Guidelines to the Clinical Management of Thalassaemia

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.

1

EED DIITTOORRSS AANNDD AAUUTTHHOORRSS:: Maarriiaa--D M Do om me enniiccaa CCaappppeelllliinnii,, M MDD – Professor, Centro Anemie Congenite, Ospedale Maggiore Policlinico IRCCS, University of Milan, Italy

Allaann CCoohheenn,, M A MDD – Professor of Paediatrics, University of Pennsylvania, School of Medicine, USA AAnnddrroouullllaa EElleefftthheerriioouu,, PPhh..DD.. – Ex-Director of the Virus Reference Laboratory, Ministry of Health Cyprus, Executive Director - Thalassaemia International Federation AAnnttoonniioo PPiiggaa,, M MDD – Professor, Dipartimento di Scienze Pediatriche e dell’Adolescenza, Universita degli Studi di Torino, Italy JJo ohhnn PPoorrtteerr,, M MDD – Professor, Department of Haematology, University College, London, UK

AAllii TTaahheerr,, M MDD – Professor Medicine - Hematology & Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut Lebanon

AUUTTHHOORRSS OOFF CCHHAAPPTTEERRSS:: A 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

COO--OORRDDIINNAATTIINNGG EEDDIITTOORR:: C Androulla Eleftheriou, B.Sc., M.Sc., Ph.D., Dipl.MBA

2

COONNTTRRIIBBUUTTOORRSS:: C 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

ACCKKNNOOW A WLLEEDDGGEEM MEENNTTSS:: The Thalassaemia International Federation would like to express its most sincere appreciation and Drr.. HHeelleenn PPeerrrryy – Editor, DDrr M Miicchhaaeell AAnnggaassttiinniioottiiss - Thalassaemia International gratitude to D Drr.. M Maatthheeooss DDeem meettrriiaaddeess – Thalassaemia International Federation, Medical Advisor and D Federation, Projects’ Coordinator for their invaluable contribution to the completion of the book.

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Contents Foreword

6

Introduction

9

CHAPTER 1

12

Genetic Basis and Pathophysiology

CHAPTER 2

18

Blood Transfusion Therapy in ‚-Thalassaemia Major

CHAPTER 3

31

Iron Overload

CHAPTER 4

64

Endocrine Complications In Thalassaemia Major

CHAPTER 5

70

Management of Fertility and Pregnancy in ß-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

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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

Index

196

About thalassaemia

202

5

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 world’s leading authorities on haemoglobin disorders, this fully updated second 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: ñ Awareness about thalassaemia, its prevention and its medical and other care; ñ Research focused on the continuous improvement of medical care and on realising a total cure for thalassaemia, and; ñ Dissemination of the knowledge, experience and expertise of countries with successful control programmes to countries in need. TIF’s activities in achieving the above include: 1. The establishment of new and promotion of existing national patient organisations; 2. ñ ñ ñ ñ ñ

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: ñ Epidemiology

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ñ Medical and other care ñ Social integration and quality of life ñ Extending knowledge of the disease, its prevention and treatment to policy makers, health professionals, patients and parents, and the community at large ñ Securing the rights of every patient for equal access to quality medical care, and ñ 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: ñ Organisation of local, national, regional European and international workshops, conferences, seminars and meetings. ñ 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 TIF’s educational programme.

TIF’s achievements are the result of voluntary, dedicated work by scientists and medical professionals from around the world, without which TIF’s 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. This new edition of Guidelines for the Clinical Management of Thalassaemia offers an invaluable tool to medical staff involved in the treatment of thalassaemia. National governments, thalassaemia

7

centres and individual health personnel caring for patients with thalassaemia are strongly encouraged to follow the recommendations of the panel of experts, as presented here.

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 TIF’s 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 to producing this updated second 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

8

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 endemic—areas 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 world’s 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.

9

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 awareness—tasks 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 Spain—countries 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.

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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 year—undiagnosed 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 other’s experience. Health authorities need to recognise Hb disorders as a significant threat to public health—one that deserves the development and implementation of national policies for treatment and prevention. The instruments required to support such policies include:

ñ ñ ñ ñ

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

11

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 Â, Á, ‚ 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 ˙2Â2, ·2Â2 and ˙2Á2 tetramers; b) “fetal” haemoglobin (HbF ·2Á2), which constitutes the predominant oxygen carrier during pregnancy ; c) “adult” haemoglobin (HbA ·2‚2), which replaces HbF shortly after birth, and; d) a minor adult component, HbA2 (·2‰2).

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, ·2‚2), 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

12

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 Ph en o ty pi c h eter o gen ei ty 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

13

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

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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

‚ - g e n e M u t a ti o n

S e ve r i ty

Indian

-619 del

‚Ô

Mediterranean

-101

‚++

Black

-88

‚++

Mediterranean; African

-87

‚++

Japanese

-31

‚++

African

-29

‚++

Southeast Asian

-28

‚++

Black

-26

‚++

Mediterranean; Asian Indian

IVS1-nt1

‚o

Mediterranean; Asian Indian

IVS1-nt5

‚o

Mediterranean

πøS1-nt6

‚+/++

Mediterranean

IVS1-nt110

‚+

Chinese

IVS2-nt654

‚+

Mediterranean

IVS2-nt745

‚+

Mediterranean

codon 39

‚o

Mediterranean

codon 5

‚o

Mediterranean; African-American

codon 6

‚o

Southeast Asian

codons 41/42

‚o

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

15

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 (G➔A) 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. HHaaeem mo og gllo ob biinn SS ddiissoorrddeerrss: 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

16

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 Bart’s 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 (·Ôthalassaemia) is common in South East Asia, while it is rare in the Mediterranean area and even rarer in Africa.

Miilldd aannaaeem M miiaa aanndd m miiccrrooccyyttoossiiss..

