6tthh IInternationalnternational CConferenceonference onon Th alassemiaalassemia 22016016
24th - 25th September, 2016 Eros Hotel, New Delhi
HEALTH AL M N IS O S I I Under the Patronage of Ministry of T O A N Health and Family Welfare N jk’Vªh; LokLF; fe”ku BLOOD CELL UNDER Government of India NHM, MOHFW
Abstract Book
Organised by : Thalassemics India www.thalassemicsindia.org i 6th International Conference on Thalassemia
Gold Sponsor
Novartis Healthcare Pvt. Ltd.
Sliver Sponsor
Fresenius Kabi India Pvt. Ltd.
Special thanks to our collaborators:
Thalassaemia International Federation
Sir Ganga Ram Hospital
Apollo Hospitals
ii HEALTH AL M N IS O S I I T O
A N
N
jk’Vªh; LokLF; fe”ku BLOOD CELL UNDER NHM, MOHFW
PREVENTION AND CONTROL OF HEMOGLOBINOPATHIES IN INDIA - THALASSEMIAS, SICKLE CELL DISEASE AND OTHER VARIANT HEMOGLOBINS 2015
National Health Mission Guidelines on Hemoglobinopathies in India
Ministry of Health & Family Welfare Government of India
1 Contributors
1. Prof. IC Verma, Head, Department of Genetics, Sir Ganga Ram Hospital, New Delhi 2. Dr Sudhir Kr Gupta, Addl. DDG (NCD), Directorate of Health Services, MoHFW, Govt. of India, New Delhi 3. Dr Roshan Colah, Former Director-in-Charge, National Institute of Immuno-haematology (ICMR Institute), KEM Hospital Campus, Mumbai 4. Professor Arun Singh, National Advisor, RBSK, National Health Mission, MoHFW, Govt. of India, New Delhi 5. Prof. DK Gupta, Consultant and Head, Department of Hematology, Safdarjung Hospital & VMMC, New Delhi 6. Prof. K Ghosh, Former Director, National Institute of Immuno-haematology, (ICMR Institute), KEM Hospital Campus, Mumbai 7. Prof Renu Saxena, Professor & Head of the Department of Hematology, All India Institute of Medical Sciences, New Delhi 8. Prof. Sunil Gomber, Director, Paediatrics, UCMS & GTB Hospital, New Delhi 9. Prof Madhulika Kabra, Head, Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 10. Dr. Sujata Sinha, Adjunct Associate Professor, Centre for Comparative Genomics, Murdoch University Perth, (Former Technical Consultant, Action on Birth Defects Project, RBSK, NHM, Uttarakhand) 11. Dr. Tulika Seth, Additional Professor, Hematology, All India Institute of Medical Sciences, New Delhi 12. Prof. Jagdish Chandra, HOD Pediatrics, LHMC and Kalawati Saran Hospital, New Delhi 13. Prof Sarita Agarwal, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 14. Prof Reena Das, Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh 15. Dr. V.K. Khanna, Sr. Consultant Pediatrician, Sir Ganga Ram Hospital, New Delhi 16. Dr. R.K. Jena, Professor & Head, Dept. of Clinical Hematology, SCB Medical College & Hospital, Cuttack 17. Dr. Sujata Mohanty, Addl. Professor, Centre of Excellence for Stem Cell Research, All India Institute of Medical Sciences, New Delhi 18. Mr. C.B.S. Dangi, Dean Faculty of Science, RKDF University, Bhopal 19. Dr. J.M Khungar, Senior Consultant, Hematology, Safdarjung Hospital, New Delhi 20. Prof. Dipika Mohanty, Senior Consultant, Hematology and Lab Director, Apollo Hospital, Bhubaneswar, Odisha 21. Dr. Menu Bajpai, Associate Professor, Hematology, ILBS, Vasant Kunj , New Delhi 22. Dr. Jitendra Sharma, Director, WHO Centre for Medical Technology, NHSRC, MoHFW, Govt, of India, New Delhi 23. Dr. Vanshree Singh, Director, IRCS, Blood Bank, New Delhi 24. Dr. Prakash Parmar, Exec, Secretary, Indian Red Cross Society, Gujarat Branch 25. Mrs. Shobha Tuli, Secretary, Thalassemics India, New Delhi 26. Ms. Vinita Srivastava, National Consultant, Blood Cell (NHM), MoHFW, Nirman Bhavan, New Delhi
2 Contents
Messages ...... 05-20
Committees ...... 21-24
Faculty ...... 25-28
Conference Programme ...... 29-32
Abstracts ...... 33-61
Posters ...... 63-68
3 Bio-Rad Laboratories HEMOGLOBIN TESTING
She doesn’t have to worry about Thalassemia
or Sickle Cell because her parents were screened for both conditions. Unfortunately, thousands of children born every day aren’t so lucky. Healthcare experts worldwide, rely on
Bio-Rad HbA2 testing to confidently advise their patients and ultimately, their children.
Bio-Rad HbA2: The choice of experts for over 25 years
Bio-Rad Hemoglobin Testing and Screening
s Thalassemia Testing
s Hemoglobinopathy Screening
s HbA1c Monitoring
s Newborn Screening for Sickle Cell Disease
A GLOBAL LEADER IN THALASSEMIA AND HEMOGLOBINOPATHY SCREENING
For more information, visit www.bio-rad.com/diagnostics
4 6th International Conference on Th alassemia, 2016
Messages
5 “Equal access to quality healthcare for every thalassemic across India.”
6 7 8 9 10 11 12 13 14 Message
Dear Participants, Dear Friends of our thalassaemia family, On behalf of the Board of Directors of TIF, I feel extremely privileged to welcome you all to the 6th International Conference on Thalassaemia in New Delhi. I wish to thank the organisers of this conference and in particular, Mrs ShobhaTuli – TIF Vice President, President of the Federation of Indian Thalassaemia Societies and Secretary of the Thalassaemics India, for their cordial invitation to the Thalassaemia International Federation, to address this great event. This very signifi cant educational event is concentrating participants from across the Indian Continent and beyond, aiming to promote the services both for the prevention of haemaoglobin disorders and the treatment of patients and very importantly to create a forum for exchanging and sharing information, knowledge and experiences. In recent decades, we have all been witnessed to the remarkable progress with regards to health and social improvements pertaining to our patients globally. These advances in the quality of care, have led to increased survival and a quality of life which were but adream in years gone by. However, these excellent outcomes are seen only in patients who have enjoyed the benefi ts of, and have adhered to the treatment opportunities off ered. In many parts of the world we can also still see big gaps, in the availability of state of the art programmes, and there is need for a major eff ort to reach all patients across the world. Without political priority and governmental programming these improvements, in all areas including prevention, clinical management and psychosocial support to our patients and their families cannot be achieved. Educating individual experts, academic research, are but a few of the major components of a wider need which encompasses health planning and health economics. What we know is that if chronic and hereditary diseases are not given the attention that they need by health planners, the result is premature death, poor quality of life and an increasing health burden. It must be understood that poor treatment, in the name of budgetary limitations, leads to increasing complications and fi nally more health expenditure as well as social injustice. There is a need for a fi rm political commitment to address this very signifi cant public health problem appropriately. The Indian Sub-continent constitutes one of the most densely populated countries in the world, where almost all forms of the haemoglobin disorders, mainly thalassaemia and sickle cell disease are highly prevalent and very heterogeneously spread across the country. TIF’s presence at this conference refl ects on its true commitment to lend its support and assistance to India, in a more systematic and focused way, as well as to reinforce the activities of each and every single thalassaemia association in this country. Our collaboration with India has been long and blessed with enthusiastic collaborators, both in the patient support associations and in the medical fi eld. As a propagation of this close collaboration with various stakeholders, was the undertaking by TIF of its biggest project to date, namely the Indian Project, in an ‘aff ected country across the world. Specifi cally, the project encompassed the development of ‘Charters of Priorities’ for the Indian Ministry of Health and Welfare and State Health Authorities of eight States, in collaboration with the Indian Medical community and the thalassaemia patients/parents associations. These Charters formed the reference base for state health authorities and associations alike to work together and collaborate with a view to instigating improvements in the quality of health care services provided to patients with haemoglobin disorders in India. The highlight of this tremendous eff ort contributed to the recent revision of the aforementioned ‘Disability Bill’ by the Indian Parliament. We are aware that much has already been achieved and we are truly grateful to the State governments of India, that much support is today provided to patients with these disorders in this country. However, we wish that these activities become more homogeneous across the country and many of the remarkable activities adopted in some States are mimicked by all States of India and that the desired result is optimum care equally provided to all patients. I wish everyone a most productive and rewarding meeting and an enjoyable stay in New Delhi, a city with a unique sense of hospitality.
Panos Englezos President
15 Message
16 Message
Dear Friends,
Greetings of the season!
Where do we stand today and how far ahead have we reached with respect to thalassemia since we last met in 2012?
It is with great enthusiasm that I am looking forward to welcoming you all to the 6th International Conference on Thalassemia in New Delhi.
Many of us are witness to the sea change inthe management of thalassemia in the past 3-4 decades. What has emerged and evolved is that care is now to be directed towards improving quality of life and longevity of thalassemics, over and above just sustenance and survival.
Prevention of births of thalassemia major is still our priority. At the same time, provision of the best care to thalassemics remains our aim.A dedicated, multidisciplinary approach is now clearly seen to be the need of the hour. Parental participation has played an exponentially greater role in care of our thalassemics.
This two-day conference plans a compact and meaningful coverage of trending topics on thalassemia. The conference schedule has been drafted to suit the needs of patients, parents, care- providers and doctors.
It promises to be an academically vibrant and pulsating programme, and we all will have the opportunity to learn from and interact with researchers who have worked for years in this fi eld.
I hope that the conference will help us in further improving the care provided to thalassemics.
Dr V K Khanna Chairman Scientifi c Committee 6th International Conference on Thalassemia New Delhi
17 Welcome Message
Dear Friends,
It gives me great pleasure to welcome you all to the 6th International Conference on Thalassemia.
The last few years have seen a host of exciting developments in the world of thalassemia. These have translated into dramatic improvements in the life span and quality of life of patients with thalassemia who have access to optimal care. This has brought new challenges, which, we must now address.
The Indian subcontinent has the largest number of patients with hemoglobinopathies. Whilst we are committed to the long term aim of prevention of thalassemia, we must ensure optimal care to all patients. State governments and non-governmental organizations are working in tandem to achieve this.
In this meeting, it is our endeavor to focus on the optimal management of thalassemia and to provide an insight into the exciting new developments that are likely to shape the management in the years to come.
Doctors, parents and patients can look forward to hearing from and interacting with the leading medical professionals in this fi eld. In addition, it will be an excellent opportunity to share our experiences, build new friendships and consolidate old ones.
It is our sincere hope, that the conference will impact on the day to day management of our patients and take us closer to the aim of optimal care for each child and adult with thalassemia.
Wishing you all a very rewarding meeting.
Amita Mahajan Secretary Scientifi c Committee 6th International Thalassemia Conference
18 Message
A hearty welcome to all delegates, participants, donors and sympathisers who are attending this 6th International Conference on Thalassemia, being held in Delhi.
At the outset I have to regret that I will not be present during the Conference due to some other pressing engagement. This is a personal loss to me.
Our aim at Thalassemics India has been to collectively fi ght this disorder and also ensure that adequate information and knowledge about this disorder is spread throughout the length and breadth of the country.
Conferences of this type are a platform to achieve both the above objectives. Our past experience has shown that experts in this fi eld from all over the world share their experiences and also talk about the possible breakthroughs.
It is this which boosts the morale of all those who are affl icted with this disorder or are connected in some way or the other with the cause.
We have come a long way and are aware that we have still miles to go and I am confi dent that with all the enthusiasm, participation and support we have received till now, we will be able to reach our goal which is ‘a fuller and complete life to the Thalassemics and a zero Thalassemic birth in the future’.
I once again welcome you all and wish the conference a Grand Success.
Regards, Deepak Chopra Organising Chairman 6th International Conference on Thalassemia
19 Message
It is a great pleasure to welcome you on behalf of the Organising Committee to the 6th International Conference on Thalassemia.
