsAg positivity in thalassaemia

major ranges from <1% to >20% and
Hepatitis B infection remains a significant
cause of chronic liver disease and
hepatocellular carcinoma in patients with
thalassaemia in many regions of the
developing world.

Sexual transmission risk is generally low.

However, insufficient data exist to
recommend changes in current
recommendations: that patients encourage
their sexual partners to be tested for
hepatitis C, and that safe sexual practices
should be encouraged.

Clinical significance of HBV markers

Despite the availability of good screening
tests for hepatitis B, the interpretation of
results may be difficult or misleading.

General measures, such as avoiding

sharing toothbrushes, razors, etc. are
advised, to avoid transmission to family
members. However, the risk of transmission
is low, and special measures such as to
segregate towels and eating utensils are
probably unnecessary.

Acute infection. HBsAg is a reliable marker

(can be present for 4-5 months). HBeAg
is also transiently present (1-3 months).
Anti-HBc IgM is the most reliable test for
the diagnosis of acute HBV infection.
Chronic infection (overt carrier) is marked
by the presence of HBsAg and anti-HBc in
the blood (usually accompanied by HBeAg
or anti-HBe). In accordance with
international definitions, overt carriers
can be classified as:

Hepatitis B Virus
(HBV)

active carriers, identified by the

presence of HBeAg or anti-HBe
antibodies and a viral load 5 log10
copies/ml (although others cite a figure

Incidence

Vaccination strategies,
screening of blood donors for
98

interpretations of screening results.

of 4 log10 copies/ml), corresponding

to about 17,200 IU/ml, according to
most recent standardisations. The great
majority of active carrier cases are
associated with the presence of hepatic
disease.

Natural history
Acute hepatitis: This is the most common
presentation, with an incubation period of 420 weeks. Severity is variable, with an icteric
period often preceded by a prodromal illness
with arthralgia and urticaria. Progression to
fulminant hepatic failure is rare (1%). Acute
hepatitis B is usually managed by supportive
measures alone.

inactive carriers, characterised by the

persistent normality of transaminase in
an anti-HBe-positive subject, associated
with levels of viremia below the
threshold (<5 Log10) and, eventually,
with IgM anti-HBc <0.2 IMx Index. In the
majority of such subjects, the
histological finding, when available, does
not reveal significant liver disease
(necroinflammatory activity <4 HAI),
while in a small minority of cases it is
possible to observe effects of a chronic
(sometimes even cirrhotic) disease
which have became silent spontaneously
or thanks to the effect of the antiviral
treatment.

Progression to chronic hepatitis B

occurs in 5-10% of otherwise healthy adults
and in 90% of neonates. In acute icteric
hepatitis B in adults, transition to chronicity
appears to be rare, probably occurring in less
than 2% of cases. For patients with chronic
hepatitis B infection, co-infection with
hepatitis C may increase the severity and rate
of progression of liver disease.

previous infection: the presence of

anti-Hbc antibodies anti-Hbs indicates
previous infection. In particular
circumstances, such as deep
immunosuppression (i.e. hemopoietic
stem cell transplantation), the possibility
of HBV reactivation after a previous
infection has been demonstrated. This
category of patients can therefore also
be defined as potential occult carriers
(Marzano, 2007).

Cirrhosis occurs at a rate of 1-2.2% per

year. Iron loading in thalassaemia may
increase the risk, as may concomitant HCV
infection.
Hepatocellular carcinoma is a wellrecognised complication of chronic hepatitis
B infection.

vaccination: the presence of HBsAg

antibodies (if anti-HBc is not present)
indicates vaccination.

Patients with thalassaemia should be

screened for all serological markers of
hepatitis B and classified according to
Table 1, which provides a list of possible

99

Test

Results

HBsAg
anti-HBc
anti-HBs

HBsAg
anti-HBc

+
+ or -

Interpretation

Recommendation

Susceptible to infection/never
exposed to virus

Consider vaccination

Acute or chronic infection

Further evaluation

HBsAg
anti-HBc
anti-HBs
anti-HBeAg

+/+
-

Resolution of previous infection

HBsAg
anti-HBc
anti-HBs
anti-HBeAg

+/-

Past infection*- potential

occult carrier.

HBsAg
anti-HBc
anti-HBs
HBeAg

+
+
+

Carrier with chronic infection

(if HBsAg+ 6 months or more)
Highly infectious

Further evaluation,
including HBV-DNA
levels

HBsAg
anti-HBc
anti-HBs
HbeAg
Anti-HBe

+
-

Carrier with chronic infection

(if HBsAg+ 6 months or more)

Further evaluation,
including HBV-DNA
levels

HBsAg
anti-HBc
anti-HBs
HBeAg
Anti-HBeAg

+
-

Immunisation without infection

* Other interpretations include:

1. Recovering from acute HBV infection, with loss of HBsAg but anti-HBs has yet to appear
(window period).
2. Immune to HBV but anti-HBs never appeared or has fallen below the level of detection.
3. Chronic HBV infection with undetectable serum levels of HBsAg.
4. False positive anti-HBc, with susceptibility to HBV infection.
* Interpretations 2 and 4 are the most common explanations of this serologic pattern.

Table 1: Possible interpretations of Hepatitis B screening results

100

Prevention:

HBV 2007 Treatment

Overview
(Hepatitis Annual Update 2007

Vaccination: All newly

diagnosed patients with thalassaemia should be
vaccinated against hepatitis B.
Three injections (at 0, 1 and 6
months) are required to
produce an antibody response
in 95% of normal individuals.
The vaccine is ineffective in
those already exposed to
hepatitis B.

website:http://clinicaloptions.com/Hepatitis/AnnualUpdates)

The primary goal of therapy for Chronic

Hepatitis B (CHB) is long-term suppression of
serum HBV-DNA which in turn will likely
reduce progression to cirrhosis, liver failure
and hepatocellular carcinoma.
The key endpoints in determining the
efficacy of therapy include suppression of
serum HBV DNA to low and preferably
undetectable levels, normalisation of ALT
levels, histologic improvements, HBeAg
seroconversion in HBeAg-positive patients,
and the relatively rare event of HBsAg
seroconversion.

In individuals acutely exposed to known

contaminated blood, hyperimmune globulin
can limit the risk of acute infection.

The information provided below is derived

from US treatment algorithms, AASLD*,
EASL**, and APASL*** Guidelines, according
to which, the currently preferred first-line
monotherapy treatment options include the
use of Adefovir, Entecavir and Pegylated
Interferon, which has almost completely
replaced standard interferon alfa-2b.

Prevention of vertical transmission:

Transmission of hepatitis B from mother to
infant occurs during the perinatal period. The
risk of infection is 26-40% if the mother is
HBeAg positive. Mothers with acute hepatitis
B during pregnancy transmit the virus in up
to 70% of pregnancies if infection occurs in
the third trimester, and up to 90% if it occurs
within 8 days of delivery.

Lamivudine and Telbivudine are not preferred

first-line drugs in most populations, because
of high resistance rates.

Measures to prevent vertical transmission

include administration of hepatitis B vaccine
and hepatitis B immuno-globulin (HBIG) to
neonates within 12 hours of delivery by a
carrier. This results in >90% reduction of the
risk of transmission.

Recent trends include treatment of patients

with any elevation of HBV-DNA with
compensated or decompensated cirrhosis.
Combination therapy with nucleos(t)ide
analogues is also now widely used in cirrhotic
patients as well as in patients with HBV and
HIV co-infection or in patients who have
undergone BMT after HBV infection.

Unlike hepatitis C, hepatitis B is highly

infectious through the sexual route and close
personal contact. Detailed advice and
immunisation need to be given to the
patients immediate family and sexual
partner(s).

* AASL: American Association for the study of Liver Disease

** EASL: European Association for the study of Liver Disease
*** APASL: Asian Pacific Association for the study of Liver
Disease

101

 The rates of genotypic resistance with

long-term therapy are high with
lamivudine (70% at 4-5 years), somewhat
less with telbivudine (21.6% in HBe-Agpositive and 8.6% in HBeAg-negative
patients at year 2), intermediate with
adefovir (30% at 5 years of therapy in
HBe-Ag-negative patients), and low with
entecavir in nucleoside-nave patients
(<1% at year 4), but higher in lamivudineresistant patients (~42% at year 4). Oral
drugs with a high genetic barrier to
resistance and/or high potency are
generally preferred to reduce the
likelihood of resistance. Interferon and
peginterferon therapy have not been
associated with the development of
resistance

Summary: Implications for Clinical

Practice
The key recommendations based on updated
treatment guidelines for treatment of
chronic Hepatitis B are as follows:
Patients with HBeAg-positive chronic
Hepatitis B should receive treatment
when serum HBV DNA levels are 20,000
IU/mL and ALT levels are elevated,
particularly 2-fold
Patients with HBeAg-negative chronic
Hepatitis B should receive treatment
when serum HBV DNA levels are 2,000
IU/mL and ALT levels are elevated
Genotype testing should be used more
broadly. Knowledge of genotype may be
useful in predicting natural history. For
example, genotype C HBV is associated
with more advanced disease and a higher
rate of HCC than genotype B in Asians.
For patients considering pegylated
interferon therapy, genotype is useful in
predicting response to therapy: HBV
genotype A responds much better than
genotype D (common genotypes in
whites), and genotype B responds
somewhat better than genotype C
(common genotypes in Asia)

Potential future therapies for chronic

Hepatitis B include pegylated interferon
and other nucleos(t)ide analogues,
particularly tenofovir that is in late-stage
studies and shows promise of high
potency and low rates of resistance. The
role of combination therapy is evolving,
primarily to reduce the rate of resistance
with long-term therapy

All patients with chronic hepatitis B and

cirrhosis with HBV DNA levels 2,000
IU/mL should be treated. In addition, it
may be appropriate to treat all patients
with cirrhosis and viraemia regardless of
HBV DNA levels, particularly if ALT levels
are elevated. Preliminary evidence also
supports the use of combination
nucleos(t)ide agents in these patients,
and therapy should probably used be
long-term, even after HBeAg
seroconversion in HBeAg-positive patients

102

Examples of treatment algorithms for specific groups with HBV infection include:

US Treatment Algorithm Recommendations for Treatment of HBeAg-Positive

or HBeAg-Negative Cirrhotic Patients
HBV DNA < 2,000 IU/mL and compensated cirrhosis
- May choose to treat or observe
- Adefovir or entecavir preferred; pegylated interferon alfa-2a may be option in early
well-compensated cirrhosis
HBV DNA 2,000 IU/mL and compensated cirrhosis
- Treat; adefovir or entecavir are first-line options
- Long-term treatment required, and combination therapy may be preferred
(adefovir or tenofovir plus lamividine, telbivudine or entecavir)
HBV DNA < 200 IU/mL or 200 IU/mL and decompensated cirrhosis
- Combination therapy preferred (adefovir or tenofovir plus lamivudine,
telbivudine or entecavir)
- Long-term treatment required
- Wait-list for liver transplantation
Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

2007 AASLD Guidelines on Management of Chronic Hepatitis B Patients with

Compensated Cirrhosis
Who to treat
- Patients who are HBeAg positive or negative
- Patients with HBV DNA > 2,000 IU/mL; no ALT specified
- Consider treating if ALT elevated for patients with HBV DNA < 2,000 IU/mL
- Observe for patients who are HBV DNA negative
Drugs of Choice
- Adefovir or entecavir preferred
Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

103

2007 AASLD Guidelines on Management of Chronic Hepatitis B Patients with

Decompensated Cirrhosis
Who to treat
- HBeAg positive or negative at any HBV DNA level
Drugs of choice
- Combination of lamivudine or telbivudine plus adefovir or entecavir
monotherapy is preferred (interferons contraindicated)
Duration of therapy
- Long-term
Other recommendations
- Refer for transpalntation
Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

Potential Management of Hepatitis B Antiviral Drug Resistance

Resistance Type

Strategy

Lamivudine

Continue lamivudine and add adefovir (preferred over switch to

adefovir) or tenofovir
Switch to emtricitabine/ tenofovir*

Adefovir

Continue adefovir and add lamivudine or telbivudine (preferred

over switch to lamivudine or telbivudine)
Switch to or add entecavir (if no prior lamivudine resistance)
Switch to emtricitabine/tenofovir*

Entecavir

Switch to or add adefovir or tenofovir*

Telbivudine

Continue telbivudine and add adefovir or tenofovir*

Switch to emtricitabine/tenofovir*

* Not approved by the FDA for the treatment of Hepatitis B

Reference: Hepatitis Annual Update 2007 website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

104

Advantages and Disadvantages of Current Therapies for Chronic Hepatitis B

Agent

Advantages

Disadvantages

Interferon alfa-2b

HBsAg loss rates

Short treatment duration
No drug resistance

Parenteral administration
Frequent adverse effects

Lamivudine

Drug resistance common

(~20%/yr and up to 70% with
4-5 yrs of therapy)

Adefovir

Oral administration
Excellent tolerance
Use in ESLD*
Use in lamivudine failures

24-to 48-week HBV response less

potent than entecavir and telbivudine
Drug resistance delayed and less
common than with lamivudine, but
more common than with entecavir
with extended therapy (0% at Yr 1, 3%
at Yr 2, 11% at Yr 3, 19% at Yr 4, and
30% at Yr 5 of therapy in HBeAgnegative patients)

Entecavir

Oral administration
Excellent tolerance
High potency in lowering
HBV DNA levels
Use in adefovir failures

Drug resistance: rare in nucleosidenave parents (estimated at < 1% at

Yr 4), but common in patients with
lamivudine resistance (estimated at
6% at Yr 1, 14% at Yr 2, 33% at Yr 3,
and 42% at Yr 4)

Pegylated
Interferon

HBsAg loss
Fixed duration of treatment
No drug resistance

Parenteral administration
Frequent adverse effects but
less than recombinat standard
interferon

Telbivudine

Oral administration
Excellent tolerance
High potency in lowering
HBV DNA levels

Drug resistance: intermediate rates

of drug resistance in treatment-nave
patients (5.0% at Yr 1, and 21.6% at
Yr 2 in HBeAg-positive patients, and
8.6% at Yr 2 in HBeAg-negative
patients)

Oral administration
Excellent tolerance
Use in ESLD*
Use in adefovir failures

* ESLD, end-stage liver disease

Reference: Hepatitis Annual Update 2007-Emmet B. Keeffe,

website:http://clinicaloptions.com/Hepatitis/AnnualUpdates

treatment of CHC/B, should be decided in

consultation with and monitored by a
specialist hepatologist.

The authors of this book have made an effort

to provide readers with essential information
on CHC and CHB treatment. However,

105

Infections
in Thalassaemia Major

briefest interaction with patients with

thalassaemia, should have the same
awareness, as should patients themselves. A
basic outline of the effects of infection in
thalassaemia and their practical implications
are provided in Table 1 (see also Table 2 for
more blood-borne infections).

Infections are the second commonest cause

of death in thalassaemia major. Clinicians
involved in the care of thalassaemia will be
fully aware of this risk and the importance of
any intervention that may limit it (Rahav,
Volach et al, 2006). However, all medical and
nursing staff, including those with the
Blood
borne
transmission

Relevance for severity

Anaemia Splenectomy

Parvovirus B19
HIV

Orientation for practical management

Iron
Iron
overload chelation

Vaccine Sensitive to broad

Suspend
available
spectrum
chelation
antibiotics
if suspected

++

+++

No

No

+++

+-

+?

No

No

Note

Pregnancy

HBV

+++

+?

Yes

No

HCV

+++

++

No

No

CMV

++

No

No

+?

+++

Yes

Yes

Yes

Meningococcus

+++

Yes

Yes

Yes

Hemophilus

+++

Yes

Yes

Yes

Klebsiella

No

Yes

Yes

Pseudomonas

++

No

Yes

Yes

Vibrio vulnificus

No

Yes

Yes

Escherichia coli

No

Yes

Yes

Salmonella

No

Yes

Yes

Yersinia

+++

+++

No

No

Yes

deferrioxamine

++

++

No

No

Yes

Deferrioxamine-

Stem cell
transplant

Streptococcus
pneumoniae

Influenzae

enterocolitica
Mucor species

Immunosuppression
Pythium

++

+++

++

Yes

No

Yes?

Farming

insidiosum

Table 1: A summary of the effects of infection in thalassaemia and their practical implications.

106

The pathogens most commonly associated

with post-splenectomy sepsis are
encapsulated organisms, particularly:

A patient with thalassaemia major must not

be considered as immuno-compromised per
se, particularly if the disease is well
compensated by treatment. On the other
hand, many alterations to the bodys immune
system have been described in thalassaemia,
including reduction in neutrophil numbers,
changes in number and function of natural
killer cells, increase in number and function
of CD8 suppress cells, occurrence of
macrophages, chemotaxis and phagocytosis
and interferon gamma production.

Streptococcus pneumoniae (accounting

for more than 75% of documented
bacterial infections in asplenic patients);
Haemophilus influenzae, and;
Neisseria meningitides.
Infections with gram-negative, rod-shaped
bacteria, notably Escherichia coli, Klebsiella
species (e.g., pneumoniae) and Pseudomonas
aeroginosa, occur with increased frequency
in asplenic patients and are often associated
with high mortality. Other gram-negative
organisms have also been implicated in postsplenectomy sepsis.

Even in the absence of any evidence-based

data on a direct relationship between these
alterations and the development of severe
infections in thalassaemia, it is recognised by
treating physicians through clinical
observations and practice that several factors
linked to the disease, its complications and
treatment may facilitate or aggravate the
severity of infections.

Protozoan infections due to Babesia have

been implicated in a fulminant haemolytic
febrile state in splenectomised patients, and
Malaria is repeatedly reported as more severe
in asplenic people with an increased risk of
death (Boone and Watters, 1995)
(for blood-borne infections see Table 2).

Where infection is suspected, the main

causes to be considered include:
Splenectomy;
Transmission of pathogens by blood
transfusion;
Iron overload and
Iron chelation.

Iron overload
The role of iron load in
susceptibility to infection has
not yet been fully established in
clinical trials. It is clear, however,
that a variety of microorganisms are more pathogenic
in the presence of iron
overload.

Splenectomy
The major long-term risk after
splenectomy is overwhelming
sepsis. In older studies, the risk of postsplenectomy sepsis in thalassaemia major is
increased more than 30-fold in comparison
with the normal population (Singer, 1973).
Modern preventative measures (see below)
have reduced this risk but the overall impact
of these measures is unclear.

The best-described association between

bacterial infection, iron and iron chelators
involves Yersinia enterocolitica (see below).

107

manifestations: erythema infectiosum or

fifth disease in children, mild to severe
aplastic crises and myocarditis. During
pregnancy severe foetal anaemia and
myocarditis may lead to lethal non-immune
hydrops fetalis.

Many other organisms, such as Klebsiella

species, Escherichia coli, Streptococcus
pneumonia, Pseudomonas aeroginosa,
Legionella pneumophila and Listeria
monocytogenes, have been shown to have
increased virulence in the presence of excess
iron. On the other hand, phagocytic
efficiency, tested in vitro, is impaired in
patients with thalassaemia with iron overload
compared with individuals without
thalassaemia.