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

17

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: ñ Maintenance of red cell viability and function during storage, to ensure sufficient transport of oxygen; ñ Use of donor erythrocytes with a normal recovery and half-life in the recipient; ñ Achievement of appropriate haemoglobin level, and; ñ 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

18

FFoorr ddeecciiddiinngg wwhhoom m ttoo ttrraannssffuussee, the following should be included in the investigations:

Recommended blood product

(i)

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

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

REEAACCTTIIOONNSS R

CAAUUSSAATTIIVVEE AAGGEENNTTSS C

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.

19

Meetthhooddss ffoorr lleeuuccoorreedduuccttiioonn iinncclluuddee:: M

immunoglobulin A (IgA) deficiency, in which the recipient’s 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.

Prre e--ssttoorraaggee ffiillttrraattiioonn of whole blood is ñ P 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.

F r oz e n ( o r c ry o p r e s e rv e d ) re d c e l l s

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: CCoouunncciill ooff EEuurrooppee –– PPooiinntt II FF6677007755 SSttrraassbboouurrgg CCeeddeexx FFrraannccee TTeell:: + +3 33 33 38 88 84 41 12 20 00 00 0 FFaaxx:: + +3 33 33 38 88 84 41 12 27 78 81 1 EEm maaiill:: p po oiin ntt__ii@ @cco oe e..ffrr IInntteerrnneett:: wwwwww..ccooee..ffrr//iinnddeexx..aasspp

Prre e--ttrraannssffuussiioonn, laboratory filtration ñ P refers to the filtration at the blood bank laboratory of packed red cells, prepared from donor whole blood. Be eddssiiddee ffiillttrraattiioonn refers to the packed red ñ B 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

RReedd cceellllss oobbttaaiinneedd bbyy ddoonnoorr aapphheerreessiiss:: This method whereby two units

Waasshheedd rreedd cceellllss may be beneficial for W 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.

20

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.

N e oc y t e or y o u n g r e d c e l l t r a n s f u s i o n 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

21

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).

AC A CD D--AA

CP C PD D

CP C P22D D

CP C PD DA A--11

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)

ASS--11 ((AAd A dsso oll))

ASS--33 ((N A Nu uttrriicceellll))

ASS--55 ((O A Op pttiisso oll))

Dextrose

2,200

1,100

900

Adenine

27

30

30

Monobasic sodium phosphate

0

276

0

Mannitol

750

0

525

Sodium Chloride

154.00

70.00

15.00

Sodium Citrate

0

588

0

Citric acid

0

42

0

[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)

22

Compatibility testing

ñ

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: ñ

ñ

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.

23

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 patient’s 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

Aggee aatt FFiirrsstt TTrraannssffuussiioonn AAllllooiim A mm muunniissaattiioonn RRaattee < 1 year old

7.7%

> 1 year old

27.9%

[Machail-Merianou et al, 1987]

Aggee aatt FFiirrsstt TTrraannssffuussiioonn AAllllooiim A mm muunniissaattiioonn RRaattee < 3 years old

20.9%

> 3 years old

47.5%

Table 3: Age and alloimmunisation in Thalassaemia

24

[Spanos et al, 1990]

Haaeem H maattooccrriitt ooff DDoonnoorr RReedd CCeellllss TTaarrggeett IInnccrreeaassee iinn Haaeem H moogglloobbiinn LLeevveell

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 patient’s 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

25

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.

AAnnnnuuaall BBlloooodd RReeqquuiirreem meenntt ((HHaaeem maatto occrriitt 6 600%%))

AAnnnnuuaall BBlloooodd RReeqquuiirreem meenntt ((HHaaeem maatto occrriitt 7 755%%))

100 – 150 ml/kg

80 – 120 ml/kg

150 – 200 ml/kg

VVoolluum mee ooff PPuurree RRBBCCss//kkgg ((HHaaeem maatto occrriitt 1 10000%%))

DDaaiillyy IIrroonn LLooaaddiinngg

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.

26

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 patient’s 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: No onnhhaaeem moollyyttiicc ffeebbrriillee ttrraannssffuussiioonn ñ N rreeaaccttiioonnss:: 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

ACCUUTTEE A

FFR REEQQUUEENNCCYY

DEELLAAYYEEDD D

FFR REEQQUUEENNCCYY

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

27

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. Alllle errggiicc rreeaaccttiioonnss are usually due to ñ A 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.

Accu uttee hhaaeem moollyyttiicc rreeaaccttiioonnss begin within ñ A 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)

De ellaayyeedd ttrraannssffuussiioonn rreeaaccttiioonnss usually ñ D 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). Au uttooiim mm muunnee hhaaeem moollyyttiicc aannaaeem miiaa is a very ñ A 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

28

shortened survival, and the haemoglobin concentration may fall well below the usual pre-transfusion level. Destruction both of the donor’s and the recipient’s 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.

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.

nssffuussiioonn--aassssoocciiaatteedd cciirrccuullaattoorryy ñ TTrraan oovveerrllooaadd 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.

nssffuussiioonn--rreellaatteedd aaccuuttee lluunngg iinnjjuurryy ñ TTrraan ((TTRRAALLII)) 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.

nssm miissssiioonn ooff iinnffeeccttiioouuss aaggeennttss ñ TTrraan 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:

nssffuussiioonn--iinndduucceedd ggrraafftt vveerrssuuss hhoosstt ñ TTrraan ddiisseeaassee ((TTII--GGVVHHDD)) is caused by viable lymphocytes in units of transfused red cell. It is a rare but often fatal

− 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);

29

− 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 Chaga’s 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.

SSu um mm maarryy RReeccoom mm meennddaattiioonnss:: ñ Careful donor selection and screening – voluntary, regular non-remunerated blood donation. ñ Confirm diagnosis of thalassaemia major. ñ Before initiation of transfusion therapy, confirm laboratory and clinical criteria. ñ Before first transfusion, extended red cell antigen typing of patients at least for C, E and Kell. ñ At each transfusion, give ABO, Rh(D) compatible blood. Matching for C, E and Kell antigen is recommended. ñ Before each transfusion, full cross-match and screen for new antibodies. ñ Keep record of red cell antibodies, transfusion reactions and annual transfusion requirements for each patient. ñ Use leucoreduced packed red cells. Pre-storage filtration is recommended, but blood bank pre-transfusion or bedside filtrations are acceptable alternatives. ñ Washed red cells for patients who have severe allergic reactions. ñ 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. ñ 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. ñ Keep post-transfusion Hb not higher than 14-15 g/dl.