We are privileged to host this Conference under the banner of Ministry of Health and Family Welfare, Govt. of India.
Over the years, the quality of life of many thalassemics has improved. The credit goes to the medical community, but also to the Thalassemia NGOs’ and to a number of individuals working in this fi eld selfl essly.
In spite of the progress made, there is a lot left to be done for its prevention and treatment.
Scientifi c Conferences are therefore a necessity and has become an avenue for the experts on Thalassemia to come on a common platform for sharing their experiences and knowledge.
Thalassaemia International Federation has always supported the organisation of Conferences on Thalassemia in India for which we are extremely grateful to them.
I am confi dent that this conference will off er a great opportunity to exchange views and to learn about the latest developments in this fi eld.
We hope you will have a fruitful conference and a wonderful stay in Delhi.
Hoping to see you there.
Shobha Tuli Organising Secretary 6th International Conference on Thalassemia
20 6th International Conference on Th alassemia, 2016
Committees
21 “A special appreciation goes to the Donors, Corporates and Organizations for their support to the 6th International Conference on Th alassemia .”
22 6th International Conference on Th alassaemia 2016
Patrons Panos Englezos President, Thalassaemia International Federation, Cyprus Dr D S Rana Chairman, Board of Management, Sir Ganga Ram Hospital, New Delhi Prof Anupam Sibal Group Medical Director, Apollo Hospitals, New Delhi
TIF Coordinator Dr Androulla Eleftheriou Executive Director, TIF
Advisory Committee Dr M B Agarwal Dr Mammen Chandy Dr V P Choudhry Dr Anupam Sachdeva Prof I C Verma
Scientifi c Committee Chairman Dr V K Khanna Secretary Dr Amita Mahajan Members Dr Rajeev Bansal, Jaipur Dr Alka Mathur, Delhi Dr Jagdish Chandra, Delhi Dr Kirti Nanal, Delhi Dr A P Dubey, Delhi) Dr Shubha Phadke, Lucknow Dr Sunil Gomber, Delhi Dr Revathi Raj, Chennai Dr Alok Hemal, Delhi Dr Praveen Sobti, Ludhiana Dr R K Jena, Cuttack Dr Tulika Seth, Delhi Dr Suman Jain, Hyderabad Dr Amita Trehan, Chandigarh Dr Nirmal Kumar, Delhi
23 Organising Committee Chairman Deepak Chopra
Secretary Shobha Tuli
Conference Secretariat Assistance Gagandeep Singh
Members Rekha Arora Dr Gautam Bose Deepak Dhingra Rita Jain Ashvini Malik Arun Sehgal
Patients Advisory Committee Shivangi Amrit Riteek Arora Nehal Dhingra Nita Kalra Nishtha Madan Viresh Piplani
24 6th International Conference on Th alassemia, 2016
Faculty
25 26 Invited Faculty In Alphabetical Order
Dr M B Agarwal Dr Dharma Choudhary Mumbai Delhi Dr Neeraj Aggarwal Dr V P Choudhry Delhi Delhi Dr Emmanuel Ako Dr A P Dubey United Kingdom Delh Dr Michael Angastiniotis Dr Androulla Eleftheriou Cyprus Cyprus Dr S K Arora Dr Heba Elsedfy Govt. of NCT of Delhi Egypt Dr J S Arora Dr Amna Abdel Gadir Delhi United Kingdom Dr Archana Arya Dr Kapil Garg Delhi Rajasthan Dr Deepak Bansal Dr Vineeta Gupta Chandigarh Uttar Pradesh Dr Rajiv K Bansal Dr Basab Gupta Rajasthan D C, Urban Health Mr Rahul Balasaria Dr Sunil Gomber Kolkata Delhi Dr Bhanu Bhakhri Dr Alok Hemal Uttar Pradesh Delhi Dr Maitreyee Dr Manas Kalra Bhattacharya Delhi KolKata Dr Shruti Kakkar Dr Dinesh Bhurani Punjab Delhi Dr Dinesh Kaul Dr Gautam Bose Delhi Delhi Dr Anil Khatri Dr Jagdish Chandra Gujarat Delhi Dr Sanjivni Khanna Dr Mammen Chandy Delhi Kolkata Dr V K Khanna Dr Prantar Chakrabarti Delhi Kolkata Dr I P S Kochar Dr Kabita Chatterjee Delhi Delhi
27 Dr K K Koul Dr Vivek Ranjan Jammu Delhi Dr Vikas Kohli Dr Ruchi Rastogi Delhi Punjab Sh Alok Kumar Dr Anil Samaria IAS, MOHFW Rajasthan Dr Philippe LeBoulch Dr Anju Seth France Delhi Ms Nishtha Madan Ms Somdutta Sarkar Delhi Delhi Dr Amita Mahajan Dr Shishir Seth Delhi Delhi Dr Harsh Mahajan Dr Tulika Seth Delhi Delhi Dr Abha Majumdar Prof Anupam Sibal Delhi Delhi Dr R N Makroo Dr Chanchal Singh Delhi Delhi Dr Mamta Manglani Dr Vanshree Singh Mumbai Delhi Dr Rashid Merchant Dr Alok Srivastava Mumbai Vellore Dr Alka Mathur Ms Vinita Srivastava Delhi MOHFW Dr Kirti Nanal Dr Manoj Kumar Sharma Delhi Delhi Sh Prakash Parmar Dr Rajni Sharma Gujarat Delhi Prof Antonio Piga Dr Poonam Shrivastava Italy Delhi Dr John Porter Dr Praveen Sobti United Kingdom Punjab Dr Anupam Prakash Dr S Sudha Delhi Delhi Dr Nita Radhakrishnan Dr Amita Trehan Delhi Chandigarh Dr K Rajeswara Rao Dr J M Walker IAS, MOHFW United Kingdom
28 6th International Conference on Th alassemia, 2016
Conference Programme
29 “For the last 30 Years, Th alassemics India has dedicated itself towards improving the quality of life of thalassemics throughout the country.”
30 Programme
Day 1: 24th September, 2016 Time Topic Speaker 08:00am-09:15am Registrations 09:15am-09:30am Chairpersons : Dr S K Arora & Dr Michael Angastiniotis Thalassemia as a Global Health Problem with focus on India Dr Androulla Eleftheriou 09:30am-10:00am Chairpersons : Dr Kabita Chatterjee, Dr Vanshree Singh & Ms Vinita Srivastava (MOHFW) Safe Blood & Adequacy Dr Poonam Shrivastava 10:00am-10:30am Chairpersons : Dr Praveen Sobti, Dr S. Sudha, Dr R. N.Makroo & Dr Vivek Ranjan Blood Transfusion Therapy in Thalassemia Dr Mamta Manglani 10:30am-11:00am Chairpersons : Dr Manoj Kumar Sharma, Dr Anil Khatri & Dr Dinesh Kaul Management of Hepatitis B & C - Hope for Cure Prof Anupam Sibal 11:00am-11:45am Inauguration 11.45am-12.00pm Tea /Coff ee Break 12.00pm-12.30pm Chairpersons : Dr K. Rajeswara Rao, IAS (MOHFW) & Shri Alok Kumar, IAS Initiatives taken by the State Governments on the Prevention and Control of Hemoglobinopathies Presentation from West Bengal Dr Maitreyee Bhattacharya Presentation from Gujarat Dr Prakash Parmar Presentation from U.P Dr Vineeta Gupta 12.30pm-01.00pm Chairpersons : Dr Rajiv Kumar Bansal, Dr Kirti Nanal, Dr Prantar Chakrabarti & Dr Vinky Rughwani Optimal Chelation in the Current Era: Shifting Paradigm Dr John Porter 01:00pm-01:20pm Chairpersons: Dr Sunil Gomber & Dr Prantar Chakrabarti Combination Chelation Therapy Dr Antonio Piga 01:20pm-02:00pm Panelists: Dr John Porter, Dr Antonio Piga, Dr Praveen Sobti, Dr Mamta Manglani, Dr Tulika Seth & Ms Vinita Srivastava (MOHFW) Moderator: Panel Discussion on Blood Transfusions & Chelation Dr Deepak Bansal 02:00pm-02:45pm Lunch 02:45pm-03.15pm Chairperson: Dr Anju Seth & Dr Bhanu Bhakhri Endocrine Issues in Thalassemia : Growth, Development & Bone Health Dr Heba Elsedfy 03:15pm-04:00pm Panelists: Dr Heba Elsedfy, Dr Archana Arya, Dr Anju Seth, Dr I.P.S Kochar & Dr Rajni Sharma Moderator: Panel discussion on Endocrine Issues Dr Deepak Bansal 04:00pm-04:30pm Tea /Coff ee Break 04:30pm-05:15pm Chairpersons : Dr Vikas Kohli & Dr Neeraj Aggarwal Prevention and Management of Cardiac Complications: The Heart of the Matter Dr J.M. Walker 05:15pm-05:45pm Chairpersons: Dr Androulla Eleftheriou, Dr V.P. Choudhry, Dr Anupam Prakash & Dr Anil Samaria Management of the Adult Thalassemic Dr John Porter 05.45pm-05.55pm Patients’ Rights Nishtha Madan 05.55pm-06:05pm Challenges in Finding Employment Somdutta Sarkar 06:05pm-06:15pm Finding a Life Partner Rahul Balasaria
31 Day 2: 25th Sepember, 2016 Time Topic Speaker 09:30am-09:50am Chairpersons: Dr J.M. Walker, Prof Jagdish Chandra & Dr Ruchi Rastogi The role of MRI in Optimal Management of Thalassemia Dr Harsh Mahajan 09:50am-10:00am Chairpersons: Dr J.M. Walker, Prof Jagdish Chandra & Dr Ruchi Rastogi A New MRI Sequence to Assess Iron Overload in Thalassemia Dr Amna Abdel Gadir 10:00am-10:30am Chairpersons : Dr A. P. Dubey & Dr Kapil Garg Optimal Monitoring in Thalassemia Prof Antonio Piga 10:30am-11:00am Chairpersons : Dr Alok Srivastava & Dr Dharma Choudhary Stem Cell Transplant in Thalassemia: Options & Dilemmas Dr Mammen Chandy 11:00am-11.30am Panelists: Dr Mammen Chandy, Dr Alok Srivastava, Dr Dharma Choudhary, Dr Dinesh Bhurani & Dr Shishir Seth Moderator: Panel Discussion on BMT Dr V.K. Khanna 11:30am-11:50am Tea / Coff ee Break 11:50am-12:20pm Chairpersons : Dr K. K. Koul, Dr Amita Trehan & Dr Alok Hemal Management of Non-Transfusion Dependent Thalassemia Dr V.P. Choudhry 12:20pm-12:50pm Chairpersons: Dr Michael Angastiniotis & Dr Rashid Merchant My Journey in to the World of Thalassemia Dr M B Agarwal 12:50pm-01:20pm Chairpersons: Dr M.B. Agarwal, Dr Alok Srivastava & Dr Alka Mathur Gene Therapy for Thalassemia: Are we there yet ! Dr Philippe Leboulch (Session Sponsored by Bluebird Bio) 01:20pm-01:35pm Chairpersons: Dr Philippe Leboulch & Dr M.B. Agarwal Gene Therapy : Progress in India Dr Alok Srivastava 01:35pm-02:15pm Lunch 02:15pm-02:35pm Chairpersons: Dr V K Khanna & Dr Manas Kalra Thalidomide in Thalassemia : Hope or Hype ? Dr Amita Trehan 02:35pm-03:05pm Chairpersons: Dr Basab Gupta (MOHFW) & Dr Chanchal Singh Fertility & Pregnancy in Thalassemia Dr Sanjivni Khanna 03.05pm-03:20pm Chairpersons: Dr Gautam Bose & Dr J.S. Arora Pulmonary Hypertension in Thalassaemia: New methods and insights Dr Emmanuel Ako 03:20pm-03:50pm Chairpersons: Dr Androulla Eleftheriou & Dr Manas Kalra New Drugs on the Horizon Dr John Porter 03:50pm-04:20pm Tea / Coff ee Break 04:20pm-04:35pm Chairpersons: Dr Nita Radhakrishnan & Dr Shruti Kakkar Pre Gestational Diagnosis in Thalassemia Dr Abha Majumdar 04:35pm-05:05pm Chairpersons: Dr Michael Angastiniotis & Dr Androulla Eleftheriou Moderator: Share Your Personal Experiences ! Gagandeep Singh 05:05pm-05:15pm Vote of Thanks Shobha Tuli 05:15pm-05:40pm Concluding Remarks Dr Amita Mahajan
32 6th International Conference on Th alassemia, 2016
Abstracts
33 “For the sake of your future child, get your blood tested on time and protect them from Th alassemia.”