In patients with an already shortened red cell

lifespan (15-20 days) combined with anaemia
due to haematological disorders such as
spherocytosis, sickle-cell anaemia,
autoimmune haemolytic anaemia and
thalassaemia, B-19 infection may cause an
acute, life-threatening red cell aplasia,
commonly referred to as transient aplastic
crisis. The cessation of erythropoiesis lasts
for 5-7 days and haematologically
complicates chronic haemolytic anaemia. The
condition is characterised by:

Several observations in vivo indicate that

infections are more frequent or severe in
patients with iron overload either related to
genetic haemochromatosis or to
transfusions, as in thalassaemia. The role of
iron overload in aggrevating Mucormycosis in
bone marrow transplanted patients has been
demonstrated.

A variable fall in haemoglobin;

Disappearance of reticulocytes from
peripheral blood (< 0.2%);
A virtual absence of red blood cell
precursors in the bone marrow at the
beginning of the crisis and
B-19 DNA viraemia.

Iron chelators
A potential risk of natural siderophores, as in
deferoxamine, is that they may be used by
micro-organisms as a source of iron, and so
become more virulent. This has been
demonstrated in vitro and in vivo for Yersinia
enterocolitica, which has a receptor on the
outer membrane that efficiently binds
ferrioxamine.

Following recovery from an acute B-19

infection, patients are typically immune to
further infections by the agent. Where
patients are immunosuppressed (e.g.
transplanted, HIV-infected) and fail to mount
an effective antibody response to the virus,
the infection may be persistent and may
mimic or trigger autoimmune inflammatory
disorders.

A clear relationship between Mucormycosis

and desferrioxamine has been reported in
dialysis patients but only sporadically in
thalassaemia. Similar observations have been
reported for Rhizopus infections.
Specific infections

B-19 may be transmitted via the respiratory

system or blood derivates. The incidence of
B-19-infected individuals with persistently
detectable levels of B-19 DNA, despite the
presence of specific IgG, is estimated at 1%
of blood donors. The resulting risk of

Viral Infections
Human Parvovirus B-19 (HPV B19)
Parvovirus B-19 is a common pathogen that
may cause a wide range of clinical

108

policies addressing the problem, as well as on

the local prevalence of blood transmissible
pathogens.

infection is estimated at between 1/625 and

1/50,000, depending on a number of factors
(including detection methods, seasonal
outbreaks, B-19 DNA load of the donor and
co-presence of B-19 IgG antibodies) (Lefrere,
Maniez-Montreuil et al, 2006). There is
currently no general rule on action to be
taken to prevent blood-borne transmission of
B-19 in high-risk populations, including
thalassaemia major patients.

With the use of standard

procedures for prevention, it is
possible to keep the risk of HIV
transmission very low; with the
use of the most sensitive
screening measures, it is
possible to lower this risk still
further.

Management of acute B-19 crises includes

close monitoring and adequate blood
transfusion adjustment. Immunoglobulin
administration may be beneficial in chronic
illness.

Natural history
In the absence of treatment, the median
time from HIV seroconversion to the onset of
AIDS in transfused patients is about 7-11
years. Factors affecting progression are
symptomatic primary infection, age at
infection and viral load (HIV1-RNA
concentration in plasma).

Human
Immunodeficiency
Virus (HIV)

Management of HIV in thalassaemia

A detailed account of the treatment and
monitoring of HIV patients is beyond the
scope of this book. Patients with
thalassaemia identified with HIV infection
should be managed in collaboration with an
infectious diseases unit with expertise in HIV.
Advances in drug treatment have
revolutionised the care of patients from
strategies aimed at preparing patients to die
to treatments that may fully control the
disease. However, accessing the bestand
most expensivetreatment will depend on
local conditions.

Risk of transfusion-associated
infection
Although sensitive and specific laboratory
serologic tests became available soon after
the discovery and description of HIV, a
number of patients with thalassaemia who
received transfusions previous to HIV
screening have been infected. Many more
are still being infected in countries where
effective protective measures for blood
safety, including blood donor selection and
testing, have yet to be applied.

The prevalence of HIV infection

in thalassaemia varies greatly
worldwide, from <1% to >20%. In Italy,

Special considerations in thalassaemia

Although antiretroviral therapy should be
administered to patients with thalassaemia
major based on the same general guidelines
used for other infected non-thalassaemic
individuals, side effects such as endocrine
dysfunction and diabetes could be more
significant.

for example, the prevalence is currently 1.7%

while in Cyprus it is 0.17%. The rate of HIV
infection as with other infections among
transfused patients depends on the timing of
introduction and quality of public health

109

Viruses
enveloped

non-enveloped

HIV-1, HIV-2, HTLV-I, HTLV-II

CMV, HHV-6, HHV-8, EBV
HBV, HCV, HGV
HAV; parvo B19, TTV

Bacteria
Gram-positive

Gram-negative

Staphylococcus epidermidis
Staphulococcus aureus
Coagulase negative stachylococci
Streptococcus viridans
Enterococcal species
Bacillus cereus
Yersinia enterocolitica
Pseudomonas fluorescens
Salmonella enteritidis
Citrobacter freundii
Serratia marcescens
Enterobacter cloacae
Coliform bacteria
Flavobacterium species

Protozoa
Plasmodium
Plasmodium
Plasmodium
Plasmodium

vivax
falciparum
malarias
ovale

Trypanosoma cruci
Babesia microti
Toxoplasma gondii
Leishmania donovani

Others
Treponema pallidum
Prions
Abbreviations in Table 2:
HIV: human immunodeficiency virus, HTLV: human T-cell leykaemia/lymphoma virus; CMV: cytomegalovirus,
HHV: human herpes virus; EBV: Epstein-Barr virus; HBV: hepatitis B virus; HCV: hepatitis A virus; parvo B 19:
parvovirus B19;TTV: transfusion-transmitted virus. Ref. A. Modell, ZLB Central Laboratory Swiss Red Cross,
Bern, Switzerland 2000.

Table 2: Transfusion transmitted pathogens

110

organ transplant recipients, CMV infection

constitutes a major, if not one of the most
important causes of morbidity and mortality.

There is general agreement that a patients

iron status influences the outcome of HIV-1
infection. In HIV-infected patients with
thalassaemia major, the rate of progression
of HIV was significantly faster in patients with
low level of chelation with deferoxamine and
higher serum ferritin concentrations. Further
to the capacity to remove iron, iron
chelators, mainly deferiprone, show
interesting antiviral properties in vitro, but
there is so far no evidence of a direct
antiviral effect. Optimal control of iron
overload with iron chelation is therefore
recommended in HIV-positive patients with
thalassaemia and the choice of chelator
should take into consideration the above
data as well as the individuals needs.
Because of an increased risk of neutropenia,
deferiprone should be used with caution in
such cases.

Unlike the case with other infectious agents,

the presence of serum CMV IgG antibodies
does not preclude infectiousness. It is
estimated that approximately 2-12% of antiCMV positive healthy donors are infectious,
i.e. can transmit the virus.
The increasing use of bone marrow
transplantation as a treatment for
thalassaemia demands special attention to
the serological status of CMV. Prevention of
transmission through blood products is
effectively achieved by the use of anti-CMV
negative donation, but this policy may be
applied only in special conditions, such as
stem cell transplantation, because exclusion
of CMV positive donors (50-75% of the adult
population are anti-HCMV positive) will affect
significantly the national pool of blood
supply. As CMV is WBC-associated virus, the
widespread use of leucocyte filtration, in
recent years recommended for all patients
with thalassaemia, no matter what their
condition, constitutes an effective
preventative measure.

While there is no direct evidence that

splenectomy facilitates the progression of
HIV infection, a decision to perform
splenectomy in an HIV-positive patient with
thalassaemia should be made with extreme
caution. Of particular concern is the removal
of an important fraction of T cells and the
potential for overwhelming infection in
immuno-compromised patients.

Bacterial infections

Human
Cytomegalovirus
(HCMV)

Yersinia enterocolitica
Mechanisms of infection
The Yersinia organism is most commonly
transmitted by the ingestion of
contaminated food, meat, milk or water,
although it is commensal in healthy
individuals. On rare occasions it becomes
virulent, crossing the intestinal membrane
and provoking life-threatening infections. The
best known factor predisposing the organism

Transfusion-associated CMV has a wide

clinical spectrum. In the immuno-competent
patient-host, it is usually sub-clinical or may
appear as an infectious mononucleosis-like
syndrome. In the immuno-compromised
host, however, such as bone marrow or

111

Post-infection sequelae include erythema

nodosum and reactive arthritis, mostly in
adults.

to virulence is the availability of a large

amount of iron, as is the case in severe iron
overloaded patients or in those undergoing
iron chelation with desferrioxamine (Vento,
Cainelli and Cesario, 2006), as described
above.

Laboratory diagnosis
Specific culture conditions (at 22oC for 48
hours) are necessary to identify Yersinia
species and in this context, the treating
physician should inform the laboratory of
his/her suspicions in order to enable it to
proceed to the correct culture conditions for
blood and stool samples.

Transfusion-associated transmission of
Yersinia enterocolitica may occur from
apparently healthy donors, albeit rarely, as
the organism can survive and multiply under
normal storage conditions (4oC). The
mortality rate among recipients of
contaminated blood is >50%.

Serologic tests for Yersinia are problematic

because of the likelihood of cross-reactivity.
However, a four-fold rise in IgG titres in serial
samples obtained 15 days apart may be
suggestive of recent infection. Overall, the
pickup rate for stool, blood culture and
seroconversion is low. In some cases
diagnosis may only be made after obtaining
samples of affected tissue (e.g. gut, lymph
node).

Clinical manifestations
The clinical manifestations of Yersinia
infection depend on the age and health of
the host. While variable, these manifestations
are severe in over 80% of cases involving
patients with thalassaemia. Fever is the most
common presenting feature, often
associated with abdominal pain and diarrhoea
or vomiting. Extra gastrointestinal
manifestations, such as acute respiratory
distress syndrome, arthralgia and skin rashes,
are also sometimes seen.

Treatment
The basic but most important point is that
anyone involved in the care of a patient with
thalassaemia with the above-described
symptoms must be aware of the risk of
Yersinia infection and its management.
Simple information leaflets issued by the
treating centre and carried by the patient or
parents of children may be of help, especially
when travelling.

The most typical clinical picture is an acute

abdomen that mimics and may even be
indistinguishable from acute
appendicitis/peritonitis, caused by
mesenteric lymphadenitis. It is important to
have this critical point in mind, as the two
conditions require a very different
antimicrobial approach.

In the absence of a quick reliable laboratory

diagnosis, treatment must begin on the basis
of clinical suspicion. In such cases, the
following measures should be taken:

The most dangerous condition is septicaemia,

which, in the absence of specific antibiotics,
may be fatal in more than 50% of cases.
Complications may include abdominal,
hepatic or splenic abscess, intussusception,
nephritis, ileo-psoas abscess and meningitis.

112

infection by Campylobacter and

Chryseobacterium meningosepticum. Despite
the in vitro data for micro-organisms such as
Listeria monocytogenes and Salmonella,
there is no in vivo evidence that the
prevalence and severity of related infections
in thalassaemia is higher than in the nonthalassaemic population.

Stop iron chelation therapy

immediately
Obtain suitable laboratory
samples
Commence antibiotic
treatment immediately
Yersinia species are typically intracellular and
therefore antibiotics with good intracellular
penetration are recommended. In mild
suspected cases, oral ciprofloxacin is the
recommended first line treatment. In
severely unwell patients, immediate
parenteral therapy is mandatory with the
same drug. I.v. trimethoprimsulfomethoxazole or cephalosporins may be
added or used as an alternative.

Klebsiella species
Klebsiella infections in thalassaemia major
and even more in HbE/b-thal are associated
with high mortality and morbidity rates are
occasionally reported in the literature. In a
large retrospective study including 160
patients, the prevalence was reported to be
7.5%, with a clinical spectrum including
sinusitis, intracranial infection, meningitis,
septicaemia and pyogenic abscesses of the
liver, lung and kidney. Mortality rate was 16%,
and permanent neurological sequelae 25%.
Predisposing factors seemed to be iron
overload and liver function derangement
(Chung et al, 2003).

It is generally advisable to continue

antibiotics for at least two weeks after
proven infection. Iron chelation should not
be restarted until the patient has been
asymptomatic for over a week. Some
patients relapse after restarting
desferrioxamine. Whenever possible, an
alternative chelator should be prescribed. In
contrast to deferoxamine, the synthetic
chelators, deferiprone and deferasirox do not
seem to trigger Yersinia enterocolitica
virulence.

Pseudomonas aeruginosa in
thalassaemia constitutes the most common
pathogen-related infection to the central
venous catheter. It may cause severe
infections such as meningitis (Wang, Lin et al,
2003). Splenectomy seems to be the main
predisposing factor.

Other bacterial
infections

Melioidosis of the musculoskeletal system

caused by Pseudomonas pseudomallei has
been sporadically reported in thalassaemia.

Other micro-organisms that may cause

severe infections and should be seriously
considered in the management of unwell
patients with thalassaemia include Klebsiella
species, Pseudomonas species, Vibrio
vulnificus, Escherichia coli, Salmonella species
and Mucor species. Recent papers also report

Vibrio vulnificus is sporadically reported as

the cause of severe infections, including
septicaemia, wound infections and meningitis
in patients with thalassaemia in South-East
Asia. Iron overload is likely to be the most
important predisposing factor.

113

have been observed in patients with

thalassaemia (Krajaejun et al, 2006).

Escherichia coli is not reported as a

significant pathogen in thalassaemia major,
being clinically significant in patients with
HbE/-thalassaemia, as for Klebsiella.

The disease has high rates of morbidity and

mortality and early diagnosis and prompt
initiation of effective treatment are
extremely important. The organism does not
respond to antifungal agents. A vaccine has
been recently developed which has
demonstrated at this preliminary stage
effectiveness in patients with thalassaemia.
(Krajaejun et al, 2006)

Salmonella species
Many in vitro data suggest that patients with
thalassaemia, particularly those that are
splenectomised, have a decreased opsonic
activity and phagocytic efficiency against
Salmonella species. Overall, however, in vivo
the prevalence of Salmonella infections does
not seem higher than in normal subjects.

Common infections
not related to
thalassaemia

Haemophilus influenzae
Thalassaemics appear to have a lower natural
immunity to this microorganism, however
vaccine-induced immunity seems to be
effective.

Dengue
Haemorragic fever due to dengue viral
infection is endemic in Southeast Asian
countries where thalassaemias are also
common. In an uncontrolled study from
Thailand, dengue was reported to be
frequent and more severe than expected in
patients with thalassaemia, underscoring the
need for providing special awareness of
proper diagnosis and management,
particularly in these regions of the world.

Fungi
Mucor species
Mucormycosis or Zygomycoses are
opportunistic fungal infections caused by
ubiquitous organisms of the Zygomycetes
class. The relationship with conditions of iron
overload and deferoxamine use is well
known.

Helicobacter pylori

In thalassaemia, severe infections have been

observed only in immunocompromised
subjects after stem cell transplantation.

In one study of patients with thalassaemia

with recurrent abdominal pain, the
prevalence of H. pylori infection was not
statistically different from matched nonthalassaemic healthy subjects.

Pythiosum insidiosum
Pythiosis is caused by the oomycete
Pythium insidiosum. Human pythiosis has
been reported in Thailand among
farmers and their relatives although
zoonosis is prevalent in many other
parts of the world. The most
severe forms (cutaneous, vascular
and disseminated pythiosis)

114

Malaria and
thalassaemia

ransfusion-related
Malaria and Chagas
disease

There is evidence that in most cases, being a

healthy carrier of a haemoglobinopathy
provides protection against the clinical
severity of malaria.
However, the same is not true for the
homozygous state. Patients with

Post-transfusion malaria and Chagas disease

have been known for more than 50 years.
Plasmodium species and Trypanosoma cruzii
may remain viable for at least two weeks in
refrigerated blood components as well as in
frozen plasma, and in this context, there are
great concerns that increased tourism to and
from endemic countries might increase the
frequency of transfusion-transmission of
these pathogens. Both infections remain an
important topic for blood transfusion
services, and national standards including
donor selection have been drawn up based
on WHO, Council of Europe, EU and North
American Authorities recommendations, in
order to prevent or minimise the
transmission of these diseases.

thalassaemia major or
intermedia are not protected
from severe malaria and may
indeed be more prone to severe
forms of the disease, depending
on their clinical condition
(anaemia, splenomegaly, iron
overload and other
complications). Patients must
therefore be provided with
specific advice for the
prevention of malaria before
and during periods of travel in
endemic areas.

115

Splenectomy in
-thalassaemia

splenomegaly causes concern about

possible splenic rupture.

Many patients with thalassaemia major

require splenectomy. However, optimal
clinical management from the time of
diagnosis may delay or even prevent
hypersplenism, thereby increasing the
efficiency of transfusion therapy and
reducing the need for splenectomy.
Throughout the care of the patient with
thalassaemia, the size of the spleen should
be carefully monitored on physical
examination and, as needed, by
ultrasonography.

Leucopenia or thrombocytopenia due to

hypersplenism causes clinical problems
(e.g. recurrent bacterial infection or
bleeding).
Splenomegaly due to periods of undertransfusion with blood of inappropriately low
haemoglobin may be reversible. Before
considering splenectomy in this situation, the
patient should be placed on an adequate
transfusion programme for several months
and then re-evaluated.

Splenectomy should be considered when:

Annual blood requirements exceed 1.5
times those of splenectomised patients,
provided that they are on the same
transfusion scheme and have no other
reasons for increased consumption. Such
reasons include new alloantibodies,
infection, and changes in the haematocrit
of the transfused units. For patients
maintaining a pre-transfusion Hb level of
about 10 g/dl, this increase in transfusion
requirements represents consumption of
more than 200-220 ml of red cells
(assuming haematocrit of transfused cells
is 75%)/kg/year (Modell, 1977; Cohen,
1980). The rate of iron overload should
also be taken into consideration. For
patients who maintain effective chelation
therapy despite increased blood
requirements, splenectomy may be
unnecessary. For patients with increasing
iron stores despite good chelation
therapy, reduction in the rate of
transfusional iron loading by splenectomy
may be an important component of the
overall management of iron overload.

It is generally advisable to delay

splenectomy until patients are
at least five years old because
of the increased risk of
overwhelming sepsis below this
age (see below).

Surgery
The two surgical techniques most commonly
employed for total splenectomy are the open
and laparoscopic approaches. The
laparoscopic approach requires a longer
operative time and may not be practical for
patients with very large spleens, but the
recovery period is shorter and there is
virtually no surgical scar. Many surgeons now
have extensive experience with this
approach.
In some centres, partial splenectomy is used
to preserve some of the immune function of
the spleen while reducing the degree of
hypersplenism (De Montalembert, 1990). The
long-term success of this approach is still
undergoing evaluation. In particular, the

Splenic enlargement is accompanied by

symptoms such as left upper quadrant
pain or early satiety. Massive

116

likelihood of splenic re-growth and the

volume of splenic tissue required to preserve
immune function are two questions
outstanding. Any surgery on the spleen
should include a careful search for accessory
spleens.

thrombotic tendency, special consideration

should be given to the use of low-dose
aspirin (80 mg/kg/d) for patients with high
platelet counts, or the use of anticoagulation
for patients with a history of previous
thrombosis or other risk factors.