30

Iron Overload

IIr ro on no ovve errlload 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 100–200 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.

IIncreased gas tro-intest inal absorpt ion o f i r on : o

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.

B l o o d t ra n s fu s i o n : 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 31

Paattiieenntt’’ss wweeiigghhtt P

200 kkgg 2

355 kkgg 3

500 kkgg 5

655 kkgg 6

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 Meecchhaanniissm M m ooff iirroonn ttooxxiicciittyy 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

32

Coom C mpplliiccaattiioonnss ooff iirroonn oovveerrllooaadd

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; Galanello, 1994). 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 PT, et al. 2000; Davis BA, et al. 2004; Borgna-Pignatti et al. 2004). Studies have identified a significantly lower risk of cardiac disease and death in at least twothirds of cases where serum ferritin levels have been maintained below 2,500 Ìg/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 Ìg/L may be associated with additional advantages (Borgna-Pignatti et al, 2004) (see Table 2).

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 patient’s specific needs. However, some general principles of monitoring iron overload apply to all treatments:

LLiivve err iirroonn ccoonncceennttrraattiioonn ((LLIICC))

SSe erruum m ffeerrrriittiinn

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:

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 Ìg/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, 1984; Davis, 2004). Day-to-day variations are particularly marked: high degrees of iron loading, inflammation, hepatitis and/or liver damage may falsely

TToottaall bbooddyy iirroonn ssttoorreess iinn m mgg//kkgg = = 1100..66 xx tthhee LLIICC ((iinn m mgg//gg ddrryy wwtt)) 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 (see Figure 2).

33

Several studies link high Liver Iron Content (LIC) (above 15-20 mg/g dry wt) to worsening prognosis (Brittenham, 1994;

Telfer, 2000), liver fibrosis progression (Angelucci, 1997) or liver function abnormalities (Jensen, 2003).

TTaab bllee 22:: M Meeaassuurriinngg aanndd iinntteerrpprreettiinngg sseerruum m ffeerrrriittiinn

Addvvaannttaaggeess A

Diissaaddvvaannttaaggeess D

ñ Easy to assess ñ ñ Inexpensive ñ ñ Repeat measures are useful for monitoring chelation therapy ñ Positive correlation with morbidity and ñ mortality

Indirect measurement of iron burden Fluctuates in response to inflammation, abnormal liver function, metabolic deficiencies Serial measurement required

LLIIV VEERR IIRROONN AANNDD RRIISSKK FFRROOM M IIRROONN OOVVEERRLLOOAADD

Figure 2: Liver risk and iron overload (Olivieri & Brittenham, 1997)

34

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 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 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 1994) 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 (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. ñ

ñ

essential in all children (see Chapter 4: Endocrine Complications).

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.

ñ

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.

E ff e c t s o n t h e e y e :

Effects on the eye: These were first noted when very high doses (>100 mg/kg/day) were given (Davies, 1991). 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.

S ke l e t a l c h a n g e s :

ñ

R ar e c o m p li c a t io n s :

Recommended standard therapy

G ro w t h re t a r d a t i o n:

Growth retardation: This may occur if desferrioxamine is administered at too high a dose. Another risk factor is a young age of starting treatment (20 ms) may take several years especially when values are 1.5-2.5 SD below the young normal mean (T score)

Figure 2

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

((B B)) BBiioocchheem miiccaall

patients who may have micro fractures.

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 et al, 2001; Chatterjee et al, 2000).

((D D))M MRRII

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.

((EE)) AAsssseessssm meenntt ooff iirroonn llooaadd aanndd cchheellaattiioonn tthheerraappyy (see Chapter 3: Iron

((C C)) RRaaddiioollooggyy

AP and lateral X-ray of the spine is important to rule out fractures even in asymptomatic

Overload).

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((2 2)) CCaallcciim miim meettiiccss Vitamin D deficiency must be corrected (oral dose of 1000-1500 IU/day) and calcium supplementation (500 mg-1G orally/day) (Sambrook et al, 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 3)) AAnnttii--rreessoorrppttiioonn aaggeennttss Bisphosphonates represent the biggest advance in the treatment of osteoporosis in the past decade in non-thalassaemic patients (Sambrook et al, 2006), with results of clinical trials showing reductions in the risk of vertebral fractures (40–50%) and non-vertebral fractures (20–40%), 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. RRoouuttee ooff aaddm miin niissttrraattiio on n aan nd dd do osse e:: They can be given as pamidronate 1-2 mg/kg body weight once a month as IV infusion for 3-5 years (Chatterjee et al 2001), orally as alendronate 70 mg orally per week (Borgna-Pignatti, 2006) or zolandronic acid two–three 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 2006). 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 2006).

((A A)) TThheerraappeeuuttiicc OOppttiioonnss ((FFiigguurree 33))

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 1)) SSeexx sstteerrooiidd rreeppllaacceem meenntt tthheerraappyy 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 et al, 2001; Chatterjee et al, 2000; Lasco et al, 2001; Carmina et al, 2004).

81

((4 4)) CCoom mbbiinnaattiioonn tthheerraappyy 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 B)) M Moonniittoorriinngg ooff TTrreeaattm meenntt

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

Reeccoom R mm meennddaattiioonnss ñ Diet and exercise ñ Vitamin D and calcium supplementation ñ Sex hormones replacement in HH-HRT ñ Anti-resorption agents-Bisphosphonate ñ 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

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).

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.

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.

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

As mentioned above, an important distinguishing feature of heart failure due to iron overload is the capacity of heart function to make a complete recovery with appropriate chelation therapy—a 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.

significant myocardial iron-overload. 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 anxiety—both 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.

Clliinniiccaall eexxaam C miinnaattiioonn

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.