34 Managing the Cardiovascular Complications in Thalassaemia Major J Malcolm WALKER MD, FRCP Consultant Cardiologist University College Hospital, London Founder & Clinical Director Hatter Cardiovascular Institute, UCLH, London
Although there has been a dramatic reduction in mortality in thalassaemia major (TM) in the last decade, cardiovascular complications of thalassaemia remain a frequent cause of morbidity and mortality.
The availability of methods to assess tissue iron burden, non-invasively using cardiac magnetic resonance scanning (cMRI) to measure the T2* parameter, has driven the improved management of these patients. However, access to this technology remains limited in those parts of the world which face the greatest challenge from thalassaemia and is rationed even in wealthy economies such as in the UK. Newer cMRI sequences may provide some improvements in the future, with decreased scanning times and improved sensitivity.
Echocardiography is easily accessible and has the capacity to provide repeatable, safe, cost eff ective and rapid assessments of the heart in thalassaemia. Echocardiography is widely available and our experience has revealed that it remains a valuable clinical tool in patient management, complementing cMRI and allowing the possibility of better managing the scarcer resource of cMRI imaging. It has previously been demonstrated that the global assessment of ventricular function using the ejection fraction (EF) can be misleading in some patients, remaining normal despite signifi cant cardiac iron loading and the risk of rapid cardiac decompensation. We have investigated newer, less load dependent and less image dependent parameters of ventricular function to assess patients with thalassaemia.
In the ageing TM population and, particularly in undertransfused patients and those with intermedia phenotypes, the complication of pulmonary hypertension is encountered. It appears likely this is multi- factorial, but a large component will be due to progressive left ventricular disease, specifi cally diastolic dysfunction leading, unless treated adequately, to the syndrome of heart failure with preserved ejection fraction, frequently abbreviated to HFpEF.
Future challenges will also include the increasing incidence of arrhythmia, specifi cally atrial fi brillation (AF) in this ageing group of patients as they now can expect to survive the risky early years of their condition. The risk of stroke needs to be precisely determined in this population and the thresholds for intervention with anti-coagulation need to take into account an increased thrombotic drive.
The multidisciplinary approach to management has proven successful in thalassaemia particularly in the treatment of cardiac complications, but the surviving cohorts now present with new clinical challenges, which we must be ready to address to prevent late consequences, such as stroke and progressive pulmonary hypertension .
35 Transfusion Therapy in Thalassemia Mamta Manglani Professor & Head, Dept. of Pediatrics, Chief, Division of Hematology-Oncology, Program Director, Pediatric Centre of Excellence for HIV Care, Lokmanya Tilak Municipal Medical College & General Hospital, Sion, Mumbai
Introduction Thalassemia syndromes are a heterogeneous group of inherited disorders known to be highly prevalent worldwide. It is an autosomal recessive disorder and is the commonest single gene disorder. The mainstay of therapy of thalassemia major is transfusion therapy and management of its complications. The transfusion therapy has undergone tremendous evolution since the early 60’s when it was understood that thalassemic children cannot survive without blood transfusions.
History of Transfusion Therapy in Thalassemia In the 1960’s, Wolman proposed a palliative transfusion therapy for thalassemia major. It was aimed at maintaining the hemoglobin at 8.5 gms%. This led to improved survival, but the chronic illness, bone disease and cardiomyopathy persisted. To overcome these problems, Piomelli and workers suggested maintaining the hemoglobin above a minimum of 10 gms%. These vigorous regimens were termed as hypertransfusion, although normotransfusion may be a more descriptive term. Hypertransfusion promotes normal growth and development, prevents the onset of severe hepatosplenomegaly and hemolytic facies, lowers the absorption of gastrointestinal iron and reduces the anemic cardiomyopathy changes.
In 1980, Propper and colleagues introduced a further improvised regimen called supertransfusion, and maintained a pretransfusion hemoglobin of above 12 gms%. However, this did not prove signifi cantly superior to hypertransfusions and was given up. Hypertransfusion remains the most accepted regimen in most parts of the world. However, in Europe, a yet newer regimen termed the “moderate transfusion regimen” was adopted and has been recommended by the Thalassemia International Federation. In this regimen, pretransfusion hemoglobin is maintained between 9 and 10.5 gms%.
Transfusion Therapy It should be given with the following aims: 1. Fulfi lling the goals in a thalassemic child a. To alleviate anemia b. To suppress ineff ective erythropoiesis c. To prevent serious growth and skeletal complication of thalassemia major
2. Ensuring optimal safety a. Acute reactions b. Transfusion transmitted infections c. Delayed reactions
Initiation of transfusions Transfusions should be started in all children with 1. A confi rmed diagnosis of thalassemia major (preferably by molecular techniques) with one of the following fulfi lled: a. Laboratory Criteria If Hb drops < 7 gms% on 2 occasions > 2 weeks apart b. Clinical Criteria irrespective of hemoglobin level Hemoglobin > 7 gms% with any of the following clinical criteria i. Facial changes
36 ii. Poor growth iii. Fractures iv. Clinically signifi cant extramedullary haematopoiesis 2. Complete genotype of red cells is ideal to avoid alloimmunization.
Evaluation prior to starting transfusions • CMV serology testing: IgM in infants and IgG in older children who may have future possibility of hematopoietic stem cell transplant. • Perform serologic testing for HIV, hepatitis A, B, and C, and liver function testing prior to initiation of transfusion. • Immunize all patients who do not have serologic evidence of infection or immunity for hepatitis B prior to transfusion. Hepatitis A immunization should be given as well. • HLA typing of all siblings of patients with transfusion-dependent thalassemia.
Type of Transfusions • Group and type specifi c packed red cells with a hematocrit of 65 to 75%. • Completely matched red cells are preferable but not practically possible. Hence, red cells compatible by indirect antiglobulin test should be transfused. • The red cells should not be more than 4 to 5 days old preferably. • Leucodepleted and saline washed red cells (especially in those with recurrent allergic reactions). Leucodepletion can be done by pre-storage fi ltration of whole blood (most effi cient method), pre- storage fi ltration of packed red cells and bedside fi ltration of the packed red cell units. The advantages of leucodepleted packed red cells include reduction in Febrile non hemolytic transfusion reactions (FNHTR), prevention of HLA allommunization and Cytomegalovirus (CMV) infection.
What to transfuse? Patients with thalassemia should receive leukocyte reduced packed red cells.
Blood products for special situations: Irradiated blood cells Washed red cells Frozen red cells or deglycerolized Neocyte transfusion red cells Provided to patients who Suitable for IgA defi cient Should be provided to patients May modestly reduce have received transplants patients and those who with rare RBC antigens for requirement as half life or bone marrow experience frequent whom it is diffi cult to cross- of RBCs would be more transplant aspirants. allergic reactions. match donors. It prevents a severe graft RBCs are frozen at Patients are exposed versus host disease -60°C in a 40% glycerol to higher number solution, can be stored up to of donors, greater 10 years. risk of infections and alloantibodies. Cost is phenomenally high.
Transfusion Programs The volume and rate of blood transfusion depends on: • The patient’s age • Clinical status • Solutions added to preserve red blood cells. • The hematocrit of the donor’s RBCs. • Target level of hemoglobin There are various regimens for transfusing blood, but the best one is moderate as compared to hyper or super transfusion regimen.
37 The moderate regimen is:
• 15 – 20 ml/kg body weight of concentrated red blood cell is given to the patient. • Average time taken is 3-4 hours (unless patient has a lower hematocrit). • Transfusion is carried out every 2-4 weeks. • This regimen aims at maintaining Hb 9-10.5g/dl before transfusion, and < 15g/dl after transfusion. • A non-splenectomized patient requires 180 ml of pure red blood cells/kg/year, while a splenectomized one 133 ml/kg/year. • If cardiac problems are present or if Hb <5, slower rate of transfusion is adopted (2-3 ml/kg/hr).
Effi cacy of a transfusion regimen Rate of fall of hemoglobin should not exceed 1g/dl/week in a splenectomized patient, and not more than 1.5g/dl/week in a non-splenectomized patient. If Hb levels fall at a greater rate investigate the following: • Alloimmunization to RBCs. • Hypersplenism or hepatomegaly when requirement is > 200 ml/kg/year. • Transfused RBCs have a shorter life span. • Increased RBC destruction due to medicines like ribavarin. • Infections like malaria causing RBC destruction.
Outdoor transfusion services
In the past, a thalassemic child had to be admitted for blood transfusion alongside other sick children of the ward. Prolonged hospital stay, cross infections, increased cost, both to the parents and the institution as well as psychological trauma were the brunt of such therapy. With the advent of outdoor transfusion centers, transfusion can be well planned causing minimal psychological trauma to the child and parents as transfusion is given in a cordial compliant surrounding with other thalassemic children.
Advantages of outdoor thalassemia centers: • It has made the therapy more convenient and compliant as it can be planned on school holidays and on the day convenient for the parents. • Group therapy as a part of the intervention program has an important role and direct benefi cial impact on outcomes. • Parents exchange and share their experiences and feelings. • It can be used as a platform to spread information, current knowledge and for genetic counseling. • This has reduced cost to parents as well as to the institution. • Trained nurse/doctor in charge plans the transfusion therapy well in advance giving suffi cient time for proper testing, • Trained nurse is responsible for maintaining the vein - the lifeline of thalassemic children, for the proper use of fi lters and for training parents about the use of desferal pumps, etc. • This change in environment has made transfusion therapy a great success.
Summary In summary, transfusion therapy in thalassemia major should be intiated as soon as the diagnosis is fi rmly established. Baseline work-up should include screening for transfusion transmitted infections. Regarding the type of blood to be transfused, preferably leucocyte depleted (using leucocyte fi lters) packed red cells should be transfused. The amount to be transfused should not exceed 15 to 20 ml/kg administered at a rate of not > 5 ml/kg/hr. In presence of cardiac compromise, the rate of infusion should not exceed > 2 ml/kg/hr. Monitoring for adequacy of transfusions as well as transfusion related complications is mandatory. Outdoor centres should be encouraged as they off er great advantages to the patient and parents.
38 Optimal Monitoring in Thalassemia Antonio Piga, MD Centre for Hemoglobinopathies Dept. of Clinical and Biological Sciences, Torino University San Luigi Gonzaga University Hospital, Orbassano, Italy.
As thalassemia syndromes include a wide spectrum of genetic defects and phenotypes, optimal monitoring cannot be standardized but should follow an expert diagnosis of severity and fi t the individual needs. At onset a full genetic and clinical assessment are key in orienting diagnosis and prognosis, keeping in mind that these, also in genetic conditions, are not fi xed tags but processes. A trend to worsen is typical of moderate/severe forms of thalassemia intermedia. A constant level of hemoglobin is not enough to exclude this: early signs of physical alterations from ineff ective erythropoiesis must be monitored by regular medical images, physical exam and auxological assessment, to prevent irreversible bone deformities. Serum ferritin is a poor marker in predicting iron load in thalassemia intermedia; transferrin saturation and its trend to raise is more informative. In general to actively keep track and dynamically follow thalassemia markers is the best tool for secondary prevention.
The same accurate tracking is key in thalassemia major. How far the disease is inhibited, is given by how regularly an appropriate pre-transfusion hemoglobin is kept since onset. Comprehensive thalassemia- specifi c clinical records allow to store basic data and obtain dynamic monitoring of transfusional and iron indexes. This permits an accurate tuning of transfusion and chelation treatment and early diagnosis of hypersplenism. Management of chelation takes advantage from direct quantifi cation of liver and cardiac iron by non-invasive methods, where available and aff ordable. A yearly frequency may be modulated on the individual basis depending on age and risk factors. Preclinical detection of disease-related or iron- related complications (a long list!) requires skilled attention and specifi c tests. Promptness of diagnosis and treatment is especially important for hypogonadism, osteoporosis and masses of extramedullary erythropoiesis.