Reduction of splenic tissue by embolisation is

a less invasive approach to hypersplenism
than complete or partial surgical
splenectomy (Pringle, 1982). However, this
approach has not gained wide acceptance
and may be complicated by fever, significant
pain and the possible need for a subsequent
total splenectomy. Embolisation does not
permit a search for accessory spleens.

The major long-term risk after splenectomy is

overwhelming sepsis. In older studies, the risk
of postsplenectomy sepsis in thalassaemia
major is increased more than 30-fold in
comparison with the normal population
(Singer, 1973). Modern preventative
measures (see below) have reduced this risk
but the overall impact of these measures is
unclear. The pathogens most commonly
associated with postsplenectomy sepsis are
encapsulated organisms (Pedersen, 1983),
particularly:

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.
Splenectomy also provides a good
opportunity for a liver biopsy to assess the
liver histology and iron concentration.

Streptococcus pneumoniae (accounting

for more than 75% of documented
bacterial infections in asplenic patients)
Haemophilus influenzae
Neisseria meningitidis
Infections with gram negative, rod-shaped
bacteria, notably Escherichia coli, Klebsiella
and Pseudomonas aeroginosa, occur with
increased frequency in asplenic patients and
are often associated with high mortality.
Other gram-negative organisms have also
been implicated in postsplenectomy sepsis.

Appropriate immunisations
should be administered at least
2 weeks before splenectomy
(see below).

Protozoan infections due to Babesia have

been implicated in a fulminant haemolytic
febrile state in splenectomised patients.
Malaria is reportedly more severe in asplenic
people (Boone, 1995) and carries an
increased risk of death.

Complications of splenectomy
Peri-operative complications include
bleeding, atalectasis and subphrenic abscess.
Postoperative thrombocytosis is common,
with platelet counts often reaching
1,000,000-2,000,000/mm3. Because patients
with thalassaemia may have an increased

Characteristics of overwhelming postsplenectomy sepsis include the sudden onset

of fever and chills, vomiting and headache.

117

(Landgren, Bjorkholm et al, 2004). The

currently available pneumococcal vaccine is a
23-valent polysaccharide vaccine that can be
given subcutaneously or intramuscularly. A
conjugate vaccine will be available shortly.
The protection rate with the 23-valent
vaccine is 70-85%. Pneumococcal vaccine
should be given at least 2 weeks in advance
of a splenectomy and then in 3-5 years. The
immune response to this polysaccharide
vaccine is poor in children less than two years
of age. Children vaccinated under the age of
two should be re-vaccinated at age two.
Patients who underwent splenectomy
without being given pneumococcal vaccine
may still benefit from vaccination postsplenectony.

The illness rapidly progresses to hypotensive

shock, and is commonly accompanied by
disseminated intravascular coagulation.
Postsplenectomy sepsis has many of the
features of adrenal haemorrhage
(Waterhouse-Friederichsen syndrome). The
mortality rate for such infections is
approximately 50%, despite intensive
supportive measures. Therefore, early
intervention on the basis of clinical suspicion,
even in the absence of many of the above
findings, is critical.
The risk of overwhelming postsplenectomy
infection varies with:
Agerisk is very high in children <2 years
of age. However, fulminant bacteraemia
has been reported in adults as much as
25-40 years after splenectomy.
Time since splenectomythe greatest risk
appears to be in the period 1-4 years
after surgery
Immune status of patient

If not administered as part of routine

childhood immunisations, Haemophilus
influenzae vaccine should be given to
patients before they undergo splenectomy
and should also be given to splenectomised
patients (Spoulou, Tsoumas et al, 2006).
Meningococcal polysaccharide vaccine should
also be administered to patients who are
undergoing splenectomy and to nonimmunised, previously splenectomised
patients.

Preventative
measures
The three types of protective measures a
physician can utilise to prevent postsplenectomy sepsis include:

These vaccines can be given at the same

time in different syringes at different sites.
Yearly administration of influenza virus
vaccine is recommended to prevent this
febrile illness that might otherwise require
intensive evaluation and management of a
febrile episode in the splenectomised host
with thalassaemia (see below).

1. Immunoprophylaxis
2. Chemoprophylaxis
3. Patient education

Immunoprophylaxis
Vaccination against Streptococcus
pneumoniae is a critical step in preventing
overwhelming infection after splenectomy

118

febrile illnesses and seeking immediate

medical attention. For all febrile episodes,
the physician should strongly consider:

Chemoprophylaxis
Chemoprophylaxis with oral penicillin, 125
mg b.i.d. for children under two years, and
250 mg b.i.d. for children two years and over
is recommended to reduce the risk of postsplenectomy sepsis. Alternative antibiotics for
patients unable to take penicillin include
amoxicillin, trimethoprim-sulfomethoxazole
and erythromycin. All splenectomised
children under five years of age should be
treated with prophylactic antibiotics. The
value of chemoprophylaxis after this age is
unproven. Some clinicians continuously treat
all splenectomised patients with prophylactic
antibiotics, irrespective of age, while others
treat patients whose spleens are removed
after the age of five years only for the first
two years after splenectomy. The use of
prophylactic antibiotics will need to be
regularly re-evaluated as improved vaccines
become available and as new data regarding
antibiotic-resistant bacteria are developed.

Evaluating the patient, including a

complete physical examination
Obtaining blood and other cultures as
indicated.
Beginning treatment with an
antimicrobial regimen effective against
Streptococcus pneumoniae and Neisseria
meningitidis.
If bacteraemia is suspected, the patient
should be treated with parenteral antibiotics
and observed in a medical facility until the
cultures are evaluated.
Patients also need to be made aware of the
potential for travel-related infections such as
babesiosis and malaria, as well as the risk
inherent in travel to an area where medical
care is not readily accessible. In the latter
case, an appropriate antibiotic should be
made available for the patient to carry with
him/her.

The importance of compliance with

prophylactic antibiotics should be stressed
repeatedly to patients and parents. However,
the limitations of antibiotic prophylaxis must
also be emphasised. Patients and parents
should recognise that chemoprophylaxis does
not prevent all cases of post-splenectomy
sepsis: the risk of death from febrile illnesses
remains, and rapid evaluation of febrile
episode is essential (see below).

Patients should be reminded always to alert

consulting physicians about their
splenectomised status.
Other complications which have been
recognized in splenectomised patients
include:
Thrombophilia
Pulmonary hypertension

Education

Thrombophilia- this is a complication

which occurs more frequently in thalassaemia
intermedia (see relevant chapter), but a
higher risk is seen in splenectomised patients.
The phenomenon of increased coagulability is
related to the fact that damaged red cells

Patient and parent education can be highly

effective in preventing overwhelming postsplenectomy infection. Physicians should
emphasise to the patient and parents the
importance of recognising and reporting

119

normally removed by the spleen, persist in

the circulation and trigger mechanisms of
Thrombin generation (see Figure 2 Chapter
11: Thalassaemia Intermedia and HbE). In
postsplenectomy patients markers of
thrombin generation such as thrombin AT III
(TAT) complexes, prothrombin fragments
(F1,2) fibrinopeptide A (FPA) and D-dimer
should be assessed annually, and anticoagulant prophylaxis prescribed where
indicated.

Pulmonary hypertension this

complication is more frequent in
thalassaemia intermedia, but it is also
increasingly identified in thalassaemia major,
especially in splenectomised patients.

120

Thalassaemia Intermedia
and HbE

compound heterozygotes for -thalassaemia,

meaning that both -globin loci are affected.
The mild clinical characteristics of TI
compared with thalassaemia major are
primarily the result of the following three
mechanisms:

Definition
The clinical phenotypes of thalassaemia
intermedia (TI) lie between those of
thalassaemia minor (heterozygous state) and
major (homozygous state), although there is
substantial clinical overlap between the three
conditions. TI was first described in 1955 by
Rietti-Greppi-Micheli, who referred to
patients as being too haematologically
severe to be called minor, but too mild to be
called major.

inheritance of a mild + mutation;

presence of a polymorphism for the
enzyme Xmn-I in the G- promoter
region, associated with increased HbF;
and
co-inheritance of -thalassaemia on the
-globin locus.

Thalassaemia intermedia encompasses a wide

clinical spectrum. Mildly affected patients are
completely asymptomatic until adult life,
experiencing only mild anaemia and
maintaining haemoglobin levels between 710g/dL. These patients require only
occasional blood transfusions, if any. Patients
with more severe thalassaemia intermedia
generally present between the ages of 2 and
6 years, and although they are able to survive
without regular transfusion therapy, growth
and development can be retarded. The
clinical spectrum of thalassaemia intermedia
indicates the need for an individualised
treatment approach. Despite the availability
of a number of treatment options, the lack
of clear guidelines can present a significant
clinical challenge (Taher, 2006; Camaschella
and Cappellini, 1995).

The phenotype of TI may also result from the

increased production of -globin chains,
occurring either by the triplication of
genotype associated with -heterozygosity,
or by the interaction of - and thalassaemia (Taher, 2006).
Analysis of the genotypes of patients with
thalassaemia intermedia is important for an
early diagnosis of the milder disease, thus
avoiding unnecessary blood transfusions.
Predicting phenotype from genotype in TI is
still difficult, due to the interaction of
genetic and environmental factors. Primary
genetic modifiers are the numerous genetic
alleles at the -chain locus, which can cause
either complete or marked reduction in chain synthesis. Secondary genetic modifiers
are those that have a direct effect on
modifying the amount of excess -chains
(inheritance of abnormal - or -chain
genes). Tertiary modifiers are polymorphisms
occurring at loci involved in bone, iron and
bilirubin metabolism that can affect clinical
expression. Relevant environmental factors
include social conditions, nutrition and the
availability of medical care (Taher, Ismaeel
and Cappellini, 2006).

Mechanism of TI
The pathophysiology of thalassaemias is
based on an imbalance of globin-chain
synthesis. In the case of -thalassaemia
intermedia, the imbalance is greater than
that seen in -thalassaemia trait and less than
that of -thalassaemia major.
Most TI patients are homozygotes or

121

accurate identification of these two

phenotypes at the onset is remarkably
difficult. Nevertheless, a careful analysis of
clinical, haematological, genetic and
molecular data may allow a reasonable
conclusion for treatment (Taher, 2006;
Wainscoat, 1987; Weatherall, 2001). (see
Table 1 for an outline of the major
differences between thalassaemia intermedia
and major).

Differential diagnosis
Differentiation at presentation between
thalassaemia major and thalassaemia
intermedia is essential for designing
appropriate treatment for an individual
patient. The accurate prediction of a mild
phenotype may avoid needless transfusions
and their complications, while the timely
diagnosis of thalassaemia major will allow an
early start to a transfusion programme, thus
preventing or delaying hypersplenism and
reducing the risk of red cell antigen
sensitisation. Unfortunately, however, the

Helpful clues in differentiating between thalassaemia major and

thalassaemia intermedia
Thalassaemia major
more likely

Thalassaemia intermedia
more likely

Clinical
Presentation (years)
Hb levels (g/dl)
Liver/ spleen enlargement

<2
6-7
Severe

>2
8-10
Moderate to severe

Haematological
HbF (%)
HbA2(%)

>50
<4

10-50 (may be up to 100%)

>4

Both carriers of high

HbA2 -thalassaemia

One or both atypical carriers:

- High HbF -thalassaemia
- Borderline HbA2

Severe
No

Mild/silent
Yes

No

Yes

No
No

Yes
Yes

Genetic
Parents

Molecular
Type of mutation
Coinheritance of
-thalassaemia.
Hereditary persistence of
fetal haemoglobin
thalassaemia
G XMN1 Polymorphism

Table 1

122

degree of ineffective erythropoiesis is the

primary determinant of the development of
anaemia, while peripheral haemolysis of
mature red blood cells and an overall
reduction in haemoglobin synthesis are
secondary determinants.

Pathophysiology of
Thalassaemia
Intermedia (TI)
Three main factors are responsible for the
clinical sequelae of thalassaemia intermedia:
ineffective erythropoiesis, chronic anaemia
and iron overload. The severity of clinical
sequelae depends primarily on the underlying
molecular defects. a-chains are highly
unstable and precipitate into erythroid
precursors in the bone marrow, causing
membrane damage and cell death (i.e.
ineffective erythropoiesis). Hypertrophy of
erythroid marrow in medullary and
extramedullary sites, a consequence of
severe ineffective erythropoiesis, results in
characteristic deformities of the skull and
face and may also cause cortical thinning and
pathological fractures of long bones. The

Complications and
management of TI
In addition to the defining symptoms of
thalassaemia intermedia, which are seen to a
lesser or greater extent in other forms of
thalassaemia, patients with thalassaemia
intermedia experience a number of specific
complications that are rare in thalassaemia
major. Figure 1 highlights the multitude of
complications in untreated thalassaemia
(Taher, Ismaeel and Cappellini, 2006;
Cappellini, Cerino et al, 2001).

Figure 1: Pathophysiological sequelae of untreated thalassaemia and corresponding clinical

manifestations

123

Splenomegaly and
Splenectomy

Extramedullary
haematopoiesis

Splenectomy is now uncommon and is mainly

performed late in life. The main indications
for splenectomy in thalassaemia intermedia
are a significant enlargement of the spleen
and a decrease in mean haemoglobin levels
in the absence of other transient factors
such as infection (Taher, Ismaeel and
Cappellini, 2006; Cappellini, Cerino et al,
2001; Borgna-Pignatti, Rigon, Merlo et al,
2003; Galanello, Piras, Barella et al, 2001). As
for the type of surgery, the laparoscopic
approach is safe and feasible and preferred
over open surgery, as a minimally invasive
alternative that may become the treatment
of choice in -thalassaemia patients who
require concurrent operations. During
splenectomy, surgeons should assess the
gallbladder for any stones and perform
cholecystectomy whenever gallstones are
found (Leandros et al, 2006).

Extramedullary haematopoiesis is a
compensatory mechanism where bone
marrow activity increases in an attempt to
overcome the chronic anaemia of
thalassaemia intermedia, leading to the
formation of erythropoietic tissue masses
that primarily affect the spleen, liver, lymph
nodes, chest and spine. These masses can be
detected by magnetic resonance imaging
(MRI). They may cause neurological problems
such as spinal cord compression and
paraplegia, and intra-thoracic masses.
In case of spinal cord compression, clinical
awareness is crucial for early diagnosis and
prevention of irreversible neurological
complications. MRI is the radiological method
of choice for diagnosing extramedullary
haematopoietic masses and for delineating
the extent of spinal cord involvement.
Management includes transfusion therapy, as
well as radiotherapy and hydroxyurea (Taher,
Ismaeel and Cappellini, 2006; Chehal, Aoun,
Koussa et al, 2003; Castelli, Graziadei, Karimi
and Cappellini, 2004; Saxon, Rees, Olivieri,
1998). Hypertransfusion is a promising
treatment method, targeting at higher Hb
levels, involving many blood transfusions
over a period of weeks to compensate for
the demands of erythropoiesis.

Gall stones and

cholecystectomy
Gallstones are much more common in
thalassaemia intermedia than in thalassaemia
major as a result of ineffective erythropoiesis
and peripheral haemolysis. Similar to
laparoscopic splenectomy, laparoscopic
cholecystectomy has more favourable and
feasible outcome than open cholecystectomy
(Taher, Ismaeel and Cappellini, 2006;
Cappellini, Cerino et al, 2001; BorgnaPignatti, Rigon, Merlo et al, 2003; Galanello,
Piras, Barella et al, 2001; Leandros et al,
2006).

Kidney stones
As a result of ineffective erythropoiesis and
peripheral haemolysis TI patients are
susceptible to kidney stones, which can lead
to hydronephrosis and kidney failure. The

124

supplementation can help accelerate the

healing of ulcers. Hydroxyurea also has some
benefit, either alone or in combination with
erythropoietin or platelet-derived growth
factor. In addition, the use of an oxygen
chamber can provide moderate relief since
tissue hypoxia may be an underlying cause of
the ulceration (Taher, Ismaeel and Cappellini,
2006; Gimmon, Wexler and Rachmilewitz,
1982).

cause is associated with hypertrophic stones

that block the renal tubules and even the
calyces. The kidneys are frequently enlarged
in thalassaemia, due to the presence of
extramedullary haematopoiesis.

Leg ulcers
Leg ulcers are more common in older rather
than younger patients with thalassaemia
intermedia. It is unclear why ulcers develop.
However, once an ulcer has started to
develop it is very painful and difficult to cure,
although regular blood transfusions may
provide some relief in persistent cases. Zinc

Thrombophilia
Patients with thalassaemia intermedia have
been shown to have an increased

Figure 2: Thrombotic mechanism in thalassaemia intermedia

125

which is thought to be the primary cause of

congestive heart failure in this patient
population (Aessopos, Farmakis, Karagiorga et
al, 2001). The mechanism underlying
pulmonary hypertension in thalassaemia
intermedia is unclear.

predisposition to thrombosis compared with

thalassaemia major patients. Such events
mainly occurred in the venous system and
comprised deep vein thrombosis (40%),
portal vein thrombosis (19%), stroke (9%),
pulmonary embolism (12%) and others (20%).
Moreover, splenectomised patients have
been shown to have a higher risk of
thrombosis than non-splenectomised
patients (Cappellini, Robbiolo, Bottasso et al,
2000). (See Figure 2 for more on the
thrombotic mechanism in thalassaemia
intermedia.)

As anaemia and iron overload are uncommon

in well-transfused and chelated thalassaemia
major patients, the two conditions are likely
to be at the root of the pathophysiology of
pulmonary hypertension. Regular transfusion
and iron chelation therapy is therefore
indicated in thalassaemia intermedia patients
who are well-stratified according to the early
detection of pulmonary hypertension indices.
Sildenafil has also been successfully used to
treat pulmonary hypertension, although data
from large patient numbers are lacking in
thalassaemia intermedia (Taher, Ismaeel and
Cappellini, 2006; Aessopos, Farmakis,
Karagiorga et al, 2001; Aessopos, Farmakis,
Deftereos et al, 2005).

Management of thrombophilia has two arms:

prevention and treatment. Prevention
consists of proper anticoagulation prior to
any surgical or other high-risk procedure.
Treatment entails the adequate use of
anticoagulation according to the
recommendations for hypercoagulable
states. Awareness is important since
thromboembolism plays an important role in
pulmonary hypertension and right heart
failure (Taher, Ismaeel and Cappellini, 2006;
Taher, Ismaeel, Mehio, Bignamini et al, 2006;
Eldor, Rachmilewitz, 2002; Cappellini,
Robbiolo, Bottasso et al, 2000; Taher, AbouMourad, Abchee et al, 2002).

Hepatitis
Hepatitis due to viral (B and C) infection is
less frequent in thalassaemia intermedia than
in patients with thalassaemia major, since
blood transfusions are much less common in
thalassaemia intermedia. Abnormal liver
enzymes (increased alanine and aspartate
aminotransferase) are frequently observed in
patients with thalassaemia intermedia,
primarily due to hepatocyte damage resulting
from iron overload. Normalisation of liver
enzyme levels is often observed during
appropriate chelation therapy (Taher, Ismaeel
and Cappellini, 2006; Cappellini, Cerino,
Marelli and Fiorelli, 2001).