PPaallppiittaattiioonnss 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

EElle eccttrrooccaarrddiiooggrraam m

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

84

ventricular voltages. Occasionally P-waves are 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.

protocol. A minimum data set should include: 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 patient’s transfusion cycle, to minimise variability of clinical parameters.

Am A mbbuullaattoorryy m moonniittoorriinngg ooff EECCGG

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.

EExxe errcciissee EECCGG

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.

R a d i oi s o t op e s t ud i e s :

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.

CCaarrddiiaacc M Maaggnneettiicc RReessoonnaannccee IIm maaggiinngg ((CCM MRR))

The CMR scan provides a combination of morphological, functional information on the heart as well as—uniquely— quantitative estimates of tissue iron overload.

EEcch hooccaarrddiiooggrraapphhyy

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

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

85

appropriate scanners in some parts of the world. Scan times have been progressively reduced with modern protocols and very few patients are unable to tolerate the procedure due to claustrophobia.

thalassaemia involves a number of general measures, along with particular cardiological interventions. Such measures might include: ñ 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; ñ 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. ñ 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.

Caarrddiioollooggiiccaall m C maannaaggeem meenntt pprroottooccoollss

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. ñ 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. ñ 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). ñ 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 patient’s 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.

SSp peecciiffiicc CCaarrddiioollooggiiccaall CCaarree

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

86

(see Chapter 3: Iron Overload for details on designing an appropriate chelation programme under these conditions).

rates in patients with established atrial fibrillation.

Diiuurreettiiccss are the mainstay in producing D 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.

Diiggooxxiinn should not be used in the early D 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

87

Managing such patients can be aided by 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.

may have advantages for the prophylactic treatment of AF.

A m i o d a ro ne

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 which—disturbances of thyroid function—is of particular relevance in patients with thalassaemia.

A n t i -a r rh y t h m i c a g e n t s :

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.

A n t i - c o a g ul a t i on :

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

Beettaa--bblloocckkiinngg aaggeennttss can also be used to B

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

88

only as a temporary measure prior to cardioversion.

C) For patients with cardiac impairment, with or without symptoms: ñ intensification of iron chelation: i.v. desferrioxamine (24 hours x 7 days/week); consider combination treatment with oral deferiprone and s/c desferrioxamine ñ slow blood transfusion with diuretics ñ specific cardiac medications: ñ ACE inhibitors, or ARII blockers where ACE not tolerated ñ beta-blockers: carefully introduce once acute heart failure stabilised; bisoprolol or carvidelol remain first choice ñ diuretics, for the symptomatic relief of fluid overload; use sparingly whilst monitoring renal function; spironolactone should be introduced if possible ñ digitalis, if in atrial fibrillation, Warfarin: if central line in situ, or if in AF

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): ñ encourage continuation of current, effective chelation ñ 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 treatment—treatment 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): ñ 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 ñ as for group A

89

treatment 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.

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. Pulmonary hypertension was initially documented in a small group of 7 TI patients with right heart failure. In a subsequent study of a large 110-patient series, agerelated 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. 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 resulting clinical phenotype impose a

In what concerns the development of PHT in TM, a recent study (Aessopos Kefarmakis, 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

90

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. 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.

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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

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R e v e r s ib ili t y :

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.

E n d -s t a g e l i v e r d i s e a s e :

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 A c u t e i n fe c t i o n :

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

Heeppaattoocceelllluullaarr ccaarrcciinnoom H maa ((HHCCCC))::

Chhrroonniicc iinnffeeccttiioonn:: develops in 70-80% of C

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.

C i r rh os i s :

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%.

E xt r a - h e p a t i c

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 2-log reduction in viral load after 12 weeks of treatment ñ R e s p o n s e a t e nd o f t r e a t m e n t (ETR): defined as absence of HCV-RNA at the end of treatment ñ Sustained viral response (SVR): absence of HCV-RNA > 6 months after concluding treatment. This is in practice equivalent to viral eradication of HCV ñ Non-responders: lack of significant decline (defined as > 2-log reduction from baseline) in HCV RNA after 12 weeks of therapy ñ Relapsers: re-emergence of HCV-RNA after a satisfactory end of treatment response

E a r l y v i r a l r e s p on s e ( E V R ) :

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.

R e s p o n s e a t e nd o f t r e a t m e n t ( ETR ) : Sustained viral response (SVR): N o n -r e s p o n d e r s : R e l a p s e rs :

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.

Moonniittoorriinngg rreessppoonnssee M

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.

T y p e o f i n t e r f e r on :

Type of interferon: Pegylated interferon ·-2a or ·-2‚ given subcutaneously once weekly

Duurraattiioonn:: 24 to 48 weeks, depending on D

genotype

S i d e e f fe c t s :

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

Prreeddiiccttiioonn ooff ppoooorr rreessppoonnssee P

Negative predictors in all patients with hepatitis C are:

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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.

TTrreeaattm meenntt dduurraattiioonn aanndd vviirraall llooaadd mo m onniittoorriinngg: 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.

M on i t o ri ng f o r s i d e e f f e c t s :

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

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.

TTrreeaattm meenntt ooppttiioonnss ffoorr nnoonn-rreessppoonnddeerrss

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.

Si de e f f e cts :

Side effects: Haemolysis occurs in most patients without thalassaemia, with a decrease in haemoglobin of 10-20% from baseline levels.

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Maan M naaggeem meenntt ooff ssppeecciiaall ppaattiieenntt ppooppuullaattiioonnss

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: ñ Children ñ Patients with cirrhosis ñ Immunosuppressed patients ñ Pregnant patients ñ Patients with acute hepatitis C

Prreevveennttiioonn P

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 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

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.

Clliinniiccaall ssiiggnniiffiiccaannccee ooff HHBBVV m C maarrkkeerrss

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

G e ne r a l m e a s ur e s

Accu uttee iinnffeeccttiioonn.. HBsAg is a reliable marker ñ A (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.

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.