39 Combination Chelation Therapy Antonio Piga, MD Centre for Hemoglobinopathies Dept. of Clinical and Biological Sciences, Torino University San Luigi Gonzaga University Hospital, Orbassano, Italy.
Three drugs are worldwide available for iron chelation, deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX). In theory long term monotherapy using whichever of the three may be safe and eff ective, but in the clinical practice often a change of drug or a combination must be considered. The basic reason is the low effi ciency of iron chelators: 80-98% of the drug is excreted or metabolized without iron binding. This happens because even in severe iron overload, only a very small proportion of excess iron is available for chelation at any moment. Removal of iron overload is then a slow process even in the absence of transfusional iron loading. Combination therapy has the potential to fi ll this gap as there is evidence that chelators together do not compete for the same iron, but have an additional or, sometimes, synergistic eff ect. In the literature the term combination is used often improperly. To lower ambiguity the following terms should be applied: - Alternate therapy: in a single day a single chelator is taken; the two chelators take turn on a weekly, monthly or quarterly basis. - Combination therapy: prescription of more than one chelator, to be taken in the same day at least for a signifi cant part of the period. - Sequential: in a single day two chelators are taken in sequence, with no substantial overlapping of the two drugs in the plasma. - Simultaneous or concomitant: in a single day two chelators are taken at the same time, with substantial overlapping in the plasma.
Of many publications on combination, a few have a randomized controlled design, but evidence exists that combination, at least of DFO and DFP, is powerful and fast in lowering tissue iron, including heart iron. Interesting fi ndings are emerging for the combination of the two oral (DFP+DFX) and DFO+DFX. Even if growing evidence indicate that the safety profi le of combination is better than supposed in theory, this treatment should be deserved to expert doctors and applied to fully informed patients.
40 Optimal Chelation in the Current Era: Shifting Paradigm John B Porter Professor of Haematology, Unviversity College London. [email protected]
Chelation therapy optimally aims to prevent iron overload accumulating to levels where tissue damage can occur. With optimal treatment, the aim should be to achieve full sequential function and full growth potential without endocrine or cardiac damage. Far too often however treatment has to ‘rescue’ patients who have started too late, or who have received inadequate chelation doses or inadequate frequency of dosing (not the same thing). We have learned that once damage to some organs has developed that this is predominantly irreversible: this applies particularly to the endocrine system. Furthermore, while myocardial siderosis is slowly reversible, many patients who have shown reversible heart failure never the less have permanent damage to the heart with long-term arrhythmias. Recent data suggests that careful use of combined chelation regimes can help to decrease high levels of iron overload both in the liver. Careful monitoring is still required to avoid the risk from overchelation. This presentation will also discuss new theoretical and practical data about how chelators may be combined to maxiimise control of iron overload while minimising the risks of over chelation1. New combinations currently at the pre-clinical stage will also be discussed2
1. Vlachodimitropoulou, K, E., Garbowski, M., Porter, J.. 2015. Synergistic intracellular iron chelation combinations: mechanisms and conditions for optimizing iron mobilization. Br J Haematol, 6, 874-83 2. Vlachodimitropoulou, EK, Porter JB, Cooper, N. Psaila, B, Sola-Visner, M. 2015 A Potential Novel Application of Eltrombopag: A Combination Agent to Enhance Iron Chelation Therapy.. Blood.128,3 126.
41 Management of the Adult Thalassemic John B Porter Professor of Haematology, University College London.
In recent years, as life expectancy in well managed thalassaemia patients advances, there has been a shift in focus from preventing siderotic cardiomyopathy and endocrinopathy in paediatric patients, to optimizing life expectancy and quality of life in adults. The age distribution of Transfusion Dependent Thalassaemia (TDT) patients attending London clinics at UCLH and Whittington Hospitals increasingly shows an ‘aging’ population. At UCLH, the % of patients now >30yo is 60%, >40yo is 34% and >50yo is 9%. This ‘right shifted’ pattern refl ects (1) The Introduction desferrioxamine and deferiprone earlier in London than elsewhere (2) Cardiac CMR monitoring since 1999 (3) The provision of psychological support embedded in the clinic for >2 decades (4) New births have been largely prevented by prenatal screening and counseling. In a decade cohort analysis of 132 patients, the median age of death was 39.0y, the mortality rate 2.4 /1000 patient y with cardiac mortality no longer the leading cause of death. Endocrine complications were more common >40yo. Using a combined morbidity score, complications increased with age - more marked > 40yo (r=0.43; p=0.006) than<40yo (r=0.27; p=0.041). Above 40yo, impaired glucose tolerance is twice as common, non- insulin dependent diabetes 5 times, and insulin dependent diabetes about 1.5 times. Increasing issues are osteoporosis and back pain mainly due to accelerated intervertebral disc degeneration. Higher endocrine complications above 40yo likely refl ect delayed availability of adequate chelation in this cohort and relative lack of reversibility of endocrinopathy compared with cardiomyopathy. The picture in adults with thalassaemia today is therefore one of increasing success but of emerging issues in long term management of these patients.
42 New Drugs on the Horizon John B Porter Professor of Haematology, Unviversity College London. [email protected]
The management of thalassaemia in the past three decades has focused on issuing increasingly safe blood and on improving the monitoring and treatment of iron overload. Curative therapy with bone marrow transplantation has also become increasingly safe and is now off ered to a wider range of patients using haploidentical and Matched Unrelated Donor transplantation. Improvements in management with non- curative therapies are now on the horizon. Many of these aim to correct ineff ective erythropoiesis that leads to leading to anemia, bone marrow erythroid hyperplasia, iron overload in severe thalassaemia syndromes. The eff ectiveness of erythropoiesis can be improved by correcting globin chain imbalance through promoting HbF synthesis, such as with hydroxyurea or butyrates. This approach has achieved variable and often only modest hemoglobin increments. However new approaches to HbF promotion are under pre- clinical evaluation. Combination strategies, for example by using erythropoietin together with hydroxyurea, have shown encouraging hemoglobin increments and signifi cant improvements in Quality of Life (QoL). A novel approach to improving erythropoiesis is by restriction of transferrin mediated iron delivery to the erythron. This has been achieved in preclinical studies using Tmprss6 inhibition, hepcidin manipulation or apotransferrin infusion. Although these approaches have not been proven clinically they have potential to improve anaemia by modulating ineff ective erythropoiesis. Another approach is to manipulate Jak2. Inhibition of Jak2 corrects the proliferation/diff erentiation imbalance, decreases splenomegaly, and is under clinical trials in thalassaemias. Another novel approach to correcting IE which has now entered Phase III trials are the actin receptor traps1. These molecule include sotatercept and luspatercept both of which appear to inhibit TGF-β signaling in the bone marrow and act mainly by inhibiting GDF11 and decreasing apoptosis of late erythropoietic progenitors. Preliminary phase II fi ndings show hemoglobin increase of more than 1.5 g/dl in NTDT, and decreased transfusion requirement in transfusion-dependent thalassemia (TDT) of up to 50%, with an acceptable tolerability profi le.
1. Porter and Garbowski. Novel erythropoiesis stimulating agents in thalassemia. Hematology Education: the education program for the annual congress of the European Hematology Association. 2015;9:303-312
43 Management of Hepatitis B & C - Hope for Cure Anupam Sibal, Smita Malhotra, Ishaq Malik Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospitals, New Delhi
More than 360 million people are chronically infected by the hepatitis B virus (HBV). Following the WHO recommendation for HBV immunization in 1991 and blood-donor screening, the prevalence of HBV infection has declined, although a signifi cant number of children are still infected each year. After exposure, the risk of chronicity is higher for newborns (90%) than for adolescents or adults (<5%). Vaccination is the most eff ective measure to prevent transmission, inducing seroprotective response (anti-HBs >10 mIU/ ml) in about 95% of subjects, with three doses. Counseling of HBV carriers and vaccination of uninfected household members are essential for reducing risk of horizontal intrafamilial transmission. Taiwan is a shining example of a country where hepatitis B vaccination has reduced the incidence of liver cancer and liver disease related deaths signifi cantly.
The goal of anti-HBV therapy in children as in adults is to improve long-term survival and quality of life by reducing the risk of progressive liver disease, cirrhosis, and liver cancer. For all patients, the ideal end point of treatment is sustained HBsAg clearance but anti-HBe seroconversion in originally HBeAg-positive patients is a good end point. Antivirals should be considered for children with elevated serum ALT levels for at least 6 months. Existing therapies for chronic hepatitis B in children are IFN-α-2b (for children ≥ 1 year), lamivudine, entecavir (for children ≥ 2 years), adefovir, tenofovir (≥ 12 years). Resistance particularly with lamivudine and adefovir pose a signifi cant problem for monotherapy. It is hoped that in the near future, better drug therapy will help achieve a cure.
Hepatitis C virus (HCV) aff ects >180 million individuals worldwide with a high propensity for chronic infection. Vertical transmission is the most common route of acquiring HCV in infants and children. At one time, HCV infection accounted for the majority of transfusion-associated hepatitis, but presently the risk is decreasing due to introduction of mandatory HCV testing. Pediatric HCV infection is characterized by high rate of spontaneous clearance, asymptomatic clinical course and no or only mild fi brosis. Cirrhosis develops in 1–2% in the pediatric age group and progression to severe disease and liver cancer occurs at least 20–30 years after infection. In children with vertically acquired HCV, 25–40% show ALT normalization and loss of HCV-RNA by the age of 2–3 years. In children infected via the parenteral route, HCV-RNA clearance is variable. Since novel, highly eff ective, all-oral treatment options with relatively few side eff ects and short duration of therapy are expected in the foreseeable future, a conservative approach is urged and treatment should be limited only to those children with a more active disease.
Existing therapies for chronic hepatitis C in children are PEG-IFN α-2a (for children ≥ 5 years at weekly subcutaneous injection), PEG-IFN α-2b (for children ≥ 3 years) in combination with ribavirin (in the dosage of 15 mg/kg/day in two divided doses). They have cure rate between 50-90 % depending on genotype and viral load. For genotype 2 and 3 treatment is given for 12 weeks and for type 1 & 4, 24 weeks. Oral DAAs like sofosbuvir, ledispavir and daclatasavir are approved for above 17 years of age. These drugs should soon become available for use in children and will off er hope for a cure.
44 Endocrine complications of Thalassemia Heba Elsedfy
Thalassemic children are living longer due to better care. Endocrine abnormalities develop mainly in those patients with signifi cant iron overload due to poor compliance to treatment, particularly after the age of 10 years. Growth retardation is commonly reported. Children are short, have low rate of growth and have either delayed or absent pubertal spurt. Key contributing factors include chronic anemia, transfusion-related iron overload and chelation toxicity. Other contributing factors include defective growth hormone-insulin- like growth factor-I axis, hypothyroidism, hypogonadism, diabetes, zinc defi ciency, chronic liver disease, undernutrition and psychosocial stress. Patients’ growth should be assessed every 6 months. Management consists of optimizing blood transfusion, improving nutrition with high caloric balanced diet and zinc, vitamin D, calcium and folic acid, supplementations; optimizing iron chelation. Also, early diagnosis and treatment of endocrinopathies and induction of puberty at a proper time are essentials. Growth hormone defi ciency is evaluated after the exclusion of other causes of short stature. Delayed puberty and hypogonadism are the most frequent endocrine complications. Delayed puberty is defi ned as the complete lack of pubertal development in girls by the age of 13 years, and in boys by the age of 14 years. Arrested puberty is a relatively common complication in iron overloaded patients. This is characterised by the lack of pubertal progression over a year or longer. Hypogonadism is defi ned in boys by the absence of testicular enlargement, and in girls by the absence of breast development by the age of 16 years. Hypogonadotropic hypogonadism is due to damage from iron deposition in the hypothalamus and pituitary gland but occasionally primary gonadal failure can also occur. Most adolescent females present with primary amenorrhea, whereas secondary amenorrhea will invariably develop with time especially in patients poorly compliant to chelation therapy. Ovarian function is normal as they produce the expected number of ova after stimulation therapy. Damage of the ovaries by iron deposition is rarer and is more likely to appear in women of 25-30 years of age because of high vascular activity in the ovaries at this age. Treatment of delayed puberty should mimic biological and biochemical pubertal changes, aiming at promotion of linear growth as well. Skeletal changes in untreated thalassaemia are unusual before 6 months of age. Increased haematopoiesis causes bone marrow expansion destroying the medullary trabeculae. Hypertransfusion reduces the extent of marrow expansion. However, iron overload and hyperuricaemia are potential consequences of repeated blood transfusions. High serum iron levels are associated with abnormalities of the synovium and articular cartilage. Skeletal dysplasia was observed in some patients receiving defrerrioxamine. Osteopenia and osteoporosis represent prominent causes of morbidity in children and adults. Despite normalization of hemoglobin levels, adequate hormone replacement, and eff ective iron chelation therapy, patients continue to show an unbalanced bone turnover. Therapies to stimulate bone anabolism as physical activity, growth hormone and/or nutritional interventions may be warranted in the younger patient. For older patients with signifi cant endocrinopathies, the primary defect may be an increase in bone resorption; for these individuals treatment with anti-catabolic agents such as bisphosphonates may be appropriate.