Pulmonary
hypertension and
congestive heart
failure
Pulmonary hypertension (PHT) is prevalent in
patients with thalassaemia intermedia. In a
study of 110 thalassaemia intermedia
patients (60.9% untransfused or minimally
transfused), 59.1% were shown to have PHT,

126

However, the mechanism involved in TI is

increased absorption from the gut rather
than blood transfusions. The resulting iron
overload can lead to a number of serious
complications, including cardiac failure and
endocrine abnormalities such as diabetes
mellitus and hypogonadism (Taher, Ismaeel
and Cappellini, 2006; Weatherall, 2001).

Endocrine function
Hypogonadism, hypothyroidism and diabetes
mellitus are quite rare in thalassaemia
intermedia. Although patients with
thalassaemia intermedia generally experience
puberty late, they have normal sexual
development and are usually fertile.
Hypothyroidism is sometimes observed late in
life (Taher, Ismaeel and Cappellini, 2006;
Cappellini, Cerino, Marelli and Fiorelli, 2001).

Initiation of iron chelation depends on the

amount of excess iron, rate of iron
accumulation, and duration of exposure to
excess iron. Increased levels of liver iron
concentration (LIC) have been observed with
small increases in serum ferritin (Fiorelli,
Fargion, Piperno et al, 1990). Thus, direct
assessment of LIC by biopsy or MRI is
recommended. Chelation therapy should be
initiated if LIC 7 mg/g dry weight of liver
(Taher, Ismaeel and Cappellini, 2006).

Pregnancy in TI
Women with thalassaemia intermedia may
have spontaneous successful pregnancies,
although complications during pregnancy
may occur. The chronic anaemia of
thalassaemia intermedia can cause an
increase in spontaneous abortions, pre-term
labour and intrauterine growth retardation,
while endocrine complications due to
haemosiderosis are common.
Folic acid deficiency is common in
thalassaemia intermedia and occurs due to
poor absorption, low dietary intake or, most
significantly, an increased demand for folic
acid from active bone marrow. During
pregnancy, women with thalassaemia
intermedia should be given oral folic acid
supplementation (around 1 mg/day), and
should be carefully monitored in order to
assess the need for transfusion therapy and
to avoid haemodynamic compromises (Taher,
Ismaeel and Cappellini, 2006; Nassar,
Rechdan, Usta and Taher, 2006).

Osteoporosis
(also see chapter on osteoporosis)
There is a high incidence of osteoporosis of
the spine and hip in both sexes in
thalassaemia intermedia. The severity
increases with age and even young patients
exhibit a spinal bone mineral density far
below that of age-matched controls.
Management consists of bisphosphonates
and calcium supplementation with follow up
bone-mass densitometries (Origa, Fiumana et
al, 2005).

Pseudoxanthoma
elasticum (PXE)

Iron overload

PXE is a rare hereditary connective tissue

disorder, characterised by generalised
degeneration of the elastic fibres with a

Just as in thalassaemia major, TI patients are

susceptible to complications of iron overload.

127

broad phenotypic expression. The clinical

picture consists mainly of cutaneous, ocular
and vascular manifestations; skin
histopathology involves swollen, irregularly
clumped and multiply-fragmented elastic
fibres in the middle and deep reticular
dermis, with secondary calcium deposition.
This condition has been described as
occurring in halassaemia.

Transfusion therapy
and iron chelation
Although transfusion therapy is not currently
a routine treatment approach for patients
with thalassaemia intermedia, it can afford
significant benefits. The decision to initiate
therapy should be based on the presence
and severity of signs and symptoms of
anaemia, including failure of growth and
development. As the rate of iron loading is
variable in thalassaemia intermedia, an
assessment of liver iron concentration is
advisable before initiating transfusion
therapy. Patients with thalassaemia
intermedia may benefit from an individually
tailored transfusion regimen, compared with
the regular transfusion regimens
implemented in thalassaemia major, to help
prevent transfusion-dependency.
Alloimmunisation is a relatively common
observation in thalassaemia intermedia,
although the risk is decreased if transfusion
therapy is initiated before the age of 12
months (Pippard, Callender, Warner and
Weatherall, 1979; Mourad, Hoffbrand, SheikhTaha et al, 2003; Cappellini, 2001).

Management of
thalassaemia
intermedia
There are a number of options currently
available for managing patients with
thalassaemia intermedia, including
splenectomy, transfusion therapy,
modulation of fetal haemoglobin production
and bone marrow transplantation (Taher,
Ismaeel and Cappellini, 2006; Cappellini,
Cerino, Marelli and Fiorelli, 2001).

Splenectomy

Transfusions are indicated where the

following are observed:
failure to thrive in childhood in the
presence of significant anaemia;
emergence of bone deformities;
increasing anaemia not attributable to
rectifiable factors;
evidence of a clinically relevant tendency
to thrombosis;
presence of leg ulcers;
development of pulmonary hypertension;
delayed or poor pubertal growth spurt
and
progressive splenic enlargement.

Splenectomy is no longer a major mode of

management. However, the main indications
for splenectomy include growth retardation
or poor health, leucopenia,
thrombocytopenia, increased transfusion
demand and symptomatic splenomegaly.
Splenectomy before the age of 5 carries a
high risk of infection and is therefore not
generally recommended.

128

eligible for transplantation is complex and is

related to both quality of life and expected
survival time of the transplanted patient. This
is particularly relevant in patients with
thalassaemia intermedia, especially in those
who are only mildly affected. In stable
asymptomatic TI patients who do not require
transfusions, bone marrow transplantation is
not needed.

Modulation of fetal
haemoglobin
production
Increasing the synthesis of fetal haemoglobin
can help to alleviate anaemia and thereby
improve the clinical status of patients with
thalassaemia intermedia. Agents including
cytosine arabinoside and hydroxyurea may
alter the pattern of erythropoiesis and
increase the expression of -chain genes.
Erythropoietin has been shown to be
effective, with a possible additive effect in
combination with hydroxyurea. Butyrates are
a further experimental category, still
unlicensed and with difficult intake. Good
responses have been reported; however,
most patients complain of the difficulty of
intake orally and intravenously. Further
clinical evaluation is required to clarify the
value of this approach (Taher, Ismaeel and
Cappellini, 2006; Karimi, H. Darzi, M. Yavarian,
2005; Dettelbach and Aviado, 1985; Dixit,
Chatterjee, Mishra et al, 2005; Perrine,
Ginder, Faller et al, 1993; Cappellini,
Graziadei, Ciceri et al, 2000; Olivieri, Rees,
Ginder et al, 1997). (For more details, see
Chapter 13: Alternative approaches to the
treatment of thalassaemia.)

Recommendations
for the management
of thalassaemia
intermedia
Two major issues regarding the management
of thalassaemia intermedia are 1) the
approach and management of complications
in adult thalassaemia intermedia patients and
2) preventing such complications in younger
patients. A stratification of the management
of TI between adults and young patients has
therefore been established.
The scheme for adult thalassaemia
intermedia patients is as follows:
each patient to be reviewed separately
and stratified by risk;
hydroxyurea introduced as a suitable
initial approach;
transfusion and iron chelation therapy
with deferoxamine subcutaneous infusion
and concomitant steroids for protection
from alloimmunisation are essential;
aspirin for stroke prevention, postsplenectomy and life-long anticoagulation
in patients with a history of thrombotic
events is a must;
liver MRI assessment of iron
concentration (or liver biopsy if MRI is

Bone marrow
transplantation
Bone marrow transplantation is an
established treatment for -thalassaemia.
Although marrow transplantation can lead to
cure, the degree of its success depends
primarily on the health and age of the
patient. The decision as to which patients are

129

unavailable) is important to determine

liver iron status for future chelation.

Definition of thalassaemia/HbE

There are no clear guidelines for the

management of thalassaemia intermedia in
the young. Thus, the authors recommend
the following:
a guarded approach to the need for
splenectomy and delay in initiating
transfusion unless considered necessary
based on the above mentioned
indications;
early initiation of transfusion and iron
chelation therapy if there is evidence of
growth abnormalities, poor performance
at school or a psychological impact
secondary to facial deformities;
regular follow-up with echocardiodoppler
for cardiac complications and initiation of
therapy at earlier disease onset to
prevent progression;
regular follow up of liver iron
concentration with MRI or liver biopsy;
discourage smoking, prolonged
immobilisation and the use of oral
contraceptives or an intrauterine device.

Haemoglobin E has the clinical phenotype of

a mild form of -thalassaemia, and is most
frequent in southeast Asia, particularly
eastern Thailand and Laos. The combination
of HbE with -thalassaemia spans
thalassaemia phenotypes, from a condition
indistinguishable from thalassaemia major to
a mild form of thalassaemia intermedia (TIF,
2002; Premawardhena et al, 2005).
Clinically, -thalassaemia/HbE may be
classified into three categories, each of
which has its own unique clinical
management requirements:

Mild thalassaemia/HbE
Mild -thalassaemia/HbE patients do not
require treatment and rarely develop clinical
problems. Haemoglobin levels may be as high
as 9-12 g/dl. Care should be taken not to

See Table 2 for indications for transfusion

and splenectomy.
Indications for transfusion

Indications for splenectomy

Growth failure or poor performance at school

Growth retardation or poor health

Transient stressful conditions

Leukopenia

(e.g.pregnancy, infection)
Symptomatic anaemia

Thrombocytopenia

CHF+PHT

Increased transfusion demand

Leg ulcers

Symptomatic splenomegaly

(Taher, Ismaeel and Cappellini, 2006)

Table 2: Indications for transfusion and splenectomy in thalassaemia intermedia

130

confuse this group of patients with

individuals having iron deficiency or with
carriers of -thalassaemia, by careful
investigation of the red cell morphology,
including iron status and haemoglobin
electrophoresis (TIF, 2002; Premawardhena
et al, 2005).

Severe
-thalassaemia/HbE
Patients present with the clinical symptoms
of thalassaemia major, including defective
physical development, bone deformities
including facial changes, anaemia, jaundice
and hepatosplenomegaly. Haemoglobin levels
can be as low as 4-5 g/dl. The clinical
management of this group of patients needs
to be addressed as in thalassaemia major
(TIF, 2002; Premawardhena et al, 2005).

Moderately severe
-thalassaemia/HbE
This group encompasses the majority of thalassaemia/HbE patients. Most patients
have steady haemoglobin levels of 6-7 g/dl.
Clinically, these patients manifest symptoms
similar to thalassaemia intermedia and
normally do not require blood transfusions
unless they develop infections precipitating
further anaemia. Other complications such as
iron overload may occur in these patients.
Where this is the case, iron chelation therapy
should be initiated. Patients in this group
often have a somewhat shortened lifespan,
but with careful monitoring and treatment
can have an open-ended prognosis (TIF,
2002; Premawardhena et al, 2005).

Complications and
management of
-thalassaemia/HbE
Complications in -thalassaemia/HbE patients
depend on the category they belong to, as
indicated above. The worst of the
complications occur in the severe group, in
which the clinical picture is similar to that thalassaemia major. This includes the
multitude of problems brought about by iron
overload due to dependence on transfusions
(see sections on complications in thalassaemia major for further explanation).

131

Stem Cell
Transplantation

Figure 1). Class II patients have an 87%

probability of survival and an 83% chance of
disease-free survival, with a 3% risk of
rejection and a 15% risk of non-rejection
mortality (see Figure 2), while Class III
patients have a 79% probability of survival
and a 58% chance of disease-free survival,
with a 28% risk of rejection and a 19% risk of
non-rejection mortality (see Figure 3).
(Centres performing transplants in patients
with broadly similar characteristics have
shown comparable outcomes [Lucarelli
1997].) In the case of Class III patients, the
introduction of conditioning regimens
containing less than 200 mg/kg of
cyclophosphamide resulted in a significant
decrease in transplant-related mortality, but
with a concomitant increased risk of graft
rejection. Among adults (aged >16), the
probability of surviving a bone marrow
transplant procedure is 66% with a 62%
probability of cure, a 35% chance of
transplant-related mortality and a 5% chance
of returning to the pre-transplant
thalassaemic condition (see Figure 4).

Outcome and patient

selection
Bone marrow transplantation from HLAidentical siblings has been increasingly
adopted for the cure of
haemoglobinopathies. Since 1981, a large
clinical experience has been gained with
more than 1,500 bone marrow transplants
performed in centres around the world. Over
that time, a number of factors the use of
cyclosporin, more effective treatment of
cytomegalovirus infection, improved aseptic
techniques and the evolution of systemic
antibiotic therapy have led to a remarkable
improvement in the outcome of bone
marrow transplantation procedures (Lucarelli,
1990).

Three patient classes have been

identified on the basis of the
following risk factors, which
have been found to have a
significant influence on posttransplant outcome:
inadequate iron chelation
therapy,
presence of liver fibrosis and
hepatomegaly

Based on these outcomes, bone

marrow transplantation in
thalassaemia should be
considered for patients at an
early age or before
complications due to iron
overload have developed.
However, a final decision must
be based on an assessment of
the relative advantages and
disadvantages of bone marrow
transplantation and
conventional therapy, requiring
the physician, patient and family
to weigh the outcome and risks
of each.

Patients in Class I have none of the above

characteristics, patients in Class II have one or
two, and patients in Class III exhibit all three
characteristics.
Among Class I children with thalassaemia
major transplanted early in the course of the
disease, the probabilities of survival and
disease-free survival are 93% and 91%
respectively, with a 2% risk of rejection and
an 8% risk of transplant-related mortality (see

132

There are several possible advantages to this

approach. First, stem cells can be obtained
easily at birth, and often in sufficient
quantity for a successful donation thus
avoiding the bone marrow harvest of a donor
at a later age. Second, it has been suggested
that graft versus host disease (GVHD) may be
less severe when stem cells are obtained at
this early point in life. Third, the routine
collection of cord blood stem cells from all
births would provide a wider pool of donors
for BMT therapy.

HLA-matched sibling
donors
The general applicability of bone marrow
transplantation is limited by the availability of
a related HLA-matched donor. There is a onein-four chance that any given sibling will be
HLA identical, with the likelihood of a
thalassaemic patient having an HLA identical
sibling donor varying according to family size.

However, the evidence of decreased GVHD

using cord blood is not persuasive. And in
many cases, the quantity of stem cells
obtained is insufficient for engraftment in an
adult recipient. Thus, while cord blood
transplantation has been successfully used to
treat some patients with thalassaemia
(Miniero, 1998), its overall value in treating
the condition has yet to be firmly
established.

Matched unrelated
donor transplantation
Because most patients with thalassaemia do
not have a compatible sibling donor, there is
interest in using unrelated but otherwise
matched donors. Unfortunately, the
complication rates of transplants using
matched unrelated donors are generally
much higher than with sibling matched
transplants. It is hoped that with continuing
improvements in matching techniques,
complication rates will be reduced to
acceptable levels. There has been some
application of transplantation using matched
unrelated donors in thalassaemia, suggesting
that if unrelated donors are from a closely
related genetic background the outcome
may be improved (Dini, 1999; Miano, 1998).
Experience so far is limited, however.

Mixed chimerism
Persistence of residual host haematopoietic
cells, normally termed mixed chimerism,
frequently occurs after bone marrow
transplantation in -thalassaemia (Andreani,
2000). Reduction of the dose of busulfan or
cyclophosphamide in the conditioning
regimens produced higher rates of mixed
chimerism a risk factor for graft failure.
None of the patients showing full donor
engraftment rejected the transplant, while
29% of patients with mixed chimerism
rejected the graft within two years of
marrow infusion. Nevertheless, a condition of
long-term (> 2 years) persistent mixed
chimerism has been observed after
successful BMT in thalassaemia. This

Cord blood
transplantation
The use of stem cells obtained from umbilical
cord blood collected at the time of delivery
has recently received considerable interest.

133

observation may have a significant impact on

the design of future bone marrow transplant
strategies.

Post-transplant
follow-up
Post-transplant clinical follow-up
of BMT is particularly important.
Within the first year, careful
monitoring of haematological
and engraftment parameters,
infectious complications and
graft versus host disease is
essential.
Long-term follow-up is of particular interest
with respect to monitoring the evolution of
multi-system problems (iron overload,
pubertal development, growth, endocrine
deficiencies) related to the primary disease. A
number of reports indicate that iron
overload, chronic hepatitis, cardiac function
and endocrine deficiencies can be more
easily managed after transplant, sometimes
permitting the healing of damaged organs. It
is particularly important to remove excess
iron after transplant. This can usually be
achieved by repeated venesection (6 ml/kg
blood withdrawn at 14-day intervals)
(Angelucci 1997).

134

Figure 1:

Figure 3:

Figure 2:

Kaplan and Meier probabilities of

survival, event-free survival,
rejection and non-rejection
mortality in 119 Class I thalassaemic
patients aged less than 17 years.

Kaplan and Meier probabilities of

survival, event-free survival, rejection
and non-rejection mortality in 126
Class III thalassaemic patients aged
less than 17 years.

Figure 4:

135

Kaplan and Meier probabilities of

survival, event-free survival,
rejection and non-rejection
mortality in 291 Class II
thalassaemic patients aged less
than 17 years

Kaplan and Meier probabilities of

survival, event-free survival,
rejection and non-rejection
mortality in 115 adult thalassaemic
patients (aged more than 16
years).

Alternative Approaches to the

Treatment of Thalassaemia

recovery from bone marrow suppression

after the use of cytotoxic drugs, attention
has focused on the possible role of cytotoxic
agents as therapies in the treatment of
serious haemoglobin disorders. Several
cytotoxic agents that alter the pattern of
erythropoiesis, favouring the expression of
foetal ()-globin genes and so increasing the
number of red cells containing HbF (F-cells),
have been explored over the past 20-25
years (Pace and Zei, 2006; Fathallah and
Atweh, 2006; Gambari and Fibach, 2007).

There is currently no definitive treatment for

any of the serious haemoglobin disorders,
other than bone marrow transplantationan
option available only to a small minority of
patients that have a suitable donor and are in
good clinical condition. Another, promising,
approach involves the use of therapeutics to
definitively correct the globin chain
imbalance in -thalassaemia, by re-activating
the foetal globin genes.

Modulation of fetal
haemoglobin

The demethylating agents 5-azacytidine and

decitabine have been administered to a few
-thalassaemia patients with good responses,
raising total haemoglobin levels by a mean of
2.5 g/dl above baseline and clearly
prolonging the lives of end-stage patients
(Lowrey, 1993; Dunbar, 1989; Ley, 1982). The
mutagenic potential and instability of
formulations of 5-azacytidine have limited its
investigation, but higher oral doses of
decitabine have been effective in baboons
(Lavelle, 2006), and studies are planned in
selected patients.

Foetal haemoglobin is the predominant non globin produced in humans until around six
months of age, when it is typically
suppressed and the production of -globin is
increased. This pattern is the norm even
when the genes are mutated, as in thalassaemia.
Patients with -thalassaemia who continue to
produce high levels of foetal globin, such as
those with Hereditary Persistence of Foetal
Haemoglobin, have less globin imbalance and
less severe anaemia.