Ch hrroonniicc iinnffeeccttiioonn (overt carrier) is marked ñ C 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)

e ccaarrrriieerrss, identified by the ñ aaccttiivve presence of HBeAg or anti-HBe antibodies and a viral load ≥5 log10 copies/ml (although others cite a figure

IIn ncciiddeennccee

Vaccination strategies, screening of blood donors for 98

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.

interpretations of screening results.

Natural history A c u t e he p a t i t i s :

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.

naaccttiivvee ccaarrrriieerrss, characterised by the ñ iin persistent normality of transaminase in an anti-HBe-positive subject, associated with levels of viremia below the threshold (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, 1997).

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: ñ inadequate iron chelation therapy, ñ presence of liver fibrosis and ñ hepatomegaly (Giardini, 1995)

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

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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, 1996). 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.

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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).

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Figure 1:

Figure 3:

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.

Figure 2:

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:

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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 (Á)-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 transplantation—an 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

TThhee ddeem meetthhyyllaattiinngg aaggeennttss 55--aazzaaccyyttiiddiinnee aanndd ddeecciittaabbiinnee 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.

HHyyddrrooxxyyuurreeaa 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.

Otthheerr aaggeennttss O

EErryytthhrrooppooeettiinnss ((EEPPOOss)) have increased haemoglobin levels significantly in some patients with thalassaemia intermedia, even eliminating transfusion requirements in some

Cyyttoottooxxiicc aaggeennttss C

Following observations that foetal haemoglobin synthesis is reactivated during

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(e.g. sodium 2,2-dimethybutyrate) (Boosalis, 2001; review Perrine, 2005). Select hydroxamic acid derivatives have had high activity in transgenic mice (Cao and Stamatoyannopoulos, 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 Á-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). PPhheennyyllbbuuttyyrraattee aanndd bbuuttyyrraattee 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 (Wilkerson, 2005). New generation agents which promote erythroid survival, and can be given daily, offer significantly more potential benefit than the first generation prototypes.

SSh hoorrtt cchhaaiinn ffaattttyy aacciidd ddeerriivvaattiivveess

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 (review Collins and 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).

Coom C mbbiinnaattiioonn tthheerraappyy

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

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

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even severe patients transfusionindependent. 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 patient’s baseline HbF, total haemoglobin and EPO levels (review Perrine, 2005). Clinical trials should be planned to find optimal drug combinations for different patient subsets.

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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 patient’s 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 patient’s 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 patient’s 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,

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ussttrraattiioonn ooff hhooww aa lleennttiivviirraall vveeccttoorr ccoonnttaaiinniinngg aa bb--gglloobbiinn tthheerraappyy ggeennee uunniitt iiss ccoonnssttrruucctteedd ffrroom m Figure 1: IIllllu tthhee nnoorrm maall ((wwiilldd--ttyyppee)) HHIIVV vviirruuss.. AA.. Structure and gene organisation of wild-type HIV virus. BB.. Replacement of the normal genes of the wild-type HIV virus with the Locus Control Region-‚globin therapy gene unit produces the lentiviral vector. NNoottee:: 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

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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

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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 patient’s 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 patient’s 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 patient’s physical, emotional and social development, taking on several characteristics of the traditional ‘family doctor’ as guardian of the patient’s 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

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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 patient’s 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 patient’s 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.

H e a l t h c a re p r o f e s s i on a l s s h o ul d s e e k , H ass far as possible, to: a ñ Listen – to be interested in the patient’s emotional and real experiences ñ Accept – to respect the patient’s point of view and be sensitive to the timing of personal communication ñ Share – to be consistently close to the patient’s positive and negative feelings ñ Understand – at an emotional and not simply an intellectual level ñ 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

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In trying to establish an ideal setting, the following points should be considered:

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 patient’s emotional state. This fact helps to sustain ambivalence towards therapy.

ñ 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. ñ 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. ñ 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. ñ 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.

The same attention to setting must be provided at any significant step, in order to better support patient/parents in coping with distressing information.

This combination of advantages and disadvantages of transfusion finds a parallel in patients’ psychological reactions to their treatment.

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 patient’s 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).

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P s y c h o l o g i c a l a s p e c ts

S u b c u t a n e o u s c h e l a ti o n

O ra l c h e l a t i o n

+

-

‘Patch’

+

+

Body image damage

+

-

Daily reminder

+

+

++

+

Aggression

Feeling different Lack of check

+

+

Constant commitment

+

+

Table 1

In general, chelation is a psychologically demanding therapy, because:

Time and movement restrictions related to the use of the pump generate feelings of being different and restricted.

ñ Iron chelation does not cure but rather treats the main complication of the basic therapy (transfusion), as ‘the patch of another patch’. ñ Like transfusion, it is a reminder of one’s illness, and even more on a daily basis. ñ Optimal chelation starts during the first years of life. ñ 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: ñ Not yet have overcome the shock of diagnosis. Administering the infusion can be painful since they feel responsible for their child’s discomfort. ñ Use chelation as a control tool when the child reaches adolescence. Patients may: ñ Adopt attitudes of out-and-out refusal, feeling ‘tortured’ instead of cared for. ñ Exploit any opportunity or excuse to skip a day’s infusion. ñ Repeatedly select the same sites for needle insertion, so trying to reduce the body image damage.

S ub c ut a n e o us c h e l a t i on Parenteral treatment implies a small act of aggression, either self-directed or inflicted by the patient’s loved ones. Skin punctures from the needles cause body image damage. The patient may feel ‘as full of holes as a colander’.

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

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ñ Tacitly encourage non-compliers to treatment in order to avoid the development of negative psychological states.

ñ 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. ñ Encourage patients to feel a sense of reward for achieving mutually agreed therapeutic goals. ñ Remember that long-term high compliance fosters good capability and self-reliance and is a key positive factor in maintaining emotional well-being.

While the underlying motivation for all the above reactions or attitudes is generally a desire to provide relief from the patient’s discomfort and to make him/her feel better, the long-term effects of such behaviour are harmful for the patient’s physical health and emotional well-being.

Orraall cchheellaattiioonn O

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.

