Thalassemia major is a major cause of transfusion dependence among patients world over. Provision of an adequate, uninterrupted and safe blood supply for these patients is the responsibility of the blood services as well as the society as a whole. Thalassemia management has evolved over a period of time and so have transfusion services. Various technological advancements have been introduced in the last few decades in order to enhance blood safety. Adoption of these newer technologies coupled with increasing awareness about voluntary blood donation in the general population can go a long way in improving the life expectancy as well the quality of life in these children.

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2. a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 8 4 e1 9 0
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/apme
Review Article
Provision of ideal transfusion support e The
essence of thalassemia care
R.N. Makroo a,*, Aakanksha Bhatia b
a Prof, Director & Senior Consultant, Department of Transfusion Medicine, Molecular Biology & Transplant
Immunology, Indraprastha Apollo Hospitals, New Delhi, India
b Senior Registrar, Department of Transfusion Medicine, Indraprastha Apollo Hospitals, New Delhi, India
a r t i c l e i n f o
Article history:
Received 21 July 2014
Accepted 28 July 2014
Available online 22 August 2014
Keywords:
Thalassemia
Transfusion support
Multitransfused
a b s t r a c t
Thalassemia major is a major cause of transfusion dependence among patients world over.
Provision of an adequate, uninterrupted and safe blood supply for these patients is the
responsibility of the blood services as well as the society as a whole. Thalassemia man-agement
has evolved over a period of time and so have transfusion services. Various
technological advancements have been introduced in the last few decades in order to
enhance blood safety. Adoption of these newer technologies coupled with increasing
awareness about voluntary blood donation in the general population can go a long way in
improving the life expectancy as well the quality of life in these children.
Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Thalassemia is an autosomal recessive disease prevalent in
India. Even though efforts are being made at various levels to
control this disease, the number of affected individuals re-mains
huge. The therapeutic options available for manage-ment
of thalassemia major are based on lifelong transfusion
dependence and iron chelation.1,2 Bone marrow transplants
are now being promoted in advanced centres as a treatment
modality, but the success rates in India are currently
unknown.
Patients with thalassemia major are, therefore, largely
transfusion dependant, forming the bulk of multiply trans-fused
individuals in a population. It is the prime responsibility
of a facility to offer its patients an adequate and uninterrupted
supply of the safest possible blood for transfusion.
Thalassemia management has evolved over a period of
time and so have transfusion services. Initially transfusions
were given to these children only as a life saving measure, but
the patients suffered due to poor quality of life and remained
incapacitated. Orsini et al.3 in 1961 and Wolman et al.4 in 1964
demonstrated that “the results of Transfusion Therapy regu-larly
and methodically repeated are absolutely superior to
those achievable with transfusion given irregularly and only
when the child appears quite anaemic”.
2. Goals of transfusion
The aims of transfusion therapy are to correct the anaemia
and maintain a circulating level of haemoglobin sufficient to
suppress ineffective erythropoiesis, while minimizing iron
* Corresponding author.
E-mail address: makroo@apollohospitals.com (R.N. Makroo).
http://dx.doi.org/10.1016/j.apme.2014.07.011
0976-0016/Copyright © 2014, Indraprastha Medical Corporation Ltd. All rights reserved.

3. a pol l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 8 4 e1 9 0 185
overload.5 It is essential to maintain red cell viability and
function during storage, to ensure sufficient transport of ox-ygen.
At the same time avoidance of adverse reactions,
including transmission of infectious agents is also important.
3. Embarking on transfusion therapy in
thalassemics
Transfusion therapy should be started as soon as a diagnosis
of thalassemia major has been established both on clinical
and laboratory observations.5
There are certain pre-requisites before embarking on
transfusion therapy. These include ABO & Rh (D) grouping of
the patient along with extended phenotyping for minor blood
group antigens like Kell, Kidd, Duffy, MNS antigens etc. Of
these, the Rh (C, c, E, e) and Kell antigens are the most
important since a large majority of antibodies reported in
literature are directed against one of these antigens.6 Thal-assemics,
by the virtue of being chronically transfused, are at
a higher risk of developing alloantibodies.