Hydroxyurea has been studied in HbE/ thalassaemia patients, with lower responses
but reduced haemolysis (Fuchareon, 1996;
Zeng, 1995). Hydroxyurea has been less
beneficial in thalassaemia intermedia than in
sickle cell disease, in which the number of
painful crises was reduced and overall health
indicators improved. The lesser benefits in
thalassaemia are perhaps due to the fact that
the cytostatic effects of hydroxyurea are
limited in the disease.

The therapeutic stimulation of

foetal globin could therefore
benefit many patients, even
rendering some transfusion
independent.
Several candidate therapies now offer the
potential to correct or modulate the
underlying pathology.

Other agents
Erythropoetins (EPOs) have increased
haemoglobin levels significantly in some
patients with thalassaemia intermedia, even
eliminating transfusion requirements in some

Cytotoxic agents
Following observations that foetal
haemoglobin synthesis is reactivated during

136

(e.g. sodium 2,2-dimethybutyrate) (Boosalis,

2001; review Perrine, 2005). Select
hydroxamic acid derivatives have had high
activity in transgenic mice (Cao, 2005).

children. EPOs may thus be particularly

helpful in patients with relatively low levels of
endogenous erythropoietin for their degree
of anaemia (Bourantas, 1997; Nisli, 1996 and
1997; Rachmilevitz, 1998; Singer, 2003). EPO
promotes survival of red blood cells and may
counteract the rapid cell death (apoptosis)
caused by precipitation of excess -globin
chains in -thalassaemia (review Silva, 1996;
Perrine, 2005).

The mechanisms by which short chain fatty

acids stimulate -globin production are being
elucidated. Some new derivatives displace a
repressor complex and cause acetylation
specifically of the foetal globin gene
promoter (Mankidy et al, 2006).
Phenylbutyrate and butyrate cause general
histone hyperacetylation, which inhibits cell
proliferation, and are counter-productive in
thalassaemia, requiring limited exposure
(Pulse therapy). Butyrates have induced fetal
globin production in approximately twothirds of patients with diverse molecular
mutations and raised total haemoglobin
levels an average of 2-3 g/dl above baseline
when given intermittently to avoid antiproliferative effects (review Perrine, 2005).
As differences in drug metabolism contribute
significantly to responsiveness to any drug,
these will certainly apply in the highly diverse
thalassaemia syndromes. New generation
agents which promote erythroid survival, and
can be given daily, offer significantly more
potential benefit than the first generation
prototypes.

Short chain fatty acid derivatives

Short chain fatty acid derivatives induce
activity from the foetal globin gene
promoter, resulting in two-to-six-fold higher
foetal globin mRNA in some patients,
especially those who have at least one 0thalassaemia mutation and EPO levels >140
mU/ml (Collins, 1995; Perrine, 2005). Their
acceptable toxicity profiles add to their
potential as long-term therapeutic agents.
Several preliminary trials with intravenous
butyrate and oral phenylbutyrate compounds
have shown increases in foetal and total
haemoglobin levels in patients with
thalassaemia intermedia, while a few
previously transfusion-dependent
thalassaemia major patients have been
maintained transfusion-independent on
home therapy for 5-7 years. Isobutyramide
has induced foetal globin and reduced
transfusion requirements in thalassaemia
intermedia and major (Cappellini, 2000;
Reich, 2000).

Combination therapy
Although pharmacological induction of fetal
haemoglobin in transfusion-dependent
patients with thalassaemia will require highpotency induction of foetal globin, weaning
of transfusions to allow renewal of patients
own erythropoiesis, adequately high EPO
levels to promote eyrthroid cell survival and
iron availability for erythropoiesis, there is
expectation that some of the agents, used in
combination or properly scheduled, could
result in complimentary effects and render
even severe patients transfusion-

The most effective compound thus far is

arginine butyrate, although this has the
disadvantage of requiring intravenous
infusion due to its rapid metabolism. Oral
derivatives that persist for many hours after
a single dose and which also stimulate
erythroid cell proliferation and survival,
similar to EPO, will enter clinical trials soon

137

independent. For example, a demethylating

agent and butyrate had synergistic activity,
much higher than additive effects, in
experimental studies (Constantoulakis, 1989).
Such combinations offer excellent potential
for patients with diverse syndromes.

An approach to rational
combinations can now be based
on a patients baseline HbF,
total haemoglobin and EPO
levels (review Perrine, 2005).
Clinical trials should be planned
to find optimal drug
combinations for different
patient subsets.

138

Gene Therapy: Current

Status and Future Prospects

vector. The corrected cells are then returned

to the patient, who in the meantime has
undergone chemotherapy (as in a donorderived bone marrow transplant) to partially
or completely destroy their diseased bone
marrow (Persons and Tisdale, 2004).

The idea of using gene therapy to treat the

haemoglobinopathies (thalassaemia and sickle
cell disease) is, in principle, straightforward.
Red blood cells (RBC) are continuously
replenished by bone marrow haematopoietic
stem cells (HSC). Therefore, the stable
transfer of a normal functioning copy of a globin therapy gene unit into the patients
own HSC would result in the generation of
normal rather than diseased RBC for life.
(Note: no donor bone marrow is needed).

Early studies with LCR--globin gene

retroviral vectors based on the mouse MoLV
virus and using an ex vivo procedure in
animal models, provided good proof of
principle. However, it proved very difficult to
accommodate LCR--globin gene units within
MoLV retroviral vectors and manufacture
them. In addition, the LCR--globin therapy
gene units that could be incorporated into
this vector system were ineffective at
producing a consistent and sufficiently high
level of -globin protein to be of therapeutic
value (Antoniou and Grosveld, 1999).
However, a major breakthrough occurred in
2000, when the laboratory of Prof Michel
Sadelain reported work involving the testing
of an LCR--globin therapy gene unit within a
class of retrovirus known as an HIV lentiviral
(LV) vector (Figure 1; May et al, 2000). Prof
Sadelain showed for the first time that the LV
vector can readily accommodate a larger and
more efficient version of the -globin
therapy gene linked to the three most
powerful LCR elements (HS2, HS3, HS4), and
that application of this vector in an ex vivo
bone marrow transplant procedure could
completely cure or rescue the -thalassaemia
condition in mouse models of this disease
(May et al, 2000; Rivella et al, 2003).

A number of major discoveries

and technical advances in gene
therapy over the last 20 years,
particularly since 2000, mean
that, at long last, gene therapy
for the haemoglobinopathies
looks a serious possibility in the
not too distant future.
In 1987, a group led by Prof Frank Grosveld
discovered the master regulator of the globin gene family, known as the locus
control region (LCR). It was found that
linking the LCR to a -globin gene unit
enables the gene to be efficiently and
reproducibly switched on, and to produce a
sufficiently high level of -globin protein to
be of therapeutic benefit, if reproduced in a
gene therapy context (Levings and Bungert,
2002; Stamatoyannopoulos, 2005).
The stable introduction of the LCR--globin
therapy gene unit into the patients HSC is
via a retrovirus delivery vector, resulting in
the permanent splicing or integration of the
therapy gene into the HSC DNA, which is
then retained for life. Overall, the gene
therapy protocol employs an ex vivo
procedure. HSC are isolated from the
patients bone marrow and infected or
transduced with the LCR--globin retroviral

Since then, a number of groups in the US

and Europe have built their own versions of
the LCR--globin gene LV vector (Persons and
Tisdale, 2004; von Kalle C et al, 2004;
Sadelain et al, 2006). The smallest version of
the LCR--globin gene LV vector has included
only LCR elements HS2 and HS3 in its design,

139

Figure 1: Illustration of how a lentiviral vector containing a b-globin therapy gene unit is constructed from
the normal (wild-type) HIV virus.
A. Structure and gene organisation of wild-type HIV virus.
B. Replacement of the normal genes of the wild-type HIV virus with the Locus Control Region-globin therapy gene unit produces the lentiviral vector.
Note: combinations of locus control region elements HS2/HS3/HS4 or HS2/HS3 have been
employed.

gene LV vector include: (i) reproducibility of

function of the vector; at present there is
significant variability in the expression of the
LCR--globin therapy gene (including its
complete switching off), which is dependent
upon the site where the LV vector has
integrated within the HSC DNA (e.g. see May
et al, 2000; Miccio et al, 2006; Han et al,
2007); (ii) insertional mutagenesis: the
integration of the LCR--globin gene LV
vector into the HSC DNA has the potential to
disrupt host cell gene function causing, in
the extreme situation, a leukaemia-type
condition (von Kalle C et al, 2004), as has
been observed in clinical trials using retroviral
vectors for gene therapy of X-linked severe
combined immune deficiency (SCID-X1; see
Nienhuis et al, 2006), which also targets the
HSC of the patient. Some researchers have

which has significantly improved the ease of

vector manufacture (Miccio et al, 2006).
In all these cases, researchers have shown
good efficacy in rescuing disease in mouse
models of -thalassaemia or of sickle cell
disease. In addition, some groups have
shown that, under laboratory conditions,
transduction of human HSC derived from
bone marrow of severe -thalassaemia major
patients with the LCR--globin gene LV
vector can correct the globin chain
imbalance in resulting RBC (Persons and
Tisdale, 2004; Sadelain et al, 2006; von Kalle
C et al, 2004; Roselli et al, 2006).
Remaining problems that need to be
addressed in order to improve both the
effectiveness and safety of the LCR--globin

140

al, 2005). Up to the end of 2006, two

patients with -thalassaemia had been
treated. It is too early in the trial to know if
any benefit has been derived.

therefore included the chicken b-globin LCR

element cHS4 in their LV vector design to try
and insulate the LCR--globin gene unit,
which has led to some improvement in the
reproducibility of functioning (Persons and
Tisdale, 2004; von Kalle C et al, 2004;
Sadelain et al, 2006). In addition, it has been
suggested that the cHS4 element may act to
shield host genes within the HSC from
interference by the LCR--globin therapy
gene unit and therefore promote safety,
although this has yet to be formally
demonstrated.

The trial has not been without controversy,

mainly related to the use of a high-risk full
chemotherapy-conditioning programme as
part of a protocol whose success is still far
from certain, let alone in relation to what is
currently achievable with a sibling-donor
bone marrow transplant.

We eagerly await the outcome

of these studies, as well as the
commencement of future trials
with LV vector designs with
higher efficacy and safety
profiles.

These studies led to the commencement of

the first Phase I/II gene therapy clinical trial
for the haemoglobinopathies in 2006. The
trial is led by Prof Philippe Leboulch in Paris
and aims to treat five -thalassaemia and five
sickle cell disease patients within the age
range of 5-35 years. The protocol, as
expected, involves an ex vivo approach,
with patients receiving a full chemotherapyconditioning programme with Busulfex to
destroy their diseased bone marrow (Bank et

141

Psychological Support
in Thalassaemia

The success of management of thalassaemia

is based, to a great extent on the
establishment of a therapeutic alliance
between caring staff and the patient
throughout the course of the disease.
Because of the disease-oriented emphasis of
medical education, many health professionals
find it difficult to come to terms with the
psychological demands of treating chronic
inherited diseases. This can be made more
difficult in thalassaemia because patients
often express strong negative feelings, which
can hamper communication. Furthermore,
after many years of treatment, patients and
family may be better informed about the
illness than non-skilled health professionals
a factor that can undermine the health
professionals perceived role. Taken together,
these factors can make honest, in-depth
communication, which is vital to successfully
coping with thalassaemia, extremely difficult
to maintain.

Why is psychological
support so
important?
It is now universally recognised that
thalassaemia, like other chronic diseases, has
important psychological implications. The way
in which the family and the patient come to
terms with the disease and its treatment will
have a critical effect on the patients survival
and quality of life. Without an understanding
and acceptance of the disease and its
implications, the difficulties of lifelong
transfusion and chelation therapy will not be
faced, leading to an increased risk of disease
complications and poorer survival. A key role
for treating physicians and other health care
professionals is to help patients and families
to face up to the difficult demands of
treatment, while maintaining a positive role.

The psychology of
inherited chronic
disease

Adherence to treatment is a basic goal, but a

general acceptance by the patient of his/her
own condition constitutes the key to normal
development from childhood to adulthood.
Monthly contact with a local thalassaemia
centre from the first years of life allows
doctors and other members of the team to
act as a reference point for the patients
overall state of health, including general
attitude and well-being. In addition, this
regular interaction provides to the whole
staff, and in particular to the treating
physician a good opportunity to promote the
patients physical, emotional and social
development, taking on several
characteristics of the traditional family
doctor as guardian of the patients overall
wellness.

Every genetic disease, regardless of its

aetiology, implies a sense of guilt that may
interfere with the primary parent-infant
relationship. As its clinical manifestations
develop in the first year of life, the disease
can have also a negative impact on the
parent-child relationship. Moreover, the
treatment is emotionally demanding, as
transfusion and chelation therapy require
repeated invasive procedures and hospital
visits.
Chronicity is a powerful source of emotional
problems that intensify at each significant

142

balance. It can also be extremely rewarding

for the healthcare professional, both in
medical and emotional terms. Where a
healthcare professional manages to maintain
a constant dialogue with his/her patients,
s/he will often discover in patients with
thalassaemia skills that greatly surpass those
of their peers when facing the great
challenges of life such as birth/death,
love/loneliness, opportunities/limits.

developmental stage of the patients life.

Patients can feel that they are different,
limited or isolated. Their state of mind can
shift rapidly from depression to anger and
vice versa. Health workers must be prepared
to accept this shift and to help patients deal
with these feelings, finding a way to their
own normalisation that implies different
individual styles in adult life.
Overall, good treatment facilitates personal
development and achievement of targets in
life, while poor care makes such
development difficult or unpredictable.

Caring for a normal

development

Communication:
healthcare
professionals with
patients

Settings and methodology for discussion are

important all along the course of the disease,
but are mandatory at crucial milestones in
the patients and parents experience:
At the onset and during the first period,
communication work is carried out with
parents, but the child has to be included as
soon as possible. From as early as three to
five years of age, young patients begin to ask
crucial questions about the duration of care
and possibilities of a cure. These should be
dealt with sensitively and honestly. Separate
interviews with patient and with parents are
recommended in the approach to
adolescence, while in adulthood individual
interviews with the patient are essential.

Healthcare professionals should seek,

as far as possible, to:
Listen to be interested in the patients
emotional and real experiences
Accept to respect the patients point of
view and be sensitive to the timing of
personal communication
Share to be consistently close to the
patients positive and negative feelings
Understand at an emotional and not
simply an intellectual level
Maintain boundaries to give help and
relief, but keeping in mind his/her role as
a physician

Communication of
diagnosis
As exemplification, it is useful to focus on
communication of diagnosis, because it is the
natural starting point of the whole course of
disease and may mark permanently
(positively or negatively) the therapeutic
relationship.

Good communication with healthcare

professionals can be extremely beneficial for
the patient, helping him/her to cope better
with thalassaemia and to maintain a sense of

143

transfusion interval may allow these

symptoms to recur. This gives the patient the
experience of instability and doubt about
his/her physical capabilities. Moreover,
because of the risk of transfusiontransmitted diseases, fears of being
contaminated are ever-present and may be
intense for real reasons (high risk of
transmission) or due to the patients
emotional state. This fact helps to sustain
ambivalence towards therapy.

In trying to establish an ideal setting, the

following points should be considered:
The room chosen and time allocated aim
to provide an atmosphere that will sustain
hope and optimism; and not make the
patient feel depressed or misled.
The diagnosis should be discussed with
both parents together, allowing ample
time to listen to their concerns and to
respond to their questions, worries and
concerns.
Information must be sincere, complete
and repeated as often as needed. The
weight of negative emotions may be so
great that parents may appear confused
even after complete information has
been given more than once.
In the months following diagnosis, the
discussion must be renewed, with the
same attention given to the setting, and
preferably with the same doctor to
preserve continuity.

In any case, the need for periodic

transfusions testifies that vital energy comes
from other people, implying a dependence at
the physical level that can invade the mental
level, limiting personal development. In
addition, transfusion therapy does not cure;
it merely provides a monthly patch for the
anaemia, giving life and well-being but also
(even if safe from infection) causing iron
overload, which necessitates additional
treatment that is also lifelong.
This combination of advantages and
disadvantages of transfusion finds a parallel
in patients psychological reactions to their
treatment.

The same attention to setting must be

provided at any significant step, in order to
better support patient/parents in coping with
distressing information.

Regularly transfused patients

can experience positive feelings,
such as gratitude for receiving
life, and negative ones such as
fear and anger at being ruined.

Psychological impact
of anaemia and
transfusion

Psychological aspects
of chelation therapy

Serious anaemia will cause the patient to feel

weak and vulnerable. Maintaining an
adequate haemoglobin level through optimal
transfusion therapy (see Chapter 2: Blood
Tranfusion Therapy in -thalassaemia Major)
eliminates these symptoms and reduces the
patients anxiety about death. However, the
decrease in haemoglobin during the

Treating staff should be very familiar with the

emotional aspects of chelation, as
compliance with therapy determines
prognosis (see Table 1).

144

Psychological aspects

Subcutaneous chelation

Oral chelation

Aggression
Patch

Body image damage

Daily reminder

++

Feeling different
Lack of check

Constant commitment

Table 1

Time and movement restrictions related to

the use of the pump generate feelings of
being different and restricted.

In general, chelation is a psychologically

demanding therapy, because:
Iron chelation does not cure but rather
treats the main complication of the basic
therapy (transfusion), as the patch of
another patch.
Like transfusion, it is a reminder of ones
illness, and even more on a daily basis.
Optimal chelation starts during the first
years of life.
Effectiveness of the drug cannot be
checked quickly and directly by the
patient. So compliance is a function of
trust; that is to say, it reflects the quality
of the treating staff-patient relationship
and a belief in long-term benefits.

Parents may:
Not yet have overcome the shock of
diagnosis. Administering the infusion can
be painful since they feel responsible for
their childs discomfort.
Use chelation as a control tool when the
child reaches adolescence.
Patients may:
Adopt attitudes of out-and-out refusal,
feeling tortured instead of cared for.
Exploit any opportunity or excuse to skip
a days infusion.
Repeatedly select the same sites for
needle insertion, so trying to reduce the
body image damage.

Subcutaneous chelation
Parenteral treatment implies a small act of
aggression, either self-directed or inflicted by
the patients loved ones. Skin punctures from
the needles cause body image damage. The
patient may feel as full of holes as a
colander.

Physicians may:
Bargain with the patient, underprescribing desferrioxamine, more for
psychological reasons than on the
rationale of iron balance.

145

 Promote the shift from parent to patient

management as early as possible. Many
patients with thalassaemia can begin to
take control of their medication regimen
from six years of age. The early initiation
of self-management limits overprotection
and stimulates autonomy in the young
patient. It also gives relief to parents and
ultimately improves the quality of life of
the whole family.
Encourage patients to feel a sense of
reward for achieving mutually agreed
therapeutic goals.
Remember that long-term high
compliance fosters good capability and
self-reliance and is a key positive factor in
maintaining emotional well-being.

Tacitly encourage non-compliers to

treatment in order to avoid the
development of negative psychological
states.
While the underlying motivation for all the
above reactions or attitudes is generally a
desire to provide relief from the patients
discomfort and to make him/her feel better,
the long-term effects of such behaviour are
harmful for the patients physical health and
emotional well-being.