45 TIC-TOC 6th International Thalassaemia Conference Amna Abdel-Gadir
Most thalassemia patients at risk of iron overload live in countries with limited treatment and investigative resources. Cardiac iron can lead to death, and diagnosis can only be reliably made using the MRI T2* technique, but this is perceived as expensive and time consuming. An alternative measure, T1, has recently shown promise as a complimentary tool to T2* due to the potential of earlier detection of iron deposition. T2* and T1 values can be obtained from parametric maps thus allowing fast scanning and instant recognition of iron loading without the need for complex post-processing.
We assessed the feasibility of ultrafast MRI in the developing world in a single center study in a government hospital in Bangkok, Thailand, utilizing an ultrafast MRI heart and liver mapping (T2* and T1) protocol. 100 thalassemia patients and 11 controls were recruited.
123 scans were performed in total and scan duration was 8.3±2.4 minutes - a fi ve-fold reduction compared with the typical 30-45 minutes. Analysis was completed within 1 minute of last image acquisition. Unrecognized myocardial iron was diagnosed in 15 (15%) of patients, and no patients had LV impairment. 96(99%) patients had liver iron by T2* of which almost half were severe. Myocardial T1 mapping strongly correlated with T2* (r2=0.81, p<0.0001), but an additional 30 patients with normal myocardial T2* had low T1 suggesting mild missed iron. Serum ferritin levels, commonly used as a measure of organ deposition, correlated poorly with myocardial and liver iron by T2* and T1 mapping measurements. In conclusion, iron quantifi cation by ultrafast MRI in the developing world using mapping is possible with important diagnostic yield and implications for future mass access to quantitative iron load measurement.
46 Stem Cell transplant in Thalassemia: Options & Dilemmas Mammen Chandy Director, Tata Medical Center, Kolkata
Haematopoietic Stem Cell Transplantation (HSCT) today off ers an alternative to life long transfusion and chelation for patients with thalassemia major. In December 1981 the fi rst allogeneic bone marrow transplant for thalassemia major was performed in Seattle. That patient is now alive and well 35 years post transplant. The team at Pesaro in Italy under the leadership of Professor Guido Lucarelli has since shown with 1003 patients that bone marrow transplantation is in fact a good alternative to transfusion chelation for thalassemia. However the procedure is associated with risk of infection, regimen related toxicity, graft versus host disease and relapse particularly in those patient who because of inadequate treatment and poor chelation have developed hepatomegaly and hepatic fi brosis. The team in Pesaro have developed a risk stratifi cation based on these three criteria : Class I: well chelated, no hepatomegaly, no hepatic fi brosis Class II: one to two adverse risk factor Class III: all three adverse risk factors
Data from Pesaro in Italy show that there is a 90% chance of disease free survival post transplant in patients who are in Class I, 85% in Class II and only 65% in Class III. The decision that a family with a child with thalassemia has to make if there is a histocompatible sibling who can serve as the donor is whether they should continue transfusion chelation with its low present risk but signifi cant late morbidity or have a transplant with its immediate risk but high probability of good quality life without the burden of life long transfusion and chelation. Transfusion and chelation can provide a near normal life expectancy in those children who remain compliant with the therapy. Therefore there is little doubt that this is a time-tested form of treatment with little immediate risk. The diffi culty is that it has to be continued life long and is expensive and sometimes the child becomes non- compliant with the chelation later in life. In a country like India the economic advantage of a bone marrow transplant for thalassemia is compelling because many families can manage a one-time investment of RS 8-12 lakhs but a life long expenditure of RS 1-2 lakhs a year is a diffi cult proposition. The question of whether to wait for gene therapy or accept the current risk of transplantation is a diffi cult one since there is some progress in this area. Once the decision to have a bone marrow transplant has been made then the next step is to perform HLA typing on the patient and sibling. If there are no matched siblings who can serve as a donor then the following alternative donors can be considered: • Cord Blood • Matched Unrelated Donors from registries • Half matched donors: sibling or parent If the parents are planning another baby then cord blood can be collected and stored: if the patient and the next baby are HLA matched, when the baby is two years old bone marrow and the stored cord blood can be used for transplantation. Matched unrelated cord blood transplants have a higher risk of rejection. With the availability of large numbers of HLA typed donors in international registries, it is possible to fi nd matched unrelated donors for patients with thalassaemia. Currently these transplants should be done only if there is a 10/10 match: there is a higher risk compared to sibling matched related transplantation. Some centers are off ering half matched transplants for thalassaemia: this must be considered experimental for the present till such time as more data is available.
47 Blood Adequacy and Safety Poonam Shrivastava
Blood transfusion is a unique scientifi c technique considered to be the ‘most frequently done transplant’ in medical practice. It is a life saving measure. No hospital can work eff ectively without blood. As per WHO, the goal of blood transfusion services is to ensure that the blood components for clinical use are safe, accessible, adequate to meet demand, eff ective and produced consistently to the appropriate standards.
Quality and safety of blood and blood products is governed by national blood policy and legislative framework to maintain uniform standard. There is marked diff erence in accessibility and adequacy of blood between low and high- income countries. Only 73 % countries (122/167) have national blood policy and 65% (108/167) have specifi c legislation covering safety and quality of blood transfusion1.
Globally approximately 112.5 million units of blood units are collected through 13000 blood centres in 176 countries1. Only 38% is collected in developing world where 82% of world’s population live.
Whole blood donation rate is an indicator for general availability of blood in a country. The blood donation rate in high- income countries is 33.1 donations per 1000 people, 11.7 in middle and 4.6 in low- income countries1.
Non remunerated regular voluntary blood donors are the safest donors . Without a system based on these altruistic donors, no country can provide suffi cient safe blood to all the patients who require transfusion. 74 countries collect over 90% of their blood supply from voluntary, unpaid donors whereas 72 countries collect more than 50% of their supply from family replacement donors1.
Blood can be used more eff ectively if it is processed into components. Percentage of blood separated into components is 96% in high-income,78% in middle and 43% in low-income countries.
All these factors contribute to scarcity of blood in low income countries. Lack of access to safe blood is a major cause of maternal mortality in developing countries.
In India, access to safe blood is mandated by law and is primary responsibility of Government. National Blood Policy was adopted in 2002. National Blood Transfusion Council is the policy formulating apex body and co-ordinates with State Blood Transfusion Councils. Drug control Department ensures licensing of blood banks. The specifi c objective of the India’s blood safety programme is to ensure reduction in the transfusion associated HIV transmission to 0.5% while making available safe and quality blood within one hour of requirement in a health facility2.
India requires 12 million blood units. In Fy2015-16, total blood collection was 10,900,013 units 2 through app 2760 blood banks of which 76% were from voluntary blood donors. The gap is not so much absolute and it is related to distribution ineffi ciency and inequitable access across all parts of the country.3 India is a vast country with diverse ethnic population having disintegrated blood transfusion services (BTS) Some are very advanced effi cient and world class whereas others are rudimentary.
Access to safe blood continues to be limited especially in rural areas in states like UP, Uttarakhand, Jharkhand, Bihar and Chhattisgarh.
Key strategies of Blood Safety programme The Govt is committed to implement comprehensive approach towards strengthening BTS through -
48 • Promotion of repeat regular voluntary blood donations and the target is to achieve 100% voluntary donations by 2020. • Promotion of blood component preparation, rational use of blood and building capacity of health care providers. • Enhancing blood access through a well networked, regionally co-ordinated BTS • Establishing Quality Management System to ensure safe and quality blood • Building implementation structures and referral linkages.
In August 2015, NBTC circulated Policy guidelines for setting up new blood banks and Regional Blood Transfusion Centres, transfer of blood units between blood banks and approval of exchange value of excess plasma for fractionation.
E- Blood Banking project has been rolled out and 2711 of 2760 (98.22%) blood Banks across the country are enrolled on digital platform of National Health Portal (NHP) Through the app anyone can know the availability of required blood components in the nearby blood banks.
The blood safety has improved. HIV sero reactivity (the prevalence of HIV in donated blood) declined from 1.2% to 0.2% between 2007 and 20143. But this is not enough and needs further improvements. From the moment of deciding for blood transfusion for a patient to actually starting blood transfusion there are several steps and procedures, conducted at diff erent places by diff erent persons involved in the transfusion chain. Error at any point may put the recipient’s life in danger. Most of errors are clerical or managerial. Standard procedures have to be laid down and followed strictly to minimise errors and improve safety as “excellence is doing ordinary things extraordinarily well.”
Recruiting low risk donors, trained and competent staff , good laboratory practices, compliance to SOPs in TTI lab, Component preparation, blood storage, compatibility tests, blood issue and transportation, cold chain, appropriate clinical use of blood and good bedside practices for giving transfusion are necessary.
New developments for safer blood There have been various technological advancements in Transfusion Medicine with a focus on safety and providing best quality safer than ever blood components.
NAT for screening of donated blood (HIV, HBV and HCV)
NAT reduces the window period and detects the infection much earlier than routine serology tests. Many blood banks in India have adopted NAT and reported high NAT yields. Using NAT tested blood components can reduce high rates of TTIs in multi-transfused patients.
Leucodepletion of blood components helps in preventing FNHTR, alloimmunisation and transmission of CMV.
Immunohematology • Screening of donors and recipients for unexpected alloantibodies is required to prevent hemolytic transfusion reactions due to allo immunization. • Rh Kell phenotyping • Molecular testing,
Automation in TTI testing and blood grouping Irradiation, Pathogen Inactivation Quality assessments NABH accreditation
49 External Quality Assessment Scheme, Blood bank software and bar coding National Haemovigilance – A voluntary programme by National Institute of Biologicals
A number of blood banks have adopted most of these p ractices but there is scope for further improvement. Blood bank staff needs to be trained in performing basic procedures like correct blood grouping methods, Coomb’s tests and routine problem solving. There is need to have screening and panel cells and rare anti- sera and advanced reference labs for solving diffi cult crosshatching cases. Another area requiring attention is non-functional basic equipments -centrifuge machine, incubators and water baths, which need repair or replacement.
Guidelines for selection of blood components for patients requiring regular transfusion e.g Thallassemia need to be framed and implemented at the earliest. BCSH guidelines for Thallassemics state that- • The patient’s red cells should be phenotyped as fully as possible prior to starting transfusion. • Where patients have already been transfused, the genotype can be determined. • An extended phenotype (or genotype) should include C, c, E, e, K, k, Jka, Jkb, Fya, Fyb, S, s. • Transfused with ABO and Rh(D) compatible blood • As a minimum, red cells should be matched for Rh and K antigens. Blood transfusion is life saving but in spite of taking all precautionary measures may cause acute or delayed complications and has risk of transmitting infections. Approximately 5 - 10% of HIV infections are transmitted worldwide through infected blood /blood components. “An investment in safe and adequate supplies of blood is a cost eff ective investment in the health and economic wealth of every nation”
References 1. WHO; Blood safety and availability; Fact sheet; Updated July 2016 2. www.naco.gov.in/upload/blood%20safety/BTS accessed on 22.08.2016 3. Blood transfusion services of India; by Dr Shobhini Rajan: Bloodline The voluntary Blood Donation Journal; 2015:36;pg1
50 Fertility and Pregnancy in Thalassemia Sanjivni Khanna
I’m coming your way Just wait and pray! I won’t be a strain I won’t cause much pain I want to be in your arms Being your’s I’ll have charms!