4. Pre-transfusion testing
The usual transfusion policy is to perform ABO and Rh (D)
typing of donors and patients and subsequent compatibility
testing. However, there are many minor but clinically signifi-cant
blood groups where alloimmunization may occur in
multitransfused patients. Once the alloantibodies develop,
finding compatible units may become difficult. Therefore, in
addition to ABO and Rh(D) compatibility, blood matched for
other minor antigens, especially from the Rh and Kell system
should be preferred. Besides antibody screening should be
repeated before each transfusion episode and if positive an
attempt should be made to identify and characterize the an-tibodies.
Thereafter it is important to always transfuse blood
units lacking the antigens against which alloantibodies have
developed.6
5. Basic requirements for transfusion
Transfusion medicine has evolved from amostly laboratory e
cantered service with a focus on serological aspects of blood,
into a clinically oriented discipline that emphasises patient
care. The implementation of safety and quality measures,
progressively put forth during the last half-century, has sub-sequently
improved the safety of blood and blood compo-nents.
The aim of blood transfusion services should be to
provide blood and blood products, which are as safe as
possible, and adequate to meet patients' need and to maintain
cut-off levels of blood and blood components in every Blood
Bank to ensure blood availability in emergency.
Providing safe, adequate, timely and uninterrupted blood
supplies to thalassemia patients is the responsibility of the
blood centre under which the child is registered. But it is also
the responsibility of the society as a whole to come forward
and donate blood so that there is no shortage of this precious
resource in the blood banks. Our society is becoming aware of
this cause but unfortunately the gap between the demand and
supply of blood in India is still very large.
Our transfusion services infrastructure is highly decen-tralized
and lacks many critical resources; overall shortage of
blood, especially from voluntary donors; limited and erratic
testing facilities; an extremely limited blood component pro-duction/
availability and use; and a shortage of health care
professionals in the field of transfusion services.7
5.1. Leucoreduced blood
In spite of several advancements that have taken place, one
thing has remained constant … …..“the requirement of the
raw material- blood”. The ideal product for transfusion in
thalassemics is Packed Red Cells, preferably leucoreduced.
As per the Department of AIDS Control (DACS), Ministry of
Health and family Welfare, Government of India, the propor-tion
of blood components prepared was 41.3% in 2009e10 and
the facility for component preparation is available only in
select centres.8 The concept of leucoreduction is further
limited. Leucoreduction involves the removal of leucocytes
from the blood components. The general norm is to use
bedside leucodepletion filters as and when required. These do
offer some protection but are not an ideal option for
leucoreduction.
India has a population of one billion and has a huge burden
of patient population requiring multiple transfusions. The
population of chronically transfused individuals is increasing
regularly with a rise in the number of hemato-oncological
problems. Alloimmunization due to red cell, platelet or HLA
antigens is a major problem associated with repeat trans-fusions.
Therefore, transfusion of leucoreduced blood com-ponents
assumes a lot of significance in these patients.9
Removal of leucocytes from various blood products has
been shown to minimize Febrile non haemolytic transfusion
reactions (FNHTR), HLA alloimmunization, platelet refracto-riness
in multitransfused patients and prevention of trans-mission
of leucotropic viruses such as EBV and CMV. It also
offers some protection against storage lesions, GVHD and
immunomodulation.10
Keeping in view the variability of leukocyte numbers in the
component and the leucoreduction method, the leukocyte
content in a blood component unit should be less than 5 106/
unit after leucoreduction (3 log reduction 99.9%) with a mini-mum
of 85% red cell recovery in 95% of the units tested, as per
the standards of the American Association of Blood Banks.11
The European council guidelines are a little more stringent
in terms of residual leukocyte content and require it to be less
than 1 106/unit.12
Broadly leucoreduction is based on the principles of filtra-tion
of centrifugation. The various methods of leucoreduction
include:
Pre-storage filtration of whole blood carried out with an in-line
filter within 8 h after blood collection.