Oral chelation
Oral administration simplifies significantly
many practical aspects of chelation
management with Deferrioxamine.
For some patients (and some healthcare
professionals), a shift to oral chelation may
seem the solution to every problem. In fact,
however, oral chelation only helps with the
issues of daily holes to the skin and
consequent damage to body image. Patients
taking oral chelators must still face the daily
feeling of being different and will still lack
the means to immediately and quickly assess
the impact of treatment and in this context
it will remain difficult for some patients even
on oral chelation to maintain adequate
compliance.

Psychological impact
of complications
During adolescence or young adulthood
various complications may occur. The
psychological implications of such
complications lie in their degree rather than
their onset. In general, asymptomatic
complications do not require medication and
do not interfere heavily with quality of life.
However, when a serious complication such
as heart disease or diabetes appears, the
patient undergoes a period of psychological
readjustment. S/he has to integrate the
hopes, enthusiasm and wishes typical of
youth with a damaged physical state and
medical features typical of old age. In such a
situation, the inadequately supported patient
may feel hopelessly ruined, giving up on
health and continued therapy.

Recommendations:
Define and resolve the practical aspects
of optimal chelation (see Chapter 3: Iron
Overload).
Avoid judging, reprimanding or
threatening the patient.
Pay due attention to the psychological
aspects of the disease, as
underestimating these undermines the
effectiveness of the treating staff-patient
relationship with an increased risk of
treatment failure.
Be involved in supporting, instead of
simply insisting or prescribing.

Table 2 outlines the impact of the most

common complications (at moderate/severe
stage) on patient emotional balance.

146

Complication

Treatment
burden

Influence
on daily life

Feeling of
difference

Dependence

Feeling of
damage

Death
anxiety

Hypogonadism

+++

++

+++

++

Hypothyroidism

++

Hypoparathyroidism ++

++

++

Osteoporosis

++

++

++

++

+++

+++

+++

+++

++

+++

+++

+++

++

+++

+++

-/+++

++

++

+++

Diabetes
Heart disease
Hepatitis
Table 2

Beginning a new job or an important loving

relationship can increase feelings of
inadequacy and fragility. Sometimes an
emotional crisis occurs and psychological
support may be required.

In contrast to the past, recent advances in

iron chelation therapy have led to a dramatic
progress in survival, in saving patients from
acute life-threatening heart failure, and
generally in improving quality of life.
Treating staff must maintain a positive
perspective and support a patients sense of
hope.
Even in very serious cases, it is still possible
to deal with suffering by sharing and working
together to find ways of accepting new limits
inherent to a given situation.

Treating staff should accompany the patient

along his/her life path, while respecting
his/her fragilities, sensitivity, and supporting
resources. The most common mistakes on
the part of healthcare professionals is that
they are being overprotective or
disinterested. On the other hand, special care
should be taken in preventing intrusions into
the patients privacy.

Challenges for the

adult patient

Summary of
psychological goals

If the disease is fully compensated, physical

conditions allow the patient with
thalassaemia to make his/her choices of adult
life without any restrictions or limitations.
Even in this ideal state, however, at a
psychological level young adults with
thalassaemia can run into more difficulties
than peers in coping with the tasks of adult
life, particularly those implying independence
and responsibility.

In terms of the psychological care of the

patient, healthcare professionals should aim
to:
Provide information that promotes
understanding of the illness
Help patient and parents to talk and to
express feelings about the illness

147

It is clearly not possible for a health

professional to provide all the above support
if the organisation of his/her healthcare
system does not provide him or her with the
opportunity to work with patients on a longterm basis. The rotation of experienced
professionals to different wards can seriously
undermine a patients psychological wellbeing, treatment and prognosis. Appropriate
psychological support therefore not only
requires motivated and able clinicians, but
also presupposes an organisational structure
that allows for the successful delivery of
optimal and comprehensive care.

Help the patient to accept the illness and

to take care of him/herself
Maintain realistic hopes
Facilitate a normal lifestyle and
encourage self-esteem
Support the full development of an adult
life
Putting these goals into practice requires
health professionals to be:
Open-minded about psychological aspects
of having and treating inherited disease
Trained in normal psychosocial
development from childhood to
adulthood
Sensitised to the special issues of this
chronic hereditary disease
Available to accompany and support the
patient throughout his/her life path

148

General Health Care and

Lifestyle in Thalassaemia

This right should be considered before other

points of view (i.e. those of parents,
relatives, school, hospital and official bodies).

Lifestyle
If the disease is fully
compensated by ideal
treatment, an individual with
thalassaemia major can enjoy a
near-normal lifestyle and
experience regular physical and
emotional development from
childhood to adulthood,
including parenthood.

Staff should:
Assure confidentiality of patient identity
and data in all circumstances, trying to be
compliant with local, International laws
and rules on privacy, if not against
patients rights.
Help parents to be aware of diseaserelated issues early on in the patients life
(e.g. teaching parents to decide with the
child, from the age of 6, if and how to
communicate with the school about
thalassaemia)
Help the patient to build up a realistic
and balanced position between being
open and being secretive about the
disease

Treating staff should promote such a

progression by trying to reduce as far as
possible the degree to which the disease
interferes with the patients personal and
social life. Where the disease cannot be fully
compensated with proper transfusional
schemes, the obstacles to a normal lifestyle
should be taken into account with a realistic
but positive approach, based on informing
and encouraging the patient, and reviewing
limitations on time and treatment schedule.

School
If the patients haemoglobin levels are
maintained close to the values recommended
in this book, no relevant interference with
academic performance should be seen.
Where the haemoglobin level is allowed to
fall too low, the patient may have difficulty in
school. However, individual variability is wide.

From a practical point of view, treating staff

should:
Manage treatment and monitoring
schedules so as to minimise any
unnecessary impact on normal daily
activity
Be aware of the particular psychological
aspects of health care for this chronic
condition (see Chapter 15: Psychological
Support in Thalassaemia)

Although normal transfusion and follow up

schedules many require a number of
absences, these should not be to the extent
where the patients school performance is
negatively affected.

Confidentiality vs.
openness

Home
Splenectomised patients should be warned
about the risk of having pets at home, due
to the possibility of bites and this increased
risk of septicaemia (Capnocytophaga

The patient should have the

right to decide if, when and
with whom to talk about the
disease.
149

canimorsus-associated). Additional care in

preventive measures may be required in
some areas due to specific infection risk (see
the example of Pythiosis in Thailand in
Chapter on Infections). Patients with active
viral hepatitis or other viral infections should
take general measures to minimize or
prevent the risk of transmission to the family.

Sexual and
reproductive life
Differences in appearance (facial
features, height, and skin
colour) may affect selfconfidence and participation in
social life. In adolescence, the
absence or delay of sexual
development is regarded by
patients as particularly
stigmatising. Timely optimal
treatment of hypogonadism
limits these effects. Carriers of a
viral infection must also address
additional uncertainties as
regards safe sexual behaviour.

Work
In general, it is important for
patients to have a positive
attitude towards their ability to
work.
In chronic diseases a shift to overprotection
is a frequent problem for all people involved
(parents, treating staff, patient association
and patients themselves). This may be
partially useful when treatment possibilities
are scarce and the physical conditions of the
patient are poor. However, well-treated
patients generally do not face difficulties in
performing work as a direct result of their
disease.

The general improvement in the health of

patients with thalassaemia, particularly in
industrilized high income (HDI) countries,
means it is now possible for them to have
children spontaneously or by induction of
pregnancy. Patient attitudes to parenthood
may range from unnecessary feelings of
psychophysical inadequacy to an
underestimation of the risks and difficulties
involved. Treating staff should help the
patient and his/her partner to achieve a
balanced position. The decision as to whether
to induce pregnancy medically can be
difficult, and the patients and partners
expectations, the risks of pregnancy and the
long-term prognosis of the patient must be
seriously taken into consideration. Exhaustive
counselling is necessary to explore these
issues in a sensitive but thorough manner.

Depending on the country, thalassaemia may

be recognised as causing a certain degree of
disability, with resulting benefits and special
employment facilities. While these may help
the family and the patient from a practical
viewpoint, care should be taken that these
entitlements do not interfere with a positive
attitude to normality, self-esteem and the
ability to work (see Chapter 15: Psychological
Support in Thalassaemia).
Symptomatic heart disease and osteoporosis
may cause difficulties for patients in
performing certain physical tasks and specific
advice in limiting at-risk activities should be
provided.

150

in the country to be visited should be

obtained, and appropriate vaccination and
prophylaxis obtained in advance. Particular
attention should be paid to the prevalence of
malaria (see below).

Routine Health Care

Vaccinations

There is no reason for patients

with thalassaemia to skip or
delay standard recommended
vaccinations.

Blood
Ideally, a patient should always receive blood
transfusions at the same place. Travel plans
should be coordinated with the patients
transfusion schedule, in order to avoid
receiving transfusions elsewhere, particularly
if visiting areas where blood supplies carry a
high risk of infection.

Additional vaccinations for patients with

thalassaemia are discussed in the Chapter on
Infections.

Dental care
Patients who are untransfused, undertransfused or who begin transfusion at a
later stage in the disease may have some
malformations of the facial bones due to
marrow expansion. This can affect growth of
the teeth and cause malocclusion.
Orthodontic care may be successful in
improving masticatory function and/or
correcting unaesthetic dental appearances.
Orthodontic schedule must take account of
the peculiar characteristics of bone disease in
thalassaemia in order, to prevent tooth
instability or loss. The degree of osteoporosis
of maxillary bone should guide the treatment
schedule.

Chelation
Travelling and holidays should be organised
so as not to interfere with regular chelation
and treating staff should not indulge the
poor guy attitude. However, requests to
comply with adjustments in the chelation
schedule to minimise interruptions must also
take into account some practical aspects
(e.g. an adolescent planning the first camp
holidays with peers), and relational aspects
(i.e. secrecy or open communication about
the disease).

Splenectomy
The splenectomised patient should always
travel with antibiotics, to assure prompt
medication in case of fever, sepsis or animal
bites. Treating staff should discourage travel
where the risk of malaria is significant, as this
disease may be more serious in
splenectomised subjects.

Travelling
Travel carries a degree of risk, which
increases if the patient cannot receive expert
local treatment. If a patient is travelling to a
remote country, it is vital that adequate
travel insurance is obtained so that if serious
complications develop, s/he can be flown
home immediately, with provision of any
necessary medical assistance. If the patient
plans a trip, treating staff should, as far as
possible, give information about the closest
hospital with services and experience in the
management of thalassaemia. As for any
traveller, detailed advice about infection risks

Nutrition
General

Patients with thalassaemia do

not have specific dietary
requirements, unless they have special

151

prescriptions. In general, a restrictive diet is

easy to be prescribed but difficult to be
maintained over the long term. In
thalassaemia, the patient already has a heavy
treatment schedule and it is
counterproductive to add further restrictions
without the likelihood of clear benefit.

Calcium

Many factors in thalassaemia

promote calcium depletion. A
diet containing adequate
calcium (e.g. milk, cheese, dairy
products and kale) is always
recommended.

During growth, a normal energy intake with

normal fat and sugar content is
recommended. During adolescence and adult
life, a diet low in highly refined
carbohydrates (sugar, soft drinks, snacks)
may be useful in preventing or delaying the
onset of impaired glucose tolerance or
diabetes.

However, nephrolithiasis is seen in some

adults with thalassaemia major, and calcium
supplements should not be given unless
there is a clear indication, instead a low
oxalate diet should be considered.
Vitamin D may also be required to stabilise
calcium balance, particularly if
hypoparathyroidism is present. In case of
liver disease, the activated form should be
preferred. However, if supplements are used,
careful monitoring is required in order to
prevent toxicity.

There is no clear evidence that a diet is

beneficial in preventing or managing liver
disease, unless at late stages.

Iron
Increased iron absorption from the intestinal
tract is characteristic of thalassaemia. The
amount depends on the degree of
erythropoiesis, the haemoglobin level and
other potential independent factors. Drinking
a glass of black tea with meals reduces iron
absorption from food, particularly in
thalassaemia intermedia (de Alarcon, 1979).
However, there is no evidence that iron-poor
diets are useful in thalassaemia major; only
foods very rich in iron (such as liver and
some health drinks or health vitamin
cocktails) should be avoided. Patients with
thalassaemia should never be given iron
supplements. Many baby foods, breakfast
cereals and multivitamin preparations contain
added iron, along with other vitamin
supplements. The patient should therefore
make a habit of reading labels carefully,
seeking expert advice if necessary.

Patients with thalassaemia should not take

additional calcium or vitamin D unless
prescribed by their medical practitioner.

Folic acid
Patients with thalassaemia who remain
untransfused or are on low transfusion
regimens have increased folate consumption
and may develop a relative folate deficiency.
Supplements (1mg/day) may be given if this
occurs. Patients on high transfusion regimens
rarely develop this condition, and usually
have no need for supplements.

Vitamin C
Iron overload causes vitamin C to be oxidised
at an increased rate, leading to vitamin C
deficiency in some patients. Vitamin C may
increase the chelatable iron available in the
body, thus increasing the efficacy of
chelation with desferrioxamine. However,

152

hepatocarcinoma is significantly raised.

Excessive alcohol consumption also results in
decreased bone formation and is a risk factor
for osteoporosis. In addition, alcoholic drinks
may have unexpected interactions with
medication.

there is currently no evidence supporting the

use of vitamin C supplements in patients on
deferiprone, deferasirox or combination
treatment. Indeed, vitamin C ingestion may
increase iron absorption from the gut, labile
iron and hence iron toxicity. Therefore,
supplements should only be considered for
patients on desferrioxamine (see Chapter on
Iron Overload).

Smoking
Cigarette smoking may directly affect bone
remodelling which is associated with
osteoporosis and is related to adverse effects
on the general health.

Some drugs, such as aspirin and throat

lozenges, as well as certain health foods,
may contain vitamin C and should be
avoided. A diet rich in fresh fruits, including
citrus fruits and vegetables, is recommended.

Drug abuse
In many countries, drug abuse is common
among adolescents and young adults. For an
individual with a chronic disease, drug abuse
can be a serious threat to an already
challenging condition, upsetting the delicate
balance of factors affecting physical and
mental health. Treating staff should aim to
help the patient maintain such a position,
bearing in mind the challenges an adolescent
patient is likely to face. A key danger is that
as with many adolescentsdrug abuse may
be seen as a compensatory way to be
popular among peers or to fit in. For young
people with thalassaemia, feelings of
dependence, difference and anxiety can
push patients to seek normality through an
abuse habit.

Vitamin E
Vitamin E requirement is high in
thalassaemia. Treating staff should
recommend a regular intake of vegetable oils
as part of a balanced diet. However, the
effectiveness and safety of vitamin E
supplementation in thalassaemia major has
not been formally assessed and it is not
possible to give recommendations about its
use at this time.

Zinc
Zinc deficiency may occur during chelation,
depending on the chelator, dose and
duration. Zinc supplementation requires close
monitoring.

Alcohol

A transparent discussion of
these issues may help the
patient to gain insight into the
associated risks.

Patients with thalassaemia

should be discouraged from
consuming alcohol, as it can facilitate

Recreational activities

the oxidative damage of iron and aggravates

the effect of HBV and HCV on liver tissue.
Where all three factors are present, the
probability of developing cirrhosis and

In general, physical activity must always be

encouraged in patients with a chronic

Substance abuse

Physical activity

153

disease. Patients with thalassaemia should

have a quality of life and range of life
experiences as much like those of others as
possible. There is no reason to prevent
patients from engaging in physical activity to
the limits of what they are capable of and
interested in doing, unless there is a precise
secondary medical condition.
Conditions requiring special attention
include:
Splenomegaly: the more enlarged the
spleen, the more rigorous treating staff
must be in recommending avoidance of
those sports and physical activities with
significant risk of abdominal trauma.
Heart disease: moderate physical
activity is beneficial, if is matched to the
clinical condition and its treatment.
Osteoporosis or back pain in adults may
limit physical activity. Osteoporosis carries
an increased fracture risk and contact
sports should therefore be avoided if
osteoporosis is present.

Driving
No special attention is needed. In some
countries, the presence of diabetes mellitus
requires special checks and limitations.

154

Organisation and
Programming of a
Thalassaemia Centre

as possible, in order to provide continuity of

care. The staff must include a charge
nurse/nurse practitioner who supervises the
nursing staff.

The importance of a
dedicated
thalassaemia unit

The thalassaemia unit should operate on an

outpatient basis: facilities for evening, night,
and overnight transfusion help minimise
inconvenience to the patients social life.

Unless the number of patients is minimal,

organisation of a thalassaemia unit is useful
both in terms of functionality and cost.
Attempting to manage many patients with
thalassaemia in big multi-purpose units (such
as paediatrics, oncohaematology and
transfusion centres) without dedicated
facilities is often counterproductive, as most
resources are used for the main activity of
the unit (acute patient, oncology patients,
transfusion, etc).

Paediatric vs. adult care

The choice between a paediatric or adult
medicine setting may be crucial. Paediatric
centres, mainly in thalassaemia major,
accumulate more experience and are closer
to prevention of genetic disease. As
treatment opportunities improve, more
patients reach adulthood (Figure 1), with a
growing number of risk factors and
complications. This requires an approach
more like that of adult internal medicine.

In a dedicated thalassaemia unit, a treating

physician specially trained in thalassaemia
oversees all aspects of treatment, referring
to specialists when indicated. Staff most
commonly involved are:
Nurse specialist(s)
Cardiologist
Endocrinologist
Diabetes specialist
Reproduction endocrinologist
Andrologist or gynaecologist
Psychiatrist/psychologist
Social worker
Hepatologist
Transplant specialist

Each patients transition from paediatric to

adult care must be accurate and smooth:
transmission of complete clinical records
shared discussion of past and current
clinical problems
Ideally, a clinician with continued care as
patients progress from paediatric to adult
stages

Programming of
treatment

The unit should be dedicated but not

isolated. The staff requires a career structure
with promotion possibilities and regular
contact with other branches of medicine;
otherwise, doctors and nurses can be afraid
of losing skills and missing promotion
opportunities, and as a result they may be
unwilling to work in the unit. It is essential
that staff turnover of the unit is kept as low

Transfusion therapy is ideally conducted

according to the procedure outlined in
Chapter 2: Blood Tranfusion Therapy in Thalassaemia Major. The day of transfusion
should be utilised as effectively as possible
ideally providing all treatment and other
medical services the patient needs during
one visit. This often includes:

155

Figure 1: Changing pattern of age distribution in patients with thalassaemia

Physical examination
Clinical and laboratory tests, scheduled by
the treating physician on the basis of
guidelines and individual need.
Clinical discussion of the case record
Individual conversation to set goals,
renew critical information, and listen to
the patient (see Chapter 15: Psychological
Support in Thalassaemia)
Ideally the patient should leave the
hospital after every transfusional event
with updated documentation.

Interaction of the
thalassaemia unit
with other hospital
facilities
The unit must be closely connected with:
A blood bank
A general laboratory
If available, a special laboratory unit,
which runs all specific procedures used in
the diagnosis, follow-up and monitoring
treatment of thalassaemia,
The clinical resources of the departments
of paediatrics, internal medicine and
haematology/oncology critical for
thalassaemia (see specialists).