An increasing number of women and men with thalassemia have planned and started healthy families of their own in the recent years. This refl ects on improvements in the basic care of thalassemics with optimal blood transfusion and chelation therapy, and thereby, an improved survival into adulthood.
In a couple, with either partner a thalassemic, evaluation of the other partner for haemoglobinopathy is essential. A woman with thalassemia minor and an unaff ected partner, has a good outcome. Women with thalassemia minor tolerate pregnancy well, though their haemoglobin tends to be lower than in the general population. It is important to note that iron defi ciency may co-exist with thalassemia trait during pregnancy and iron supplementation would be advisable in such cases. There maybe higher chances of fetal growth restriction, decreased amniotic fl uid around the fetus and delivery by caesarean section.
If the partner of a woman with thalassemia minor is aff ected by a haemoglobinopathy, genetic counseling will be in order.
The spectrum of thalassemia intermedia(TI) varies from mild to severe forms and the management depends on a thorough assessment of the lady. Testing the partner is essential. Women with TI are usually fertile. They, however, run a risk of thrombosis. Blood transfusions maybe required during pregnancy. Multispecialty teams join hands to manage such cases.
The ability to achieve, and the chances of successfully carrying a pregnancy and delivering a healthy baby in women with thalassemia major (TM) is a challenging task, and an area which needs special care. Needless to say that multispecialty team management is the basic premise in the management of such cases. Partner evaluation is mandated. 80-90% patients with TM have decreased fertility, which is caused by iron deposition in the pituitary gland resulting in a decreased production of gonadotrophin (FSH/LH) hormones. This results in low sex hormone (estrogen/testosterone) production from gonads (ovary/testes). Sexual development is adversely aff ected and the woman may not be having monthly periods. However, the positive side is, that the function of ovaries/testes is usually intact and can be saved. In other words, the ovaries/testes can be made to function.
Other endocrine disturbances such as diabetes and hypothyroidism may be present and need attention. Planned pregnancy is strongly advised. Induction of ovulation maybe carried out. Induction of spermatogenesis is also possible. In-vitro fertilization maybe required.
If both partners are TM, use of donor gametes, usually sperm, is advisable.
If the partner of a TM lady is heterozygous, pregnancy can be planned with advice on the need for prenatal fetal testing and, to proceed accordingly. The procedures, any of which maybe required include CVS, amniocentesis and cordocentesis if TM woman’s partner is thalassemia minor. Pre-implantation genetic diagnosis is another option if partner is heterozygous. Adoption may be advised in some cases.
51 Aggressive preconceptional chelation is needed in TM and some TI women. No chelation is carried out in the fi rst three months of pregnancy, as it may cause fetal abnormalities. Chelation is avoided in the later months also, however, if necessitated, desferrioxamine is the only agent which may be used.
Preconceptionally, the woman’s cardiac status is vital to assess. Thyroid, liver, pancreas and bones should receive due attention. Red-cell antibodies, HBsAg and HCV status have to be checked. Folic acid should be started. Vitamin D and calcium may need to be supplemented. Bisphosphonates have to be stopped 6 months in advance of a pregnancy.
During pregnancy, regular checkups, ultrasound examinations, cardiac, diabetic and thyroid follow-up is done. Transfusions are given to maintain pretransfusion haemoglobin of 10g/dL during pregnancy.
Pregnancy does not alter the natural history of thalassemia major. There is no increased risk of fetal malformations. There is however a two-fold risk of fetal growth restriction and preterm labour. There is also a risk of vertical transmission of viruses and of iso-immunisation.
Antenatal thromboprophylaxis is provided according to recommendations. Desferrioxamine infusion is given for the duration of labour.
Timing and method of delivery is as per obstetric needs. Spontaneous onset of labour can be awaited if there are no pregnancy-specifi c complications. If the case is complicated by diabetes mellitus or cardiac disease, an earlier delivery may be preferred. Continuous electronic fetal heart monitoring is instituted. Active management of placental delivery(third stage of labour) is conducted to reduce blood loss. Thalassemia by itself is not an indication for caesarean section(CS), however, approximately 80% women require CS due to disproportion between baby and pelvic sizes. Babies are usually normal in size but the mother with TM may have a short stature and skeletal deformities. Epidural anaesthesia is preferred over general anaesthesia for caesarean sections as the patient may be at risk of diffi cult intubation on account of maxillo-facial deformity. Spinal anaesthesia may prove diffi cult if there is osteoporosis with reduced heights of vertebral bodies and also if there is scoliosis.
Postpartum thromboprophylaxis is important. Low molecular weight heparin is given for 7 days after discharge following a normal vaginal delivery and for 6 weeks following a CS. Breast feeding is safe and should be encouraged unless the woman is HIV/HCV RNA and/or HBsAg positive because of risk of vertical transmission via breast milk. It is important to continue calcium and vitamin D supplements during breastfeeding. Bisphosphonate therapy for osteoporosis should only be begun after stopping breastfeeding.
Contraceptive options include barrier methods or progestin-only pills. It is advisable to avoid estrogen containing pills and intrauterine devices.
Family support is vital in addition to medical care. There is no substitute for t ender loving care.
52 Management Non Transfusion Dependent Thalassemia V P Choudhry MD FIAP, FIMSA, FIACM, FISHTHM Sr. Consultant, Hematology Batra Hospital & Medical Research Centre, New Delhi Fortis Escort, Faridabad
Thalassemias constitute wide range of disorders with varied clinical presentation depending upon the mutation on α or β globin chain involved along with other inherited alleles and polymorphic gene modifi ers. Over the last two- three decades a thalassemia state in which course is mild & does not require regular blood transfusion has been well recognised and has been termed as non transfusion dependent thalassemia (NTDT). The disorders which have been included in NTDT are (a) β thalassemia intermedia ( α or β ) (b) Hb EB – thalassemia (c) hemoglobin S β thalassemia (d) Hemoglobin H disease (e) Hb C disease etc. The clinical presentation of children with NTDT is quite varied and often diagnosis of NTDT is established in 2nd or 3rd decade of life. The course is so variable because of various genetic factors such as (a) Primary modifi ers – which are dependent on gene mutation which determines the amount of β-globin production e) Secondary modifi ers i.e. degree of α – β chain imbalance along with compensatory HbF levels & c) Tertiary modifi ers like, iron overload, bilirubin level and presence of complications. Management of NTDT is highly individualized as the clinical presentation course & occurrence of complications are variable i) The major objective of management include to ensure normal growth & development, ii) early detection of complications & their management.
Hydroxyurea Treatment Since, the clinical presentation & course of the disease is dependent upon the imbalance between β vs non β globin chains. Eff orts have been made to increase the foetal hemoglobin to reduce the imbalance and to ameliorate the clinical course & complications of the disease. Several drugs like Azacytidine, Decitabine, Butyrate, Erythropoietin and hydroxy urea have been used to induce foetal Hb. Among these agents hydroxyurea has been observed to the more cost eff ective & safe agent. Hydroxyurea not only increases Hb F level but also augments the β globin gene & have been found to eff ective in a) delta β thalassemia b) β thalassemia intermedia with high Hb F levels along with xmn polymorphisim and (c) allo immunized individuals requiring frequent blood transfusion. This drug has also been found to be eff ective in NTDT patients associated with complications like a) hypercoagulability b) pulmonary hypertension c) leg ulcers & d) extra medullary hematopoiesis. This drugs need to be monitored for its adverse eff ects. Prolonged use of this drug is indicated in those who are benefi tted with this therapy. Transfusion therapy in NTDT is indicated in presence of a) severe anemia (Hb < 5 gm/dl), b) condition of stress much as surgery, infections etc c) during pregnancy d) children with growth failure e) lack of pubertal development in girls by 13 years in boys by 14 years of age. Patients with extramedullary hematopoiesis, thrombotic or cerebrovascular disease, pulmonary hypertension and persistent severe anemia will require regular transfusion therapy like patient with thalassemia major. Chelation therapy should be initiated once serum. ferritin exceeds 800 ng/ml. Serum ferritin below 500 ng/ml & liver iron content below 5 mg /gm of dry weight of liver should be maintained. Patient need to the monitored closely by serum ferritin & MRI T2* studies. Oral iron chelation dose should be so adjusted to meet the above objectives.
Spleenectomy Patient of NTDT often develop massive splenomegaly which often results in a) poor growth & development b) increased blood transfusion c) hyperplenism. These patient need to undergo spleenectomy. These patient require prolonged penicillin prophylaxis and should be closely monitored for early detection & management of complication like a) pulmonary hypertension b) extramedullary hematopoesis c) thrombosis, d) cholelithiasis e) osteoporosis etc. Some patient over years behave like thalassemia major & these should be managed like thalassemia major. Bone marrow transplantation should be considered in such cases to off er permanent cure if HLA matched donor is available.
53 Role of MRI in Optimal Management of Thalassemia Harsh Mahajan
Developments in the life-sustaining transfusion procedures and iron chelation therapy for the treatment of thalassemia have greatly improved the quality of life of thalassemia patients and increased their life expectancy. Despite this, iron accumulation in multiple organs still remains the major complication in these patients and the primary cause of morbidity and mortality. With liver and heart being the most susceptible organs to iron buildup, eff ective management of the disease, besides the therapeutic approaches, also involves longitudinal monitoring of the iron levels in the body which might be of great value in taking timely actions to prevent the failure of normal functioning of the organs. Conventional methods to evaluate the iron levels in the body include laboratory measurements of serum ferritin and liver biopsy, however, they come with their own limitations. Invasive nature of these techniques makes it not suitable for recurrent monitoring, and blood iron levels and liver iron content does not ideally refl ect or correlate with the cardiac buildup making it diffi cult to assess the risk of cardiac failure from these measures.
Recent advances in imaging, especially in the fi eld of Magnetic Resonance Imaging (MRI) have greatly augmented the utility of imaging in thalassemia and provides a non-invasive and organ specifi c evaluation alternative to address the limitations of the conventional methods.
T2* MR imaging is increasingly being used to evaluate the liver and cardiac iron load, by utilizing the local magnetic fi eld disturbances induced by the hemosiderin molecules in iron. Greater the iron content, greater are the magnetic fi eld disturbances resulting in faster MR signal decay. T2* decay rates of tissues can be measured quantitatively and are proportional to the tissue iron concentration allowing for a non-invasive evaluation of iron accumulation in the organs.
T2* imaging, being a non-invasive technique has become a important tool in the armamentarium of clinicians in evaluating tissue specifi c iron measures and has made frequent surveillance of iron burden in the liver and heart a possibility. This has led to improved management of therapeutic approaches to prevent potential iron accumulation related complications from occurring, thereby improving the quality of life of thalassemia patients.