Pre-transfusion, laboratory filtration: Packed RBC prepared
from donor whole blood then filtered prior to release from
blood bank
Bedside filtration: Packed red cell unit is filtered at the
bedside.

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It is generally accepted that pre-storage leucoreduction is
the most ideal method since it eliminates the scope of release
of inflammatory cytokine from the leukocytes during storage,
thereby effectively reducingFNHTRs. It also minimizes the risk
of HLA-alloimmunization in multitransfused patients, as it
removes the intact leukocytes as against bedside filtration,
where leukocyte fragments after storage can pass through
filters and alloimmunize the recipient against donor antigens.9
Pre-storage leucofiltration can also minimize the risk of
leucotropic virus and bacterial transmission as leukocytes
disintegrate and release the intracellular organisms after 72 h
of storage in blood components. There is a reduction in micro-aggregate
formation and haemolysis. Besides, it is always
easier to perform leukocyte quality control in the laboratory
rather than by the patient's bedside.9
6. Washed red cells
A blood component obtained from whole blood after centri-fugation,
removal of the plasma and subsequent washing
with isotonic solutions at þ4 C. This is a suspension of RBCs
from which most of the plasma, leucocytes and platelets have
been removed. Saline washing of red cells removes plasma
proteins in the donor product that are the target for antibodies
in the recipient. These can be used in patients who develop
repeated severe allergic transfusion reactions. It is also rec-ommended
for patients who develop post-transfusion febrile
reactions, even when leucodepleted RBCs are used.13
7. Frozen red cells
A blood component obtained by freezing RCCs (within 7 days
of collection) with an appropriate cryoprotectant and storing
at a temperature between 60 C and 80 C. The frozen RBCs
can be preserved for up to 10 years.13 They can be used to
maintain a supply of rare donor units like Bombay Blood
Groups or for certain patients who have unusual red cell an-tibodies
or who are missing common red cell antigens.
8. Age of PRC
The unit age of blood component being issued from the blood
banks is a major bone of contention between transfusion
specialists and their clinical colleagues. When red cell con-centrates
are prepared, a considerable part of the glucose and
adenine is removed with the plasma. Newly developed addi-tive
solutions, however, allow maintenance of red cell
viability even if more than 90% of the plasma is removed, as
they contain considerably higher levels of the necessary nu-trients.
However, storage of blood, even under controlled
conditions does alter some cellular functions. The haemo-globin
oxygen release function (which is extremely important
in thalassemia) is impaired during storage due to progressive
loss of 2, 3-diphosphoglycerate. Even though the 2, 3-DPG can
be regenerated after a few hours of transfusion, severely
compromised patients, neonates and young children do not
tolerate these changes well. Therefore, thalassemic children
should preferably be given PRC units within two weeks of
collection.5,14
9. Neocyte transfusion
It is well known that young red cells (neocytes) survive longer
after transfusion and therefore may contribute to the exten-sion
of the intervals between transfusions. Neocytes are new
red cells which comes from bone marrow afresh. They have a
longer life span, say about 120 days in the circulation. These
young red cells survive longer after transfusion and therefore
may contribute to the extension of intervals between trans-fusions.
They are of lesser weight as compared to the older
cells (Gerocytes). Because of this property, these cells can be
separated and collected, selectively, by apheresis method
from a blood donor.15
10. Compatibility testing
As already mentioned, before embarking on transfusion
therapy for thalassemia patients, blood grouping and
extended antigen typing should be performed. Wherever
possible, at least Rh and Kell matched units should be pro-vided.