Several programmes for thalassaemia patient

data have been set up. Some of them have
been computerised and can be distributed to
the interested centres upon request (TIFs
website: www.thalassaemia.org.cy).

156

Figure 2: An example of organisational interaction of the thalassaemia unit with other hospital
facilities [Kattamis 1989]

Updating staff on new aspects of

thalassaemia and its treatment
Discussing and resolving organisational
aspects of the units activities
Renewing staff motivation to work in the
field of thalassaemia, so as to prevent
professional burnout

The well-functioning blood bank is of primary

importance for the management of
thalassaemia. Its functions are not only to
find the huge amount of blood needed for
the treatment of thalassaemia, but also to
secure the ideal blood for the patient, in
order to minimise the risks involved in
transfusion (e.g. alloimmunisation and
infections). The doctor from the Thalassaemia
Unit must keep blood bank staff sensitised to
the needs of chronically transfused patients

The organisation of a
Thalassaemia Unit

The supervising physician should schedule

regular meetings of the staff for the purpose
of:

The organisation of the Thalassaemia Unit in

this fashion optimises treatment, while

157

 Capacity for expert diagnosis

Expert clinical management
The use of outcome measures and quality
control, including survival and
complication rates, quality of life
measures and other measures of patient
interest
Sufficient activity which means a
minimum number of patients to ensure
adequate staff experience for quality care
High level expertise and experience of
staff
Epidemiological surveillance, including
patient registers
Collaboration with national and
international centres
Close links with patient associations

ensuring the greatest possible level of

comfort and convenience for patients with
thalassaemia and their families. It is essential
that patients with thalassaemia feel that the
unit is their own place, and that the medical
staff have the patients best interests as top
priority. Long-term management implies
collaboration of the patient and the family
with the well-organised thalassaemia unit
team, to ensure continuous, appropriate
treatment and a long and productive life for
the patient with thalassaemia.
A Thalassaemia Unit is expected to be a
centre of expertise for the management of a
chronic disorder. As such, it should be in a
position to provide multidisciplinary
knowledge, as described above, with the aim
of improving both survival and quality of life.
In addition, the centre will provide support to
local physicians treating patients with limited
access to expert centres, mainly due to
distance.

In such a system, the patient is fully

supported for self-management and is
considered a partner in the decisions
affecting his/her treatment, a fact that may
assist in patient adherence to long-term
treatment protocols.

The European Union has established criteria

for such centres of expertise (Rare Disease
Task Force Criteria), which could be used as a
standard in organising or running an expert
or Reference Centre, such as:

158

Outline of Diagnostic
Dilemmas in Thalassaemia

I - Increased transfusion requirements

VII - Worsening jaundice

A - Hypersplenism
B - Alloantibody
C - Autoantibody
D - Infection with HPV-B19 virus

A - Gilberts
B - Increased haemolysis
C - Drug Reaction
D - Liver failure

II - Fever

VIII - Leg cramps

A - Infection due to Bacterial

B - Yersinia
C - Klebsiella
D - Delayed transfusion reaction

A - Hypocalcaemia
B - Hypoparathyroidism

Diagnostic Dilemmas
in Thalassaemia

III - Back Pain

A - Osteoporosis and microfractures
B - Prolapse in disc
C - End plate degeneration
D - Prolapse

V - Chest Pain

Thalassaemia is an extremely demanding

disease. Patients must commit themselves to
a lifetime of transfusion and chelation
therapy, with all its attendant side effects. At
the same time, thalassaemia poses
considerable challenges to treating
physicians, who often struggle to resolve
competing complaints that together pose
diagnostic dilemmas. The following chapter
addresses some of those dilemmas, including
increased transfusion requirements, fever,
back pain, abdominal pain, chest pain,
dyspnoea, worsening jaundice and leg
cramps.

A - Pericarditis and myocarditis

B - Rib fracture (extramedullary expansion)
C - Pulmonary embolism

I. Increased transfusion
requirements

IV - Unexplained Abdominal Pain

A - Cholelythiasis
B - Pancreatitis
C - Portal vein thrombosis
D - Renal stones
E - Hepatic capsule distension
F - Yersinia

VI - Dyspnoea

The recommended treatment for

thalassaemia major involves regular blood
transfusions, usually administered every two
to five weeks, to maintain the pretransfusion haemoglobin level above 9-10.5
g/dl. This transfusion regimen promotes
normal growth, allows normal physical
activities, adequately suppresses bone
marrow activity and minimises transfusional
iron accumulation. While shorter intervals
between transfusions may reduce overall

A - Dysrhythmia
B - Delayed Transfusion reaction
G - Pump failure
D - Pulmonary hypertension

159

anti-Kell alloantibodies are most common.

However, 5-10% of patients present with
alloantibodies against rare erythrocyte
antigens or with warm or cold antibodies of
unidentified specificity.

blood requirements, the choice of interval

must take into account other factors, such as
the patients work or school schedule.
Reasons for increased consumption include
hypersplenism, new alloantibodies, infection
and changes in the haematocrit of
transfused units.

Autoimmune haemolytic anaemia is a very

serious complication of transfusion therapy
usually combined with underlying
alloimmunisation. Even red cells from
seemingly compatible units may have
markedly shortened survival, and
haemoglobin concentration may fall well
below the usual pre-transfusion level.
Destruction both of the donor red cells and
of the recipients red cells occurs. Steroids,
immunosuppressive drugs and intravenous
immunoglobulin are used for the clinical
management of this situation, although they
may give little benefit. Autoimmune
haemolytic anaemia may occur more
frequently in patients beginning transfusion
therapy later in life.

I-A. Hypersplensism
Throughout the care of the patient with
thalassaemia, the size of the spleen should
be carefully monitored on physical
examination and, as needed, by
ultrasonography. Physicians should be on the
look out for hypersplenism with stasis,
trapping and destruction of red blood cells in
an enlarged spleen.
Splenectomy should be considered when
annual blood requirements exceed 1.5 times
those of splenectomised patients, provided
that they are on the same transfusion
scheme and have no other reasons for
increased consumption. (Reasons for
increased blood requirements include new
alloantibodies, infection and changes in the
haematocrit of transfused units.)

I-C. Autoantibody
Autoimmune haemolytic anaemia (AIHA)
refers to a collection of disorders
characterised by the presence of
autoantibodies that bind to the patient's own
erythrocytes, leading to the premature
destruction of red cells. Specific
characteristics of the autoantibodies
(especially the type of antibody), its optimal
binding temperature, and whether
complement is fixed, constitute factors that
influence the clinical picture. However, in all
cases of AIHA the autoantibody leads to a
shortened red blood cell survival (i.e.,
haemolysis) and, when the rate of haemolysis
exceeds the ability of the bone marrow to
replace the destroyed red cells, to anaemia
and its attendant signs and symptoms.

Enlargement of the spleen is accompanied by

symptoms such as left upper quadrant pain
or early satiety, or when massive
splenomegaly causes concern about possible
splenic rupture.

I-B. Alloantibody
The development of one or more specific red
cell antibodies (alloimmunisation) is a
common complication of chronic transfusion
therapy. Thus it is important to carefully
monitor patients for the development of
new antibodies and to eliminate donors with
corresponding antigens. Anti-E, anti-C and

160

I-D. Infection with HPV-B19

II-B. Yersinia

Parvovirus B 19 - In patients with an already

shortened red cell lifespan (15-20 days) and a
low haemoglobin level due to haematological
disorders such as spherocytosis, sickle-cell
anaemia, autoimmune haemolytic anaemia
and thalassaemia, B 19 infection may cause
an acute, life-threatening red cell aplasia,
commonly referred to as transient aplastic
crisis. The cessation of erythropoiesis lasts
for 5-7 days and haematologically
complicates chronic haemolytic anaemia.
Attention must thus be given not only to
aplastic crises, but also to other clinical
problems such as myocarditis, which may
indicate infection with the virus.

Unlike most other bacteria, Yersinia

enterocolitica makes no siderophores of its
own and therefore lives most efficiently in an
iron-rich environment such as that found in
unchelated patients with thalassaemia or
uses the DFO in chelating patients which is a
siderophore to obtain iron and thrive. The
Yersinia organism is most commonly
transmitted by the ingestion of
contaminated food, meat, milk or water,
although it is commensal in healthy
individuals. It can also be transmitted
through blood.
Fever is the most common presenting
feature, often associated with abdominal
pain and diarrhoea or vomiting. Extra
gastrointestinal manifestations, such as
arthralgia and skin rashes, are sometimes
seen. Complications may include abdominal
abscess (right iliac fossa), nephritis or splenic
abscess.

II. Fever
Fever is an elevation of body temperature
that exceeds the normal daily variation. A
wide differential exists, spanning all types of
infections from bacterial to viral to fungal,
along with a multitude of syndromes and
organic diseases leading to fever.

Generally antibiotics are continued for at

least two weeks after proven infection. Iron
chelation should not be restarted until the
patient has been asymptomatic for over a
week. Relapse after restarting
desferrioxamine has been noted in some
cases. If this occurs, a longer period of oral
antibiotics may be necessary to eradicate the
infection. Iron chelation can be
recommenced after the infection has been
eliminated.

II-A. INFECTION DUE TO

BACTERIA
In patients with thalassaemia, the causes may
include other infections with Klebsiella and
Yersinia, or other bacterial pathogens and
delayed transfusion reactions. Iron overload
and infection are common causes of death.
Hence clinical experience mandates that
fever and infection, even in the nonsplenectomised patient, be thorough;y
investigated and treated swiftly and
aggressively. It is recommended that iron
chelation be stopped while the cause of
unidentified fever is investigated.

II-C. Klebsiella
Of the multitude of bacteria described in
association with iron overload, Klebsiella
species should be addressed as a potential
pathogen. In vitro Klebsiella species have
been shown to have increased virulence in

161

the presence of excess iron. Infection with

Klebsiella can be fatal in patients with
thalassaemia.

III-A. Osteoporosis
There is a high incidence of osteoporosis of
the spine and hip in both sexes in
thalassaemia, with severity increasing with
age. Even young patients exhibit a spinal
bone mineral density far below that of agematched controls.

Although there is evidence of altered host

immunity in thalassaemia syndromes, only
limited information is available regarding the
effects or functions of mononuclear
phagocytes in relation to micro-organisms
and the influence of iron overload and iron
chelation on their activity and pathogenicity.

III-B, III-C & III-D.

Microfractures, disc prolapse
and end plate degeneration

II-D. Delayed transfusion

reaction

Patients with thalassaemia may exhibit

dramatic skeletal abnormalities, frequently
leading to marked changes in the facial
structure and body habitus and delayed
skeletal maturation. Skeletal changes are due
largely to the expansion and invasion of
erythroid bone marrow, which widen the
marrow spaces, attenuate the cortex and
produce osteoporosis.

Delayed transfusion reactions occur 5-10

days after transfusion and are characterised
by anaemia, malaise and jaundice. These
reactions may be due to an alloantibody that
was not detectable at the time of transfusion
or to the development of a new antibody. A
sample should be sent to the blood bank to
look for a new antibody and to recrossmatch the last administered units.

The skull and facial bones are often strikingly

abnormal. Marrow expansion causes dramatic
widening of the diploic spaces and produces
a characteristic hair-on-end radiographic
appearance of the skull. In addition, there is
prominent frontal bossing, delayed
pneumatisation of the sinuses and marked
overgrowth of the maxillae. As a result, the
upper incisors are jumbled and the malar
eminences are especially prominent,
producing malocclusion and the
characteristic faces. The ribs and bones of
the extremities become box-like and
eventually convex, due to expansion of the
bone marrow. Premature fusion of the
epiphyses can result in characteristic
shortening of the limbs, particularly the
arms. Of equal concern is the thinning of the
cortices due to marrow expansion, which
often results in pathologic fractures.

III. Back Pain

Back symptoms are the most common cause
of disability in patients and account for a
huge portion of primary care physician visits.
The differential spans congenital anomalies
of the lumbar spine (spondylolysis,
spondylolisthesis), trauma with sprains and
strains, lumbar disk disease and organic
causes such as osteoporosis.
Patients with thalassaemia experience myriad
bone complications. The differential diagnosis
includes osteoporosis, microfarctures, disc
prolapse and end plate degeneration.

162

Compression fractures of the spine, often

with spinal cord compression and neurologic
deficits, have been reported in children with
thalassaemia. Compression fractures and
paravertebral expansion of extramedullary
masses often become particularly prominent
in the second decade of life.

IV-B. Pancreatitis
Acute pancreatitis is an inflammatory
condition of the pancreas characterised
clinically by abdominal pain and elevated
levels of pancreatic enzymes in the blood. A
number of conditions are known to induce
this disorder with varying degrees of
certainty. However, the pathogenesis of this
disorder is not fully understood.

IV. Unexplained abdominal

pain
Correctly interpreting abdominal pain
constitutes a particular challenge in
thalassaemia. The list includes pain
originating in the abdomen (peritoneal,
mechanical obstruction, vascular, abdominal
wall), pain referred from extra abdominal
sites (thorax, spine, genitalia), metabolic
causes (uremia, porphyria) and neurogenic
causes.

Although a number of situations can

precipitate acute pancreatitis in humans, only
a small fraction of patients with these
predisposing factors develop the diseases3
to 7 percent with gallstone, 10 percent of
alcoholics and a few patients with
hypercalcemia.
With regard to patients with thalassaemia,
pancreatitis is caused by myriad factors. First
and foremost is increased transfusion
requirement, leading to increased turnover
of red blood cells and hence further
precipitation of gallstones.

Of the multiple complaints patients with

thalassaemia present with, unexplained
abdominal pain spans a wide differential
diagnosis including chloelythiasis,
pancreatitis, portal vein thrombosis, hepatic
capsule distention and kidney stones.

IV-C. Portal vein thrombosis

IV-A. Cholelithiasis

Venous thrombo-embolism (VTE) is

increasingly recognised in paediatrics as a
complication of improved treatment
strategies for previously lethal childhood
diseases. The basic pathological process
underlying VTE is Virchow's triad (stasis,
endothelial injury and hypercoagulability).

A prominent feature of children with chronic

haemolytic anaemia is the development of
premature bilirubin gallstone disease and
biliary tract inflammation. This is particularly
true of children with -thalassaemia, twothirds of which have multiple calcified
bilirubin stones by the age of 15.
Fortunately, true episodes of cholecystitis or
cholangitis are rare. In the absence of clearcut symptoms, gall bladder removal is thus
rarely indicated.

Central venous catheters (CVCs), which

present a foreign intravascular surface,
damage vessel walls and disrupt blood flow,
are responsible for approximately 60 percent
of VTEs in children. In patients with
thalassaemia, CVCs are resorted to when
frequent transfusions are required.

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absence of transfusion, the accelerated rate

of iron turnover enhances dietary iron
absorption from the gut, resulting in a
chronic state of iron overload. In the liver,
iron first infiltrates Kupffer cells and then
engorges hepatocytes, ultimately provoking
fibrosis and, potentially, end-stage liver
disease, in a manner analogous to that seen
in idiopathic haemochromatosis.

Thrombosis of the hepatic venous system

usually occurs within the portal venous
system. Older children may develop portal
vein thrombosis (PVT) secondary to liver
transplantation, infections, splenectomy,
sickle cell disease or the presence of
antiphospholipid antibodies. PVT may
manifest acutely with symptoms of an acute
abdomen, particularly in adolescents, or be
asymptomatic for long periods of time until
symptoms reflecting chronic vascular
obstruction (portal hypertension) occur (e.g.,
splenomegaly or gastrointestinal bleeding
secondary to oesophageal varices). In
addition, the debris released from
intravascular destruction of red blood cells
may accumulate and plug the portal vein,
particularly after spelenctomy.

V. Chest pain
Chest discomfort is one of the most common
challenges faced by physicians treating
thalassaemia patients. The differential
diagnosis includes conditions affecting
organs throughout the thorax and abdomen,
with prognostic implications that vary from
benign to life-threatening. Failure to
recognise potentially serious conditions such
as acute ischemic heart disease, aortic
dissection, tension pneumothorax or
pulmonary embolism can lead to serious
complications, including death. In
thalassaemics, the differential diagnosis spans
pericarditis and myocarditis, extramedullary
causes and pulmonary embolism.

IV-D. Renal stones

The kidneys are frequently enlarged in
thalassaemia, due to the presence of
extramedullary haematopoiesis. Less well
understood is the tendency for the renal
tubules to be dilated. The urine is frequently
dark, due to increased concentrations of bile
pigments; large amounts of urate, uric acid
and oxalate are also seen.

V-A. Pericarditis and

myocarditis

IV-E. Hepatic capsule

distension

Cardiac symptoms and premature death from

cardiac causes are still major problems in
thalassaemia. Heart complications are the
leading causes of death and one of the main
causes of morbidity. In the absence of
effective iron chelation therapy, many
patients develop evidence of iron-induced
myocardial damage with cardiac failure,
cardiac arrhythmia, sudden death or a
distressing slow death from progressive
congestive cardiac failure.

Hepatomegaly is prominent early on in

thalassaemia, due to increased red cell
destruction as well as extramedullary
erythropoiesis in the liver. Liver enlargement
tends to be somewhat more prominent in
children with thalassaemia than in those with
congenital haemolytic anaemia. Later in the
first decade of life, hepatomegaly becomes
fixed and non-reducible by blood transfusion,
due to development of cirrhosis secondary to
increased iron deposition. Even in the

164

pulmonary embolism occurs as part of the

full picture of thrombosis. Data indicate that
thrombotic events primarily occur in the
venous system, comprising deep vein
thrombosis (DVT) (40%), portal vein
thrombosis (19%), stroke (9%), pulmonary
embolism (12%) and others (20%). Moreover,
splenectomised patients have been shown to
have a higher risk of thrombosis than nonsplenectomised patients. There are several
possible reasons for this, including the
procoagulant activity of circulating damaged
red blood cells, as it is thought that RBC
remnants expose negatively charged
phosphatidyl-serine through the flip-flop
phenomenon and subsequently initiate
thrombosis.
Deep vein thrombosis, pulmonary
thromboembolism and recurrent arterial
occlusion have been described in patients
with TI, mostly occurring without any other
risk factors. It is important to be aware of
these complications since thromboembolism
plays an important role in cardiac failure.

The regular assessment of cardiac status can

identify the early stages of heart disease,
enabling prompt intervention.
The characteristic lesion in the heart is
caused by iron deposition in the myofibres,
with associated myofibrillar fragmentation
and diminished mitochondrial volume per
myocyte. Classically, it has been suggested
that there is a poor correlation between
myocardial iron content, fibrosis and cardiac
functional impairment. Iron distribution in
the heart is relatively uneven. It has also
been suggested that viral myocarditis is a
contributing factor to acute cardiac
deterioration.

V-B. Rib fracture

(extramedullary expansion)
Extramedullary haematopoiesis (EMH) is a
compensatory mechanism where bone
marrow activity increases in an attempt to
overcome the chronic anaemia of
thalassaemia intermedia (TI), leading to the
formation of erythropoietic tissue masses
that primarily affect the spleen, liver and
lymph nodes. These masses can be detected
by magnetic resonance imaging (MRI). They
may cause neurological problems such as
spinal cord compression and paraplegia, and
intrathoracic masses. Extramedullary
haematopoiesis can be managed by
radiotherapy, since haematopoietic tissue is
highly radiosensitive, as well as transfusion
therapy and hydroxyurea.