Reeccoom R mm meennddaattiioonnss::

ñ Define and resolve the practical aspects of optimal chelation (see Chapter 3: Iron Overload). ñ Avoid judging, reprimanding or threatening the patient. ñ 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. ñ 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.

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Coom C mpplliiccaattiioonn

TTrre eaattm meenntt bbuurrddeenn

IIn nfflluueennccee oonn ddaaiillyy lliiffee

FFeeeelliinngg ooff ddiiffffeerreennccee

Deeppeennddeennccee D

FFeeeelliinngg ooff ddaam maaggee

Deeaatthh D aannxxiieettyy

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 patient’s 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 patient’s 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: ñ Provide information that promotes understanding of the illness ñ Help patient and parents to talk and to express feelings about the illness

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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 patient’s 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.

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

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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: ñ 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 patient’s rights. ñ Help parents to be aware of diseaserelated issues early on in the patient’s 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) ñ 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 patient’s 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 patient’s 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: ñ Manage treatment and monitoring schedules so as to minimise any unnecessary impact on normal daily activity ñ 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 patient’s and partner’s 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.

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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 Vaacccciinnaattiioonnss V

There is no reason for patients with thalassaemia to skip or delay standard recommended vaccinations.

Blloooodd B

Ideally, a patient should always receive blood transfusions at the same place. Travel plans should be coordinated with the patient’s 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.

Deennttaall ccaarree D

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.

Chheellaattiioonn C

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).

SSp plleenneeccttoom myy

TTrraavve elllliinngg

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.

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 Geenneerraall G

Patients with thalassaemia do not have specific dietary requirements, unless they have special

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Caallcciiuum C m

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.

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.

IIrro onn

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.

FFo olliicc aacciidd

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.

Viittaam V miinn CC

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

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).

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.

SSm mookkiinngg

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.

Drruugg aabbuussee D

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 adolescents—drug 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.

Viittaam V miinn EE

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.

ZZiin ncc

Zinc deficiency may occur during chelation, depending on the chelator, dose and duration. Zinc supplementation requires close monitoring.

A transparent discussion of these issues may help the patient to gain insight into the associated risks.

Substance abuse Allccoohhooll A

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

Phhyyssiiccaall aaccttiivviittyy P

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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: ñ 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. ñ Heart disease: moderate physical activity is beneficial, if is matched to the clinical condition and its treatment. ñ 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.

S p l e n om e g a l y : H e ar t d i s e as e : O s t e op or os i s

Drriivviinngg D

No special attention is needed. In some countries, the presence of diabetes mellitus requires special checks and limitations.

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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 patient’s 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).

P a e d i at r i c v s . ad u l t c ar e 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: ñ Nurse specialist(s) ñ Cardiologist ñ Endocrinologist ñ Diabetes specialist ñ Reproduction endocrinologist ñ Andrologist or gynaecologist ñ Psychiatrist/psychologist ñ Social worker ñ Hepatologist ñ Transplant specialist

Each patient’s transition from paediatric to adult care must be accurate and smooth: ñ transmission of complete clinical records ñ shared discussion of past and current clinical problems ñ 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:

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Figure 1: Changing pattern of age distribution in patients with thalassaemia

ñ Physical examination ñ Clinical and laboratory tests, scheduled by the treating physician on the basis of guidelines and individual need. ñ Clinical discussion of the case record ñ Individual conversation to set goals, renew critical information, and listen to the patient (see Chapter 15: Psychological Support in Thalassaemia) ñ 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: ñ A blood bank ñ A general laboratory ñ If available, a special laboratory unit, which runs all specific procedures used in the diagnosis, follow-up and monitoring treatment of thalassaemia, ñ 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 (TIF’s website: www.thalassaemia.org.cy).

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Figure 2: An example of organisational interaction of the thalassaemia unit with other hospital facilities [Kattamis 1989]

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

ñ Updating staff on new aspects of thalassaemia and its treatment ñ Discussing and resolving organisational aspects of the unit’s activities ñ Renewing staff motivation to work in the field of thalassaemia, so as to prevent professional burnout

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

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ñ Capacity for expert diagnosis ñ Expert clinical management ñ The use of outcome measures and quality control, including survival and complication rates, quality of life measures and other measures of patient interest ñ Sufficient activity – which means a minimum number of patients to ensure adequate staff experience for quality care ñ High level expertise and experience of staff ñ Epidemiological surveillance, including patient registers ñ Collaboration with national and international centres ñ 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:

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Outline of Diagnostic Dilemmas in Thalassaemia

II -- IIn nccrreeaasseedd ttrraannssffuussiioonn rreeqquuiirreem meennttss

VIIII -- W V Woorrsseenniinngg jjaauunnddiiccee

A - Hypersplenism B - Alloantibody C - Autoantibody D - Infection with HPV-B19 virus

A - Gilberts B - Increased haemolysis C - Drug Reaction D - Liver failure

IIII -- FFe evveerr

VIIIIII -- LLeegg ccrraam V mppss

A - Infection due to Bacterial B - Yersinia C - Klebsiella D - Delayed transfusion reaction

A - Hypocalcaemia B - Hypoparathyroidism

Diagnostic Dilemmas in Thalassaemia

IIIIII -- B Baacckk PPaaiinn A - Osteoporosis and microfractures B - Prolapse in disc C - End plate degeneration D - Prolapse

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.

IIV V -- UUnneexxppllaaiinneedd AAbbddoom miinnaall PPaaiinn A - Cholelythiasis B - Pancreatitis C - Portal vein thrombosis D - Renal stones E - Hepatic capsule distension F - Yersinia

V -- CChheesstt PPaaiinn V

II.. IInnccrreeaasseedd ttrraannssffuussiioonn rreeqquuiirreem meennttss

A - Pericarditis and myocarditis B - Rib fracture (extramedullary expansion) C - Pulmonary embolism

VII -- DDyyssppnnooeeaa V

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

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blood requirements, the choice of interval must take into account other factors, such as the patient’s work or school schedule. Reasons for increased consumption include hypersplenism, new alloantibodies, infection and changes in the haematocrit of transfused units.