In addition prior to each transfusion, antibody
screening and crossmatching with donor units is essential. In
case the antibody screen is positive, the exact antibody
specificity should be determined and appropriately matched
and antigen negative units be provided to the patient.6
11. Extended antigen typing
Provision of Rh and Kell matched blood, although ideal, can be
very tedious and time consuming, unless extended antigen
typing of all the donor units is readily available. It has been
consistently observed that the most commonly encountered
antibodies in clinical practice are directed against the Rh
(mainly C, c, E, e) and Kell antigens.2,16,17 With the phenotypes
available for all donor units in the inventory, antigen matched
units can be directly picked up for crossmatching. Provision of
blood for patients becomes faster and safer. In addition to of-fering
protection against development of alloantibodies
against the common immunogenic antigens, extended typing
for all donor units is also a beneficial initiative for thalassemics
who are already alloimmunized against one or more of these
antigens. In such cases, each time the patient requires trans-fusion,
the need for typing several units for finding appropriate
antigen negative units is eliminated. Alloimmunized thalas-semia
patients can therefore receive blood at the same time as
the non alloimmunized ones without any delays.
12. Molecular blood typing
Patients with thalassemia major form the bulk of multiply
transfused patients in a population. Since, these patients
receive repeated transfusions on a regular basis, the red cells
in their circulation are largely an admixture of cells from

5. a pol l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 8 4 e1 9 0 187
different donors. Serological methods of antigen typing for
blood group antigens is therefore not reliable for them, unless
it is performed prior to the first transfusion episode. Under
these conditions the only suitable alternative for antigen
detection is at the molecular level. Molecular testing methods
were introduced to the blood bank and transfusion medicine
community more than a decade ago after cloning of the genes
made genetic testing for blood groups, that is genotyping,
possible. High-throughput genotyping platforms that utilize
microarray and chip technologies have now been developed.
It is now possible to predict blood group phenotypes from
tests on genomic DNA, with a high degree of accuracy. Mo-lecular
Immunohematology is changing practice in blood
centres, hospital blood banks, and reference laboratories.18,19
Serology has been the Gold Standard for testing and will
remain so, but, there are situations in which the genotype is a
superior, or the only, approach possible. PCR assays for blood
group genes avoid interference from donor-derived DNA by
targeting and amplifying a region of the gene common to all
alleles. This approach, in contrast to targeting and amplifying
one specific allele, allows reliable blood group determination
with DNA prepared from a blood sample collected after
transfusion.
In transfusion-dependent patients who produce alloanti-bodies,
an extended antigen profile is important to determine
additional blood group antigens to which the patient can
become sensitized. In addition with reliable extended
grouping available, antigen matched units (at least for Rh and
Kell antigens) can be provided to the patients in case baseline
serological typing results are not available.18,19
13. Adverse effects associated with repeated
transfusions
Repeated blood transfusion exposes thalassemia patients to a
variety of risks like transmission of infectious diseases, iron
overload and alloimmunization. Transfusion reactions (Hae-molytic/
non haemolytic) may occur with any transfusion.
13.1. Risk of TTI transmission
Among the various inherent risks associated with repeated
transfusions lie the risks of contracting Transfusion Trans-missible
Infections like HIV, Hepatitis B Hepatitis C, among
others.
Although measures such as adoption of strict donor se-lection
criteria, encouragement and maintenance voluntary
non remunerative pool of blood donors and temporary or
permanent deferral of those with high risk behaviours judged
by the use of questionnaires are a routine practice globally,
the final decision on whether or not to use a blood/blood
product for transfusion relies on the results of infectious
marker tests. The Drug and Cosmetics Act that governs
transfusion services in India mandates testing for several in-fectious
markers for HIV, Hepatitis B, Hepatitis C etc. Although
tests for HBV were in place in the early eighties itself, testing
for HIV has been enforced since 1989 and more recently since
June 2001, testing for HCV has becomemandatory.20 Different
centres use different screening modalities and kits that differ
in their sensitivities and specificities. In spite of extensive
screening protocols none of the transfusion services across
the globe can ensure 100% blood safety from any of these in-fectious
diseases.