VI. Dyspnoea
A cardinal symptom of diseases affecting the
cardiorespiratory system is dyspnoea, defined
as an abnormally uncomfortable awareness
of breathing. The differential covers general
topics of obstructive disease of airways,
diffuse parenchymal lung diseases,
pulmonary vascular occlusive diseases,
diseases of the chest wall or respiratory
muscles, and heart diseases. Such an
extensive differential necessitates meticulous
work up to reach a diagnosis. However,
dysrhythmia, pump failure, pulmonary
hypertension and delayed transfusion
reaction lead the list of probable causes of
dyspnoea in thalassaemia.

V-C. Pulmonary embolism

Patients with TI have an increased risk of
thrombosis compared with a normal age and
sex-matched population and with
thalassaemia major patients, especially
following splenectomy. In TI patients,

165

response occurring after re-exposure to a

foreign red cell antigen previously
encountered by transfusion, transplantation
or pregnancy. The antibody, often of the
Kidd or Rh system, is undetectable on
pretransfusion testing but increases rapidly in
titer following the transfusion.
These delayed reactions are seen generally
within 2 to 10 days after transfusion.
Haemolysis is usually extravascular, gradual
and less severe than in the case of acute
reactions, but rapid haemolysis can occur. A
falling hematocrit, slight fever, mild increase
in serum unconjugated bilirubin, and
spherocytosis on the blood smear may be
noted. The diagnosis is often made by the
blood bank when ordering more blood for
another transfusion, the direct antiglobulin
test and antibody screen which were
previously negative, now have become
positive.

VI-A. Dysrhythmia
Significant cardiac disease from iron overload
typically occurs in the absence of symptoms.
However, when symptoms do occur, they
include palpitations, syncopes, shortness of
breath, epigastric pain, decreased exercise
tolerance and peripheral oedema. The
development of symptoms of heart failure
implies advanced disease with a poor
prognosis.
Once the ventricles have enlarged, cardiac
arrhythmias are more common. These tend
to be of atrial origin, but ventricular
tachycardia is also occasionally seen. Sudden
death is likely to be arrhythmic in origin and
is more likely to be due to ventricular
arrhythmia than atrial.
The decision to treat arrhythmias in patients
with thalassaemia must be carefully
considered, bearing in mind that iron toxicity
is the primary cause of this complication.
Intensive chelation treatment has been
demonstrated to reduce arrhythmias. In the
majority of instances, the arrhythmias are
supraventricular, although ventricular
tachycardia may occur in seriously ill
individuals. The development of arrhythmia
may be associated with a deteriorating
ventricular function and can be improved by
addressing the latter problem. Arrhythmias
require very careful assessment. For most
supraventricular arrhythmias, reassurance of
the patient is generally appropriate, whereas
patients with ventricular arrhythmias should
be warned as to the potential severity of
their condition.

VI-C. Pump failure

The characteristic lesion in the heart is
caused by iron deposition in the myofibres,
with associated myofibrillar fragmentation
and diminished mitochondrial volume per
myocyte. Classically, it has been suggested
that there is a poor correlation between
myocardial iron content, fibrosis and cardiac
functional impairment. Iron distribution in
the heart is relatively uneven. It has also
been suggested that viral myocarditis is a
contributing factor to acute cardiac
deterioration.
An important distinguishing feature of
cardiac dysfunction due to iron overload is
the capacity of patients, if detected early, to
make a complete recovery with appropriate
chelation therapy. This fact may not be
widely appreciated by physicians and
cardiologists unaccustomed to dealing with

VI-B. Delayed transfusion

reaction
Delayed haemolytic transfusion reactions
(DHTRs) are due to an anamnestic antibody

166

deposition of bilirubin. Tissue deposition of

bilirubin occurs only in the presence of
serum hyperbilirubinemia and is a sign of
liver disease or, less frequently, a haemolytic
disorder. Of the many diseases presenting
with icterus, physicians should suspect any of
the following: unconjugated
hyperbilirubinemia, haemolytic, Crigler-Najjar
type II, Gilbert's syndrome, conjugated
hyperbilirubinemia, hepatocellular conditions,
cholestatic conditions and drugs. Malignant
causes should not be missed, including
pancreatic, gallbladder, ampullary and
cholangiocarcinoma.
In patients with thalassaemia, worsening
jaundice is another way of presenting to the
clinic. Hence the following discussion will
shed light on the differential of worsening
jaundice in thalassaemics.

patients with thalassaemia. It must be

emphasised that supporting the failing
circulation in these patients for several weeks
may be required in order to achieve
recovery.

VI-D. Pulmonary hypertension

Pulmonary hypertension (PHT) is prevalent in
patients with TI (59.1%), and is thought to be
the primary cause of congestive heart failure
(CHF) in this patient population. The
mechanism underlying PHT in TI is unclear,
although evidence indicates a local
pathophysiological response in the
pulmonary vascular bed that is independent
of thromboembolism due to DVT. Suggested
mechanisms include endothelial dysfunction
with increased inflammation and apoptosis,
decreased nitric oxide and nitric oxide
synthase production, pulmonary
haemosiderosis and local thrombosis. Several
echocardiographic studies have confirmed
that cardiac ejection fraction is rarely
affected in TI. Nevertheless, patients with TI
often have an increased cardiac output and
left ventricular wall dimensions proportional
to the dilutional volume overload secondary
to chronic anaemia.
As anaemia and iron overload are uncommon
in well-transfused and chelated patients with
thalassaemia major, they are likely to be at
the heart of the pathophysiology of PHT.
Regular transfusion and iron chelation
therapy is, therefore, indicated in TI patients
who are well-stratified according to the early
detection of PHT indices. Sildenafil has also
been successfully used to treat PHT, although
large-scale data for TI patients are lacking.

VII-A. Gilberts syndrome

The most common inherited disorder of
bilirubin glucuronidation is Gilbert's
syndrome, which has also been called
"constitutional hepatic dysfunction" and
"familial nonhaemolytic jaundice". Although
many patients present as isolated cases, the
condition is known to run in families.

VII. Worsening jaundice

Gilbert's syndrome is usually diagnosed in

young adults who present with mild,
predominantly unconjugated
hyperbilirubinemia. It is rarely diagnosed prior
to puberty when alterations in sex steroid
concentrations affect bilirubin metabolism,
leading to increased plasma bilirubin
concentrations. The disorder is more
commonly diagnosed in males, possibly due
to their relatively higher level of daily
bilirubin production.

Jaundice, or icterus, is a yellowish

discoloration of tissue resulting from the

The physical examination is usually

unrevealing, except for icterus. However

167

haemolysis even in normal subjects, usually

within hours to days after the onset of
exposure to the agent.
Amyl nitrite and butyl nitrite, primarily via
inhalation, have been used to increase sexual
arousal. Nitrites bind to haemoglobin,
producing methemoglobinemia that may be
so profound as to induce coma. The resulting
methemoglobinemia and haemolysis may be
more pronounced in patients who are G6PD
deficient. The possible presence of the latter
disorder should be suspected if methylene
blue infusion does not quickly turn the
chocolate colour of blood back to normal.

situations that exaggerate hyperbilirubinemia

may bring the patient to medical attention
and have corresponding physical findings.
Thalassaemia patients with inherited Gilberts
syndrome are at increased risk for haemolysis
and, as a result, would present with clinical
manifestations of icterus and elevated
bilirubin.

VII-B. Increased haemolysis

Patients with thalassaemia are more
susceptible to haemolysis, whether
intracorpuscular (intrinsic) or
extracorpuscular (a distinction made here
because the causes of intrinsic RBC defects
are all hereditary). Injury to the RBC
membrane due to the production of excess
- or -globin genes in thalassaemia is an
example of an intrinsic defect leading to
haemolysis. Extracorpuscular causes of
haemolysis, on the other hand, are almost
always acquired conditions that lead to the
accelerated destruction of otherwise normal
RBCs. Examples include antibodies directed
against RBC membrane components, such as
autoimmune haemolytic anaemia,
alloimmune haemolytic anaemia, delayed
(haemolytic) transfusion reaction, and some
drug-induced haemolytic anaemias.
Hypersplenism, which includes stasis,
trapping and destruction of RBC in an
enlarged spleen, is also part of
extracorpuscular haemolysis.

VII-D. Liver failure

Hepatitis due to viral (B and C) infections is
less frequent in TI than in patients with
thalassaemia major, since blood transfusions
are much less common in TI. Abnormal liver
enzymes (e.g., increased alanine and
aspartate aminotransferase) are frequently
observed in TI patients, primarily due to
hepatocyte damage resulting from iron
overload. Normalisation of liver enzyme levels
is often observed during appropriate
chelation therapy.

VIII. Leg cramps

Electrolyte disturbances such as
hypocalcemia, endocrine deficiencies and
neuromuscular and vascular issues may all
result in leg cramps.
One-third of patients with thalassaemia major
suffer from leg cramps, muscle wasting and
weakness. The differential diagnosis includes
hypocalcemia and hypoparathyroidism.

VII-C. Drug reactions

A variety of drugs have been implicated as
causes of drug-induced oxidant haemolysis.
Although any defect in the antioxidant
defence mechanisms, such as G6PD
deficiency, substantially increases
susceptibility to haemolysis, the drugs
referred to below can produce oxidative

VIII-A. Hypocalcaemia
Several acquired causes of
hypoparathyroidism have been identified in

168

children, including thyroid surgery and iron

deposition in the parathyroid gland as a
result of frequent transfusions (as in thalassaemia major).

VIII-B. Hypoparathyroidism
In the past two decades, several cases of
hypoparathyroidism (HPT) in -thalassemia
major have been observed. HPT is thought to
be mainly the consequence of iron
deposition in the parathyroid glands. The
onset of HPT was preceded or followed in
most patients by other endocrine and/or
cardiac complications. No clear relationship
between HPT and serum ferritin levels was
established, suggesting either an individual
sensitivity to iron toxicity or early damage of
the parathyroid gland before chelation.
Furthermore, the fact that no new cases of
HPT have been diagnosed at a time when
improved chelation therapy regimes have
been introduced suggests that chelation may
have helped to prevent the development of
HPT.

169

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WEBSITES
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187

GROWTH CHARTS

188

189

190

191

Index
Description

Page Number

A
Adefovir
Adult Haemoglobin (Hb A)
Alendronate
Assisted reproduction techniques ART
Arrhythmias
Alloimmunisation
Allergic transfusion reactions
Acute haemolytic reactions
Autoimmune haemolytic anaemia
Arrested puberty
Amenorrhoea
Acarbose
5 - Azacytidine
Alchohol consumption
Aplastic crisis
Antioxidants
Agranulocytosis
Arthropathy
Anticoagulants
ACE inhibitors
Amiodarone
Abdominal pain

101, 102, 103, 104, 105

14
81
70
84,85, 88, 166
19, 21, 25, 29, 128, 160
22, 30
30
30, 160
60, 65
66
69
136
86, 153
108, 161
39
52, 54, 56, 59
52, 56, 59
49, 88, 117, 129, 126
87, 89
88
58, 112, 114, 159, 163

B
Blood donation
Bone marrow expansion
Back pain
Bisphosphonates
Butyrates
Bumetanide
Beta blocking agents

20, 32
16, 79, 162
154, 162
75, 81, 127
129, 137
87
84, 89

C
Chimerism
Cirrhosis
Chelaton
Cardiac disease
Calcium

133
93, 94,
33, 40,
73, 76,
69, 74,

192

99,
85,
83,
81,

164
128, 144-146, 151, 161
164
127, 152

Circulatory overload (transfusion)

Calcitriol
Cytotoxic agents
Confidentiality
Cytomegolovirus (CMV)
Chagas disease
Chemoprophylaxis

31
69
136
149
111, 132
115
119

D
Diabetes mellitus
Deferiprone
DNA
Delayed puberty
Desferioxamine DFO
DEXA scan
Disc prolapse
Diet
Deferasirox
Delayed transfusion reactions
Decitabine
Dental care
Drug abuse
Driving
Dengue fever
Digoxin
Diuretics

43, 68, 92, 147

50, 52, 54, 153
12
65, 67
40, 65, 74, 108, 112
74, 79
80, 162
82, 151-153
58, 60, 63
30, 162, 166
136
151
153
154
114
87
87

E
Entecavir
Extramedullary haemopoiesis
Echocardiography
Ejection fraction (LVEF)
Electrocardiogram (ECG)
Erythropoietin (EPO)

101, 105
80, 123, 124, 165
85
38, 51, 73, 85
84
129, 136

F
Ferritin
Fetal haemoglobin (Hb F)
Fractures
Fertility
Folic acid

35, 41, 50, 57

14, 136
80, 81, 162
70
74, 127, 152

193

Filtration (Leukoreduction)
Frozen red cells

22, 29
22

G
GVHD
Growth
Growth velocity
Glucose tolerance
Gene therapy
Gallstones (cholelithiasis)
Gilbert's syndrome
GM CSF

31, 133
45, 64
64
68, 92
139
117, 124, 163
167
52

H
HLA
Hepatitis C (HCV)
Hepatocellular carcinoma
Hepatitis B (HBV)
HIV
Hypersplenism
Hypothyrodism
Heart failure
Haemoglobin E (Hb E)
Haemoglobin Lepore
Haemoglobin S (Hb S)
Haemoglobin H (Hb H)
Hb Constant Spring
Hb Bart's Hydrops Fetalis
Hypogonadic hypogonadism
Hormone replacement therapy (HRT)
Hydroxyurea
Hypoparathyroidism
Hypocalcaemia
Heart function

31, 133
31, 74, 92-99, 126
93, 99
31, 74, 98-105
31, 74, 109-111
116, 160
67, 97
36, 83, 89, 126, 166
18, 121, 131
18
18
19
19
19
65, 67, 70, 79, 81, 127, 150
74, 77, 81
124, 125, 129, 136
69, 169
69, 169
38, 42, 51, 56, 58, 83

I
Iron load (haemosiderosis)
Interferon (pegylated)
Iron absorption
Insulin
Insurance (travel)

33-40, 107, 128

95, 97, 101
33, 152
69
151

194

Immune function
Influenza virus vaccine
Indwelling intravenous lines
Intensive chelation
Immunoprophilaxis

107, 116
118
48
48, 86, 165
118

J
Jaundice

167

K
Klebsiella

113, 161

L
Liver fibrosis
Liver failure
Liver biopsy
Lamivudine
Lifestyle
Liver iron concentration (LIC)
Labile plasma iron (LPI)
Leg cramps
Leg ulcers

36, 52, 92, 132

93, 168
37, 94, 117
101, 105
149
35, 42, 50, 57, 59, 92, 127
39, 57
168
125, 128

M
Matched unrelated donors (MUD)
MRI
MRI cardiac
Malaria
Myocarditis

133
37, 80, 124, 92
38, 42, 51, 56, 85
115, 151
38, 84, 164

N
Neutropenia
Neocytes
Nonhaemolytic febrile transfusion reactions
Nephrolithiasis (kidney or renal stones)
Non transferring bound iron (NTBI)

52, 95
23
29
124, 152, 164
39

195

O
Osteoporosis
Ovulation
Oxidative damage

69,74, 77, 79, 127, 154, 162

70, 71
39, 153

P
Puberty
Pregnancy
Pre pregnancy counselling
Preimplantation genetic diagnosis (PGD)
Pubertal staging
Physical activity
Parvovirus B19
Palpitations
Pericarditis
Pancreatitis
Portal vein thrombosis
Pulmonary embolism
Pulmonary hypertension
Pseudoxanthoma elasticum
Pamidronate

65-67
47, 70-78, 127, 150
70, 73
71
66
153
108, 161
84, 166
164
163
163
165
90, 126, 166
127
81

S
Survival
SQUID
Spermatogenesis
Splenectomy
Short chain fatty acids
School
Smoking
Splenomegaly
Splenic embolisation

43, 135
37
70, 72
29, 107, 116, 124, 128, 160
137
149
153
124, 154
117

T
Thrombocytopenia
Transfusion requirement
Transplantation (Stem cells)
Transfusion related acute lung injury (TRALI)

52, 97, 116, 128

23, 28, 29, 97, 116
129, 132-135
31

196

V
Vaccinations
Vitamin D
Vitamin C
Vitamin E
Vision

98, 99, 101, 118, 151

69, 81, 152
35, 41, 46, 54, 152
153
45, 53

W
Washed red cells
Work

22
150

Y
Yersinia enterocolitica

31, 44, 108, 111-113, 161

Z
Zolandronic acid
Zinc deficiency

81
53, 64, 65, 153

197

About Thalassaemia
International Federation
The Thalassaemia International Federation (TIF) was established in 1987 with the mission to
promote the establishment of national control programmes for the effective prevention and
appropriate clinical management of thalassaemia, in every affected country of the world. TIF, a
Federation umbrella, is comprised of 98 national thalassaemia associations from 60 countries,
representing hundreds of thousands of patients worldwide.
TIF has been in official relations with the World Health Organisation (WHO) since 1996, and has
developed an extensive network of collaboration with scientific and medical professionals from
more than 60 countries around the world, as well as with other national and international health
bodies, pharmaceutical companies and other disease-orientated patients organisations.
TIFs educational programme is one of its most important and successful activities. It includes
the organisation of local, national, regional and international workshops, conferences and
seminars, and the preparation, publication, translation and free distribution of leaflets,
magazines and books for health professionals and patients/parents, to more than 60 countries.

MISSION: EQUAL ACCESS TO QUALITY HEALTH SERVICES FOR ALL

WITH THALASSAEMIA
MOTTO: UNITY IS OUR STRENGTH

WORLD HEALTH ORGANIZATION (WHO) RESOLUTION:

no. EB118.R1 (29 May 2006)
THALASSAEMIA AND OTHER HAEMOGLOBINOPATHIES

198

1.

Blood Safety Kit (1999) In English

2.

Guidelines to the Clinical

Management of
Thalassaemia 2000 Translated into 6 languages

3.

4.

5.

6.

7.

Compliance to Iron
Chelation therapy with
Desferrioxamine 2000
Reprint 2005 - Translated
into 4 languages

8.

A guide to the
establishment and
promotion of nongovernment
patients/parents
organization 2007 - In
English

9.

Guidelines to the Clinical

Management of
Thalassaemia Second
Edition - 2007 - In English

10.

Thalassaemia Major and

Me Childrens Book
2007 - In English

11.

About - - thalassaemia
2007 - In English, Italian,
French

12.

About - - thalassaemia
2007 - In English, Italian,
French

13.

About sickle cell disease

2007 - In English, Italian,
French

14.

Educational Folder Information for the

community, the carrier of
and the patient with a
Haemoglobin disorder.

About Thalassaemia 2003 - Translated into 11

languages
Prevention of
Thalassaemias and Other
Haemoglobinopathies
Volume I (2003) Translated into 2 languages

Prevention of
Thalassaemias and Other
Haemoglobiopathies
Volume II (2005) - In
English
Patients Rights 2007 - In
English

199