54 Gene therapy for thalassemia: Are we there yet? Philippe Leboulch University of Paris 11 and CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Fontenay-aux-Roses, France; Harvard Medical School and Brigham & Women’s Hospital, Boston, MA, USA.; Mahidol University and Ramathibodi Hospital, Bangkok, Thailand
The β-hemoglobinopathies (beta-thalassemia and sickle cell disease) are the most prevalent inherited disorders worldwide and aff ect millions. Patients with betathalassemia major cannot survive without monthly, lifelong transfusions together with iron chelation therapy, and severe cases of sickle cell disease suff er from multiple life-threatening complications. Both categories of patients often have a shortened life expectancy in spite of supportive therapies, which impose an enormous fi nancial burden on aff ected countries. The only available curative therapy is allogeneic hematopoietic stem cell transplantation, although most patients do not have an HLAmatched sibling donor, and those who do still risk graft rejection or graft-versus-host disease with associated morbidity and early mortality. This is why autologous gene therapy, by ex vivo transfer into the patient’s own hematopoietic stem cells of a derivative of the normal β-globin gene whose expression is appropriately regulated, is an attractive novel therapeutic modality. In addition, the very large number of known mutations causing beta-thalassemia makes gene therapy by gene addition ideally suited for regulatory product approval rather than the many mutation-specifi c products that would be required for site-specifi c gene correction. However, gene therapy of these disorders is especially challenging given the requirement for massive hemoglobin production in a lineage specifi c manner and the lack of selective advantage for corrected hematopoietic stem cells. During the past two decades, we and others have devised lentiviral vectors and applicable protocols to achieve the permanent correction of mouse models of the beta-hemoglobinopathies. The fi rst approved human clinical trial worldwide resulted in the conversion to transfusionindependence of a patient with severe βE/β0-thalassemia, who required monthly transfusions since early childhood (Nature 2010). This patient demonstrated prolonged transfusion-independent for ≈ 9 years years after gene therapy, and the originally identifi ed partially dominant integration site (HMGA2) is no longer preeminent. A further optimized vector with high-grade purifi cation is now being used in subsequent multi-center clinical trials in the USA, France, Australia, and Thailand both for beta-thalassemia major and severe sickle cell disease. As of the last public disclosure, ≈ 40 subjects have been enrolled, of whom approximately half have undergone the gene therapy procedure. Currently analysable patients with betathalassemia major have rapidly decreased their transfusional needs or become completely transfusion- independent, with polyclonal distribution of vector bearing progenitors. With regard to the fi rst analysable patient with sickle cell disease, the anti-sickling globin variant utilized in the vector (βT87Q) is expressed at ≈ 50% level of all hemoglobin chains – a level well above the expected sickling inhibitory threshold - resulting in the correction in disease-specifi c biological markers and no hospitalization for sickle cell complications or acute episode despite weaning off transfusions, which this patient was receiving regularly for 6 years before gene therapy. Prospects for bringing this novel therapeutic approach to medical practice and for complementary approaches to increase safety and effi cacy will be discussed.
55 Pulmonary Hypertension in Thalassaemia: New Methods and Insights Emmanuel Ako United Kingdom
Haemoglobinopathies, including thalassemia, have been recognised as one of the most common causes of Pulmonary Hypertension (PH) worldwide. The pathophysiology is multifactorial, characterised by chronic haemolysis, loss of splenic function (splenectomy), hypercoagulability, vascular infl ammation, liver dysfunction, hypoxaemia, iron overload, left ventricular dysfunction and increased cardiac output. PH in thalassemia is a complex disorder that is not only prevalent but usually ignored or overlooked by general cardiovascular physicians. Screening for PH should therefore be an essential component of a patient’s assessment and care. Non-invasive techniques such as echocardiography are widely available and play a key role in surveillance for cardiovascular complications. Tricuspid Regurgitant Jet (TRJ), in particular trends, is very important in assessing the individual patient. New rapid scanning techniques in Cardiac MR are also being developed. Septal curvature ratio (SCR), is a recently validated measurement that strongly correlates with pulmonary artery systolic pressure, thereby allowing for a complete assessment. An eff ective transfusion and chelation therapy restore tissue oxygen delivery and prevents haemolysis, and therefore theoretically have an important role in prevention and treatment of PH. This is important given randomised control studies looking at PAH-specifi c medications have been disappointing in haemoglobinopathy patients.
PH in patients with haemoglobinopathies, although frequently overlooked, presents a challenging clinical dilemma with signifi cant prognostic implications and requires a particular management with disease- specifi c measures that may prevent its development.
56 Employment Challenges Somdutta Sarkar
• Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. • Importance of Employment for Thalassemics – supplements the idea of living ‘a normal life’, social inclusion, fi nancial stability, productivity leads to fulfi llment, improved quality of life. In the United States, the cost and availability of healthcare is partially or completely covered by employers, while Canadians with thalassemia benefi t from governmental insurance plans. • Physical challenges to regular 9-to-5 employment - transfusions, chelation, medical complications & co-morbidities (including cardiac, respiratory, endocrine, and skeleto-muscular), requirement of medical leaves/ off days, inability to perform physically strenuous jobs, occasional limitations in full and free life activity participation, chronic fatigue, etc. • Social challenges – lack of proper legislation, lack of well-defi ned rights or uniform fair employment practices, strict medical assessments for job entrances but confl icting medical opinions about results, crude categorization with disorders like HIV-AIDs or hepatitis, diff erences in approach among organizations, discriminatory or exclusionary health policies, misconceptions & prejudice, etc. • Disclosure – yes or no/ pros and cons. Consider: Thalassemia-minor carriers do not face problems because their reports do not show any blood disorder. Thalassemia-major patients are capable of doing most jobs depending on person-to-person physical capacity, but are discriminated against regularly. Job hunting can be frustrating. • Present Condition in India – As opposed to better practices in developed countries with stricter implementation of Equal Employment Opportunities or social security benefi ts, many kinds of disabilities in India fall into a grey area. So far, disability legislations like The Persons with Disabilities (Equal Opportunities, Protection of Right and full Participation) Act 1995, the National Trust Act 1999, the Mental Health Act 1987, and Rehabilitation Council of India Act 1986 have focused solely on ‘visible disabilities’, ie. locomotor impairments, sensory impairments, developmental disabilities, and psychiatric illnesses. People with chronic/genetic/rare disorders experience disabling limitations but remain outside the purview and protection of disability legislations. The Rights of Persons with Disabilities Bill 2014 is a silver lining in the cloud with proposed guarantees of basic human rights such as equality and non-discrimination, participation and inclusion in community life, inclusive education, non-discrimination in employment, equal opportunity policy, social security and healthcare, special provisions and reservations, as well as accessibility for persons with disabilities including thalassemia. Article 19 (1) states, importantly, no establishment shall discriminate against any person with disability in any matter relating to employment. It cannot be foretold how much the bill will actually contribute to the inclusion and employability of thalassemics in India, but it is the fi rst concrete step taken towards recognizing thalassemia as a disability and extending the deserved entitlements to those living with this condition, and it can only ease the challenges faced by them to an extent. • There is presently no formal data available on the prevalence of employment and education diffi culties for people with thalassemia. What factors might contribute to success or diffi culties in these areas have not been studied. However…
57 • Recent Study on Education and Employment Status of Children and Adults with Thalassemia in North America (2011) - Individuals with thalassemia in North America can achieve higher education, although full-time employment remains a problem. Seventy percent of adults were employed of which 67% reported working full-time. Adults with thalassemia in North America attain higher education compared to the general U.S. population. Whereas the employment rate for adults with thalassemia was comparable to the general U.S. population, the full-time employment rate was somewhat lower. The positive relationship between regular chelation and employment rates in transfused adults may be due to improved health and a reduction in complications compared to patients who were not chelating regularly. Alternatively, these patients may be more motivated in general, as evidenced by their ability to adhere to regular chelation therapy. Regardless, eff ective chelation requires discipline and commitment, two qualities for which employers look. • Conclusion – Need of awareness, social support, clear legislation, equal opportunities and self-confi dence. “We may encounter many defeats but we must not be defeated.” (Maya Angelou)
58 Finding a Life Partner Rahul Balasaria
Every person in his journey of life and the pursuit to live a fulfi lling one, desires to have achieved various milestones as he progresses. One of them is fi nding a life partner. From the time a person fi rst starts to understand the notion of love and marriage, he/she starts to imagine about their future husband/wife. These notions and ideas keep changing as they pass through various phases of life and as their prism to look at the world changes. For growing adolescent and as young adults these are sometimes the most confusing and sometimes the most exciting times of the life. Confusing, since each encounter with a diff erent person leaves them with choices which are either hard or may seem like a dream. Exciting, as for some it might seem like they have got the partner of their dreams. In either case, it may not be the end, as life has a habit of throwing surprises especially in the growing up years.
For a normal individual this journey is somewhat still manageable as they somehow fi nd their way through all these challenges. They eventually fall in love with a school friend, a college friend or a co-worker or possibly anywhere. In India, there’s another option where traditionally the family or relatives pitch in with help and arrange for a suitable life partner based on their experience and mutual trust between the families of groom and the bride.
Life for thalassemic in most cases is not that simple and there are various challenges that they face in addition to the normal challenges faced by any growing individual especially when it comes to marriage or fi nding a life partner. Apart from the physical problems posed by the disease itself there are psychological factors such as self-esteem barriers, inferiority complex, confi dence and others that play their role in keeping them away from living their full social life. Although with the full support of the families and the doctors they are able to tide over the daily disease related issues, for the psychological issues they are mostly on their own as the problems are more internal than external. For example, most thalassemia patients wouldn’t even socialize or feel eligible to get married because of the social taboos related to this disease. Because of the little awareness in the general, thalassemia patients are considered as incompetent and there are apprehensions about them leading a normal married life amidst the potential bride/groom families at the time of meeting the thalassemia patients. This assumption by the general public though, is not correct, as well managed thalassemia patients have been doing quite well both internationally and in India both in work and in personal life.
Travelling to Vietnam for the International Conference on Thalassemia by Thalassemia International Federation in the year 2015, I had the privilege to met patients who are working, married to partner without any thalassemia traits and even having their own child, living a very normal life just as any other family in the society. When I became more observant, I realized that there were such patients who had normal partners living in India as well.
In my opinion, something needs to be done from both, the patient’s side as well as the society’s side. Let me start with patient’s side fi rst. As patients, we should be aware that our prime objective should be to take care of ourselves and to manage our health to the best of our abilities. However, this should be intended not just to have a life partner, instead so that we can lead a more fulfi lling life irrespective of any partner or not. It is about our own acceptance and improving our life and not so that others fi nd us eligible for the marriage.
Being focused towards health, working out daily, being sincere with medicines and being dedicated for having a overall well groomed personality and skills, helps to build confi dence and have a better outlook towards life in general. I encourage all my thalassemia friends to socialize and meet new people from
59 diff erent walks of life that will enable us to fi nd new inspiration and grow into new horizons. The starting point should ideally be to believe that we can do everything that any human being is capable of. This will happen when we have our basics in order which is being sincere towards our own health.
As society, parents, counsellors and the NGOs working for the welfare of the patients will need to address the psychological and emotional challenges of the patients in addition to the physical challenges being posed to them. Sometimes in order to take care of the patients we never realize that the patients are growing up and that we need to make them self reliant by making them take responsibilities beyond what they have been asked to do with time. Giving them newer challenges to handle on their own under your guidance will make them better leaders and help them grow. They should be encouraged to do their tasks by themselves in the adolescent stage and encouraged to further contribute something to the society as they grow. It could be by way of involving them in volunteering for the social cause or simply by delegating some tasks that can help them learn. Having them to do with something where they contribute to others will inspire them to manage themselves better and give a sense of belongingness with the society at large. This serves to tell the patients, in a way, that there are many others who could use their help and that their life is of value to others. “Growing and Giving” are the two best ways to inspire greatness.
Lastly, I believe that fi nding a life partner should not be the end goal of any individual. Having a life partner is just one just one part of the journey called Life. We are living in a world today where even the normal marriages are falling apart due to misplaced and unreasonable expectations. Even normal people today, in order to save their sense of “freedom” are shying away from getting married, fearing the loss of their freedom, however not realizing that this illusionary sense of freedom itself is the bondage of their loneliness. This is fear of not being able to live with another person because they don’t fully believe in themselves.
We should realize that Life is much beyond fi nding a life partner. Being of help to others and conducting ourselves in a way that inspires others will serve us better rather than to coast our way through life making an attempt to please others in order to fi nd a life partner. In our journey of life we will meet a lot of people and with sincere interest in them, we will eventually end up with the right person when we are truly ready. Until then, we need to keep travelling and keep enjoying the journey.
60 Patients’ Rights: Legislations and Beyond Nishtha Madan Developmentalist & Special Educator, ASMS. Sarvodaya Kanya Vidyalaya, Mahipalpur, Directorate of Education, GNCT of Delhi
Key Words Thalassemia patients, Person with Disability Act, 2005, rights and entitlements, awareness, treatment
Various activities in the fi elds of awareness and treatment of Thalassemia have been initiated and implemented by the Government of India. But thalassemic patients still have a need for better quality of treatment which will further lead to a better quality of life. One can attain quality life only if attitudinal barriers are broken and safe, fi ltered and phenotype matched blood is provided.