The prevalence of TTIs in Thalassemics in India has been
variably reported. Most studies have agreed that HCV is the
most frequently detected TTI in Indian thalassemics. The re-ported
prevalence varies from 11.1% to 62.2%.6,21,22 HBV on the
other hand has shown a prevalence ranging from 2.8% to
59.6%.6,22 There is an effective vaccine against Hepatitis B and
vaccination prior to commencement of transfusion therapy
and timely boosters,can effectively protect against transfusion
transmitted hepatitis B.23 However no such vaccine is yet
available for HCV. In case of HBV, however, the major concern
is transmission of infection during the “Core Window period”
i.e “Occult Hepatitis B” in the donor. This is especially true in
centres where neither anti HBc testing nor the advanced
Nucleic Acid Testing is performed for screening donor units.24
HIV infection has emerged today as a most alarming dis-ease
and one of the worst effects of blood transfusion.
Fortunately, owing to advanced testing techniques like 4th
generation ELISA and NAT, better donor interview and
screening methodology and increasing awareness about this
infection in the general population, seroprevalence rates
among thalassemics are relatively lower than those for other
TTIs. HIV prevalence among the multi transfused thalasse-mics
has been reported as 9.3% by Dubey et al.25 and 2.38% by
Makroo et al.6
ELISA has been a gold standard for testing of infectious
markers and highly sensitive assays are now becoming
available. However, the current immunoassays detect virus-induced
antibodies or viral antigens, not the virus itself and
the greatest threat is donation by seronegative donors during
the window period between initial infection and detectable
seroconversion. In fact, the residual risk of transfusion-transmitted
HIV infection has been estimated at 2%, by Moore
at al.26
13.1.1. Nucleic acid testing (NAT)
The introduction of NAT for screening of donated blood has
revolutionized blood safety. NAT is a method of testing blood
that is more sensitive than conventional tests that require the
presence of antibodies to trigger a positive test result. While
an infection occurs, NAT is used to detect the low levels of
viral genetic material present in the body.
Scientific models estimate that NAT reduces the infectious
window period by 35e91% for HIV-1, HCV, and HBV with in-dividual
donation testing (IDT), and by 17e87% with mini-pool
(pools of 16) nucleic acid testing, thereby minimizing, but not
eliminating, the chances of contracting TTIs following blood
transfusion.27,28 Blood donor screening for infectious markers
by ELISA when combined with ID NAT is currently the safest
mode of blood screening.29
13.1.2. Pathogen inactivation
Pathogen inactivation or Pathogen Reduction (PR) provides a
proactive approach to cleansing the blood supply. In the
plasma fractionation and manufacturing industry, pathogen
inactivation technologies have been successfully imple-mented.
The ultimate goal of pathogen inactivation is to

6. 188 a p o l l o me d i c i n e 1 1 ( 2 0 1 4 ) 1 8 4 e1 9 0
maximally reduce the transmission of potential pathogens
without significantly compromising the therapeutic efficacy
of the cellular and protein constituents of blood. This must be
accomplished without introducing toxicities into the blood
supply and without causing neo-antigen formation and sub-sequent
antibody production. This technique is however, not
available in India, as yet.
In spite of thorough blood testing absolute safety from
TTI's cannot be promised anywhere in the world and a small
but definite risk remains. With administrative lapses and
economical crisis affecting several smaller transfusion cen-tres,
especially in suburban and rural India, quality assurance
programmes suffer major setbacks, further increasing the risk
of contracting disease during transfusion.
Although thalassemia management has drastically
improved in recent years, unfortunately the services are not
uniform in all the centres. It must also be noted that infections
like HIV, Hepatitis B C, although most commonly result from
parenteral routes, iatrogenic spread through infected needles,
IV sets and other equipments is also any important cause
especially in these patients who undergo repeated hospitali-zation
and investigations.