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. 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 recipient’s 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.

II--A A.. HHyyppeerrsspplleennssiissm m 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.)

II--C C.. AAuuttooaannttiibbooddyy 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.

II--B B.. AAllllooaannttiibbooddyy 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

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II--D D.. IIn nffeeccttiio on nw wiitth hH HP PV V--B B1199

IIII--B B.. YYeerrssiin niiaa

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.

IIII.. FFe evveerr 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.

IIII--AA.. IIN NFFEEC CTTIIO ON ND DU UEE TTO O BA B AC CTTEER RIIA A 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.

IIII--C C.. KKlleeb bssiieellllaa 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

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IIIIII--A A.. O Osstteeo op po orro ossiiss

the presence of excess iron. Infection with Klebsiella can be fatal in patients with thalassaemia.

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.

IIIIII--B B,, IIIIII--C C& & IIIIII--D D.. Miiccrro M offrraaccttu urreess,, d diisscc p prro ollaap pssee aan nd de en nd dp pllaatte ed de eg geen neerraattiio on n

IIII--D D.. D Deellaayyeed d ttrraan nssffu ussiio on n rreeaaccttiio on n

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.

IIIIII.. B Baacckk P Paaiin n 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.

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IIV V--BB.. PPaannccrreeaattiittiiss

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.

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.

IIVV.. UUnneexxppllaaiinneedd aabbddoom miinnaall ppaaiinn 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 diseases—3 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.

IIV V--CC.. PPoorrttaall vveeiinn tthhrroom mbboossiiss

IIV V--AA.. CChhoolleellyytthhiiaassiiss

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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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.

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.

V.. CChheesstt ppaaiinn V 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.

IIV V--DD.. RReennaall ssttoonneess 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.

VV--AA.. PPeerriiccaarrddiittiiss aanndd myyo m occaarrddiittiiss

IIVV--EE.. HHeeppaattiicc ccaappssuullee ddiisstteennssiioonn

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

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The regular assessment of cardiac status can identify the early stages of heart disease, enabling prompt intervention.

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 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.

VV--BB.. RRiibb ffrraaccttuurree ((eexxttrraam meedduullllaarryy eexxppaannssiioonn)) 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.

VII.. DDyyssppnnooeeaa V 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--CC.. PPuullm V moonnaarryy eem mbboolliissm m 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,

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VII--AA.. DDyyssrrhhyytthhm V miiaa

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.

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.

VII--CC.. PPuum V mpp ffaaiilluurree 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

VVII--BB.. DDeellaayyeedd ttrraannssffuussiioonn rreeaaccttiioonn Delayed haemolytic transfusion reactions (DHTRs) are due to an anamnestic antibody

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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.

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.

VII--DD.. PPuullm V moonnaarryy hhyyppeerrtteennssiioonn 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.

VIIII--AA.. GGiillbbeerrtt’’ss ssyynnddrroom V mee 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. 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.

VIIII.. W V Woorrsseenniinngg jjaauunnddiiccee

The physical examination is usually unrevealing, except for icterus. However

Jaundice, or icterus, is a yellowish discoloration of tissue resulting from the

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situations that exaggerate hyperbilirubinemia may bring the patient to medical attention and have corresponding physical findings. Thalassaemia patients with inherited Gilbert’s syndrome are at increased risk for haemolysis and, as a result, would present with clinical manifestations of icterus and elevated bilirubin.

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.

VIIII--BB.. IInnccrreeaasseedd hhaaeem V moollyyssiiss 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.

VIIII--DD.. LLiivveerr ffaaiilluurree V 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.

VIIIIII.. LLeegg ccrraam V mppss 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.

VIIII--CC.. DDrruugg rreeaaccttiioonnss V 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

VIIIIII--AA.. HHyyppooccaallccaaeem V miiaa Several acquired causes of hypoparathyroidism have been identified in

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children, including thyroid surgery and iron deposition in the parathyroid gland as a result of frequent transfusions (as in ‚thalassaemia major).

VIIIIII--BB.. HHyyppooppaarraatthhyyrrooiiddiissm V m 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.

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Aessopos A, Farmakis D, Karagiorga M et al. Cardiac involvement in thalassaemia intermedia: a multicentre study. Blood. 2001:97;3411-3416

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WEBSITES National Evidence-Based Clinical Guidelines Fertility: assessment and treatment for people with fertility problems_. February 2004. http://www.rcog.org.uk RCOG Clinical Green Top Guidelines. Management of HIV in Pregnancy (39) - April 2004. http://www.rcog.org.uk

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APPENDIX A

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193

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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 pubity Amenorrhoea Acarbose 5 - Azacytidine Alchohol consumption Aplastic crisis Antioxidants Agranulocytosis Arthropathy Anticoagulants ACE inhibitors Amiodarone Abdominal pain

101, 105 12 81 70 84, 88, 166 19, 20, 24, 128, 160 28 28 28, 160 65 66 69 136 153 108, 161 37 50 50 21, 88, 126 87 88 163

B Blood donation Bone marrow expansion Back pain Bisphosphonates Butyrates Bumetanide BMP Beta blocking agents

18, 93, 98 79, 123, 162 162 74, 81 136 87 88 88

C Chimerism Cirrhosis Chelaton Cardiac disease

134 93, 99 38, 108, 127, 144, 151 73, 76, 83, 154

196

Calcium Circulatory overload (transfusion) Calcitriol Cytotoxic agents Confidentiality Cytomegolovirus (CMV) Chagas disease Chemoprophylaxis

69, 81, 152 29 69 136 149 111 30, 115 118

D Diabetes mellitus Deferiprone DNA Delayed pubity Desferioxamine DFO DEXA scan Disc prolapse Diet Deferasirox Delayed transfusion reactions Decitabine Dental care Drug abuse Driving Dengue fever Digoxine Diuretics

68, 92 48, 74 12 65 39, 65, 77, 108, 112 74, 79 162 151-153 55 28, 162, 166 136 151 153 154 114 87 87