A lot of emphasis has been laid on right to equal opportunities, full participation, but less is done in case of protection of rights especially when patients with thalassemia are concerned. Lack of awareness of Thalassemia is leading to lost opportunities for Thalassemia patients as their effi ciency stands questioned and the employers fear of hiring a person with a disorder stands out.
The talk will also highlight existing legislative provisions and what more is needed to support and improve services for patients with thalassemia
61 62 6th International Conference on Th alassemia, 2016
Posters
63 “Let us all work together to make our country free from Th alassemia .”
64 Seroprevalence of Hepatitis C Virus in Multi- Transfused Patients of Beta Thalassemia Major Surjeet Singh Senior Resident SMS Medical College, Jaipur
Background Transfusion Transmitted Infections (TTIs) are a major challenge to the health of thalassemia patients. At present hepatitis C infection is the most prevalent TTI.
Aims & Objectives To fi nd out the seroprevalence of hepatitis C in multi- transfused patients of beta thalassemia major and its association with various factors like age , number of transfusions, intertransfusion interval, alanine transaminase(ALT) and serum ferritin.
Materials And Methods The study was conducted in the department of pediatrics, SPMCHI, S. M.S MEDICAL COLLEGE, JAIPUR from April 2015 to March 2016. It was a hospital based descriptive type of observational study. A total of 300 patients were enrolled, that were between 18 months to 18 years and who received ≥ 8 blood transfusions. ANTI HCV antibody was detected in serum using HCV BI-DOT. HCV RNA PCR was done for the viral load.
Results Out of 300 patients, 72(24%) were positive for anti HCV antibody. Out of 72 patients only 33(11%) patients had detectable viral load in RNA PCR. Increasing age signifi cantly raised the chances of seropositivity (p=.002). There was signifi cant association between number of transfusion and Anti –HCV positivity (p<.001) [(3/28)10.7% patients who had received transfusion between 8-50 were positive while the no. was (33/94)35.10 % for those who had received >200 transfusion]. A shorter transfusion interval was signifi cantly associated with higher positivity (p=0.000) [(10/10)100% patients who had intertransfusion interval between 0-7 were anti HCV positive, while only (1/18) 5.5% had anti HCV positivity].
Conclusion There is a high prevalence of hepatitis C virus (24%) in thalassemia patients in our set up, due to the problems associated with the window period and non availability of NAT(nucleic acid amplifi cation test), so employing NAT will result in reduction of post transfusion hepatitis C.
65 MMULTIFACETEDULTIFACETED AAPPROACHPPROACH TTOO TTHALASSEMIAHALASSEMIA CCAREARE & MMANAGEMENTANAGEMENT - OOURUR EEXPERIENCEXPERIENCE & LLESSONSESSONS LLEARNEDEARNED AARPANRPAN BLOODBLOOD BANK,BANK, NASHIK,NASHIK, INDIAINDIA Dr. Patil Shashikant, Dr. Kale Vaishali, Dr. Tated Nandkishor, Dr. Jain Atul, Dr.Kasodkar Dr.Kasodkar Ratnakar, Mrs. Ugaonkar Varsha, Dr. Nikam Snehal BACKGROUND If managed properly with adequate overall medical care and good quality & safe blood transfusion support, the life expectancy of Thalassemia Major can be increased significantly.
AIM
To implement a comprehensive Thalassemia Care and management programme under one roof.
MATERIAL METHODS - Thalassemia Major Patients within the expanse of North Maharashtra were registered under 'Arpan Thalassemia Society' - A programme for medical management including Iron chelation therapy, Hematologic, Cardiologic, Paediatric, Orthopedic, Pathological, Radiological evaluation was defined. - A monitoring programme was formulated using guidelines given by Indian Academy of Paediatrics. - All patients were offered ID-NAT Tested, Inline - Leucodepleted blood free of cost with the help of corporate support. - All the patients were followed up for Febrile nonhemolytic reactions, Sero-conversion for TTI, Alloimmunisation, Growth, Iron overload for a period of 3 years.
RESULTS 1. N=181 patients; Mean Age =18 yrs (Age range - 2yrs to 30 yrs) Study period - 3 years 1 Total transfusion received - 4662. 2. Seroconversion for Transfusion Transmitted Infections : None 3. Transfusion reaction : FNHTR - 1 patient 4. Serum Ferritin level in Thalassemia patients (as per Table-1) 5. T2* MRI revealed severe cardiac iron overload in 9/58 (16%) 6. RBC alloimunisation : 3/181 (1.6%) patients 7. Stunted growth : 25/181 (13.81%) patients. 8. Endocrinological Disorders: Hypoparathyroidism - 18/181 (9.9%) patients and Primary hypothyroidism - 9/191 (4.9%) patients Table –2 Number of transfusions and onset of RBC alloimunisation TTI (HIV, HBV, HCV) FNHTR (0%) (0.5%) Patient Number of Number of Specificity of transfusions transfusions after alloantibody which alloantibody Iron Overload EndocrinoligcalEndocrinoligcal detected (Sr. Ferritin>2000) DisordersDisorders HypoparathyroHypoparathyro (50%) Problems in clinical care of dism(9.9%)(9.9%) HypohyroidismHypohyroidism Thalassemia (4.9%)(4.9%) Patient 112726Anti -C
Severe cardiac Patient 2 87 32 Unidentified iron Overload T2* MRI Alloimmunisation Patient 3 26 21 Unidentified (16%) (1.6%)
DISCUSSION
1. Proper Thalassemia management apart from transfusion is necessary and Indian Academy of Paediatrics has given good guidelines for the same. 2. Prevalence of HIV, HBV & HCV is reported in the range of 6% to 45% across India. (1,2) Prevalence of HIV, HBV, HCV in thalassemia kids: Worldwide(ELISA tested Transfusion) Vs Arpan Thalassemia Society, Nashik, India (NAT Tested transfusion) Infection World-wide(ELISA tested Arpan Thalassemia Transfusion) Society,Nashik (NAT tested Transfusion) HIV ~ 9% 0 % HBV ~6% 0 % HCV 10-45% 0 % 3. Utilisation of NAT testing technology for donor unit screening definitely improves blood safety & absence of seroconversion in our multitransfused Thalassemia patients can be attributable to the same. 4. Iron overload including cardiac iron overload is a major hazard associated with multiple transfusion. Our observation in this regard match with other published study. (3,4) 5. FNHTR caused due to leucocytes in transfused components can be reduced significantly by using leucodepleted components.(5) 6. Alloimmunisation to the extent of 9.46% has been reported in the Indian scenario. Alloimmunisation rate observed by us is comparatively lower, possibly due to more sensitive cross matching technique & a dedicated repeat donor pool.(6) 7. The occurrence of stunted growth (13.81%) & endocrine disorders (hypoparathyroidism 9.9% & hypothyroidism 4.9% observed in our cohort are lesser than published data.(7)
CONCLUSION Implementing a comprehensive transfusion therapy and health monitoring programme for Thalassemia patients under one roof is feasible with support from corporate & society. Careful periodic monitoring of these patients & implementation of NAT Tested, Leucodepleted & phenotype matched blood transfusion can go a long way to improve the quality of life and overall life expectancy of Thalassemia major pts. REFERENCES 1.Mathur M, Wanjari K, Turbadkar D et al. Seroprevalence of HIV, hepatitis C and hepatitis B in multitransfused thalassemics . Indian J Med Microbiol 2008; 26:205-06. 2. Hardik Bhavsar, Kanu Patel et al. Prevalence of HIV, Hepatitis B and Hepatitis C infection in Thalassemia major patients in tertiary care hospital, Gujarat. NJIRM July- Sep 2011;2(3):47-50. 3. Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C. Longitudinal study of survival and causes of death in patients withthalassemia major in Greece. Ann N Y Acad Sci. 2005;1054:445-50. 4. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Complications of beta-thalassemia major in North America. Blood Jul 1 2004;104(1):34-9. 5. Rebulla P Transfusion reactions in thalassemia. A survey from the Cooleycare programme.The Cooleycare Cooperative Group. Haematologica.1990 Sep-Oct;75 Suppl 5:122-7. 6. Bhaskar S.,Murali Mohan V et al. Red cell alloimmunization in multitransfused patients with beta Thalassemia major –A study from South India. IJMPS. 2013;58(1):31-40. 7.De Sanctis VEleftheriou APrevalence of endocrine complications and short stature in patients withthalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF). Pediatr Endocrinol Rev.2004 Dec;2 Suppl 2:249-55.
CULTURAL EVENTS OF THALASSEMIA CHILDREN
66 Effi cacy and Safety of Hydroxyurea in β -Thalassemia Major Geeta Mandhani, Mamta Manglani, Sujata Sharma Division of Paediatric Haematology-Oncology, Lokmanya Tilak Municipal Medical College & General Hospital, Sion, Mumbai, Maharashtra, India-400 022
Background β -thalassemia major is the commonest hemoglobinopathy with gene defect in β globin chain synthesis. With new transfusion regimens and early iron chelation therapy, near normal life span can be achieved. Only few clinical trials with hydroxyurea have been done in thalassemia major and no conclusions either favouring or disfavouring its use have been reached.
Aims and Objectives 1. To study the effi cacy and safety of Hydroxyurea in patients with β -thalassemia major. 2. To determine the reduction in mean packed cell requirement (cc/kg/year) after hydroxyurea and 3. To study the side eff ects of Hydroxyurea
Materials and Methods Prospective Randomized controlled open labelled study done on 60 subjects with 30 cases and 30 controls in a thalassemia day care centre at a tertiary hospital. The 30 cases in study group received Hydroxyurea as per the standard protocols.
Results A total of 60 patients were enrolled, 30 cases and 30 controls. The mean HbF values were signifi cantly higher in responders compared to non responders at 4 months and 8 months (p<0.05), however, it was not signifi cant at 12 months. The mean PRC requirement at baseline and at the end of study (12 months) in the control group as well as in the non responder showed a signifi cant increase (p < 0.0001 & p < 0.0002 respectively),whereas in the responder group it showed a signifi cant decline (p=0.0183).Myelosuppression (thrombocytopenia and neutropenia) was found to be signifi cantly higher in the study group (p< 0.05)
Conclusion Hydroxyurea has some effi cacy in some children by reducing the transfusion requirements in thalassemia major too, but specifi c parameters predicting the outcome are not known.
67 Thalassemia and Sickle Cell Society Door No. 22-8-496 to 501, Ist and 2nd fl oor, Chatta Bazar ‘X’ Road, Opp: City Civil Courts, Purani Haveli, Hyderabad, Telangana 500002
Thalassemia and Sickle cell Society (TSCS) is a registered non- profi t organization (Reg no: 5359) founded in 1998 by patients, parents, doctors, and well - wishers. This is the only society in Andhra Pradesh and Telangana dedicated for the diagnosis, treatment, management and prevention of patients suff ering from thalassemia and sickle cell disorders.
Currently there are around 2229 children registered for treatment out of which 77% are Thalassemia major and 23% are combination of Sickle Cell anemia, Sickle Thal, E beta Thal & Thal Intermedia.
The facilities available with TSCS are: 1. Day Care Transfusion Unit with 30 beds; 2. A full-fl edged and well equipped Blood Bank functioning round the clock and 3. Computerised Diagnostic Centre.
Services to thalassemia patients includes provision of saline washed blood and medical check-up & counselling free of cost. We also provide diagnostic services and Iron chelating drugs at a subsidised rates. Awareness camps for identifying thalassemia patients and prevention of Thalassemia are done on regular basis. Additionally periodic medical check-ups with specialists like Haematologist, Dentist and Ophthalmologist are also provided to our patients.
In 2014, TSCS was recognised by State Government for Aarogyashree scheme for white card holders and Department of Scientifi c and Industrial Research as Scientifi c and Industrial Research Organizations (SIROs) for carrying out research.
Besides the current services we are working towards off ering specialized services of Bone marrow & stem cell transplant to the patients as BMT is only cure for Thalassemia.
Our eff orts has led to extended family members getting their HPLC test done for Thalassemia carrier status; prevention of marriages among carriers; patients getting their DNA test done and subsequently parents getting prenatal diagnosis done.
68 69 70 THE NEW GENERATION OF AUTOMATED BLOOD COMPONENT SEPARATOR
71 72