E Entecavir Extramedullary haemopoiesis Echocardiography Ejection fraction (LVEF) Electrocardiogram (ECG) Erythropoietin (EPO)

101, 105 124, 165 85 36, 49, 54, 73 84 129, 136

F Ferritin Fetal haemoglobin (Hb F) Fractures Fertility

33, 48, 53, 55, 75 12, 129, 136 81, 162, 165 70

197

Folic acid Filtration (Leukoreduction) Frozen red cells

127, 152 19, 20, 29 20

G GVHD Growth Growth velocity Glucose tolerance Gene therapy Gallstones (cholelithiasis) Gilbert's syndrome GM CSF

29, 133 43, 64 64 69 139 124 167 50

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

133 74, 92, 94, 126 93, 99 74, 98, 128 74, 109 116, 160 67 36, 126, 166 16,130 16 16 17 17 17 67, 70, 78 74, 81 121, 124, 129, 136 69, 169 69, 169 36, 40, 49, 54, 56, 73

I Iron load (haemosiderosis) Interferon (pegylated) Iron absorption Insulin

26, 31, 107, 127 95, 101, 105 31, 151 69

198

Insurance (travel) Immune function Influenza virus vaccine Indwelling intravenous lines Intensive chelation Immunoprophilaxis

150 107 118 47 46 118

J Jaundice

117

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

50, 92, 132 93, 168 35, 94 101, 105 149 33, 39, 48, 53, 55, 92 37 168 125

M Matched unrelated donors (MUD) MRI MRI cardiac Malaria Myocarditis

133 36, 92 36, 40, 49, 74, 85 114, 115 36, 164

N Neutropenia Neocytes Nonhaemolytic febrile transfusion reactions Nephrolithiasis (kidney or renal stones) Non transferring bound iron (NTBI)

50 21 27 123, 164 37

199

O Osteoporosis Ovulation Oxidative damage

74, 79, 127, 162, 154 70, 71 37

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 45, 51, 70, 127 70, 73 71 66 153 108, 161 84 164 163 163 165 90, 120, 126, 166 127 81

S Survival SQUID Skeletal dysplasia Spermatogenesis Splenectomy Short chain fatty acids School Smoking Splenomegaly Splenic embolisation

40, 49 35 43 70, 72 107, 116, 124, 128 137 149 153 124, 154 117

T Thrombocytopenia Transfusion requirement Transplantation (Stem cells) Transfusion related acute lung injury (TRALI)

50, 97, 116 23, 25, 26, 97 129, 132 29

200

V Vaccinations Vitamin D Vitamin C Vitamin E Vision

99, 101, 118, 151 69, 81 33, 39, 45, 52, 152 153 43, 50

W Washed red cells Work

20 150

Y Yersinia enterocolitica

42, 111, 161

Z Zolandronic acid Zinc deficiency

81 51, 153

201

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. TIF’s 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.

MIISSSSIIO M ON N:: ““EEQ QU UAALL AAC CC CEESSSS TTO OQ QU UAALLIITTYY H HEEA ALLTTH H SSEER RV VIIC CEESS FFO OR RA ALLLL WIITTH W H TTH HAALLAASSSSA AEEM MIIA A”” MO M OTTTTO O:: ““U UN NIITTYY IISS O OU UR R SSTTR REEN NG GTTH H”” WORLD HEALTH ORGANIZATION (WHO) RESOLUTION: no. EB118.R1 (29 May 2006) ““TTH HA ALLA ASSSSA AEEM MIIA AA AN ND DO OTTH HEER RH HA AEEM MO OG GLLO OB BIIN NO OP PA ATTH HIIEESS””

202

1.

2.

““BBlloooodd SSaaffeettyy KKiitt”” (1999) In English

8.

Guuiiddeelliinneess ttoo tthhee CClliinniiccaall “G Maan M naaggeem meenntt ooff TThhaallaassssaaeem miiaa”” 2000 Translated into 6 languages 9.

3.

4.

““CCoom mpplliiaannccee ttoo IIrroonn CChheellaattiioonn tthheerraappyy wwiitthh DDeessffeerrrriiooxxaam miin ne e”” 2000 – Reprint 2005 - Translated into 4 languages

10.

““AAbboouutt TThhaallaassssaaeem miiaa”” 2003 - Translated into 11 languages 11.

5.

6.

7.

““PPrreevveennttiioonn ooff TThhaallaassssaaeem miiaass aanndd OOtthheerr HHaaeem mo og gllo ob biin no op paatthhiieess”” Volume I (2003) Translated into 2 languages

12.

““PPrreevveennttiioonn ooff TThhaallaassssaaeem miiaass aanndd OOtthheerr HHaaeem mo og gllo ob biio op paatth hiieess”” Volume II (2005) - In English

13.

““PPaattiieennttss’’ RRiigghhttss”” 2007 - In English

14.

203

““AA gguuiiddee ttoo tthhee eessttaabblliisshhm meenntt aanndd pprroom mo ottiio on no off n noonn-ggoovveerrnnm me en ntt ppaattiieennttss//ppaarreennttss’’ oorrggaanniizzaattiioonn”” 2007 - In English ““GGuuiiddeelliinneess ttoo tthhee CClliinniiccaall Maan M naaggeem meenntt ooff TThhaallaassssaaeem miiaa”” Second Edition - 2007 - In English ““TThhaallaassssaaeem miiaa M Maajjoorr aanndd Me M e”” – Children’s Book – 2007 - In English ““AAbboouutt -- ‚‚ -- tthhaallaassssaaeem miiaa”” – 2007 - In English, Italian, French ““AAbboouutt -- ·· -- tthhaallaassssaaeem miiaa”” – 2007 - In English, Italian, French ““AAbboouutt ssiicckkllee cceellll ddiisseeaassee”” – 2007 - In English, Italian, French EEdduuccaattiioonnaall FFoollddeerr -Information for the community, the carrier of and the patient with a Haemoglobin disorder.