13.2. Alloimmunization
A safe blood supply does not only imply thorough testing for
infectious markers, but also protection from alloimmuniza-tion.
Alloimmunization rates in thalassemics are markedly
higher than those observed in the general patient pop-ulations.
30 The rate of alloimmunization in patients of thal-assemia
major in different parts of the world ranges from 2.8
to 37%.17,31,32 In India the rates of alloimmunization in thal-assemics
ranges from 3.7% to 9.48%, with Rh and Kell anti-bodies
being the most frequent.2,6,16,33 Singer et al.17 have
proven in their study that provision of Rh and Kell matched
blood to thalassemia patients is recommended.
However, lack of trained manpower and facilities in a
resource limited country like ours make such special pro-visions
for these children difficult.
13.3. Iron overload
The inevitable consequence of regular life-saving transfusions
in thalassemia major is the accumulation of excess iron
within tissues. This causes progressive organ damage and
dysfunction which, without treatment, can lead to an increase
in morbidity and mortality.34 For patients requiring regular
blood transfusions, iron chelation may represent life-saving
therapy. A landmark study investigating role of desferox-amine
(Desferal;) in prevention of complications of trans-fusional
iron overload showed that survival to at least 25 years
of age in poorly chelated b-thalassemia major patients was
just one-third that of patients whose iron levels were well
managed by deferoxamine.35 Guidelines from the Thalas-semia
International Federation recommend that a careful re-cord
of transfused blood should be maintained for each
patient, which includes the volume or weight of the admin-istered
units, haematocrit of the units or the average hae-matocrit
of units with similar anticoagulant-preservative
solutions, the patient's weight.5
14. Bone marrow transplantation: the
permanent therapy
Bone marrow transplantation (BMT) remains the only avail-able
definitive cure and success rates can be very high in
appropriately selected patients, i.e. low-risk younger children
with a matched family donor. In these circumstances BMT
may be justified medically, ethically as well as financially, in
fact, the cost of low-risk BMT is equivalent to that of a few
years of non-curative supportive. Bone marrow trans-plantation
is now available in several centres in India as well.
It is the ultimate path for a transfusion free life for these
children. The aim of marrow transplantation in patients with
thalassemia is to improve survival by reducing both morbidity
and mortality. Disease-free survival is a desirable objective
that cannot be obtained with other therapy. However, it is
important to weigh the risks and benefits of BMT with those of
regular transfusions with good chelation therapy.
Even though several measures have been taken by the
government and various NGO in improving thalassemia care,
complications associated with transfusion therapy like im-munization,
TTIs and iron overload, limited access to safe,
adequate and timely blood supply, limited pool of regular,
repeat voluntary blood donors that constitute a safe blood
supply, lack of proper clinical management, financial con-straints,
lack of awareness and social stigmas associated with
the disease are still the common problems faced by our thal-assemic
children.
15. Thalassemia transfusion support at
Indraprastha Apollo Hospitals, New Delhi
At the Indraprastha Apollo Hospitals, we have over 50 thal-assemic
patients registered, taking regular transfusion once
or twice a month. The centre is equipped with latest state of
the art technology for blood component preparation, Immu-nohematology
and infectious marker testing.
At the time of registration, baseline investigations are
performed. These include ABO and Rh (D) typing, antibody
screening followed by identification, wherever required.
Serological testing for Rh (C, c, E, e) and Kell antigens is per-formed
in patients receiving their first transfusion. In addi-tion,
infectious marker testing for HIV, HBV and HCV is also
performed at the time of registration.
Antibody screening is repeated prior to each transfusion
episode and infectious markers testing is also repeated at
regular intervals.
The department has recently introduced Molecular Blood
typing facility for extended blood group genotyping. All thal-assemia
patients have undergone the test and genotypes are
available in the records of the department.
For infectious marker testing the department is using
highly sensitive ELISA tests employing the latest 4th genera-tion
kits for HIV testing. In addition, all units also undergo
Individual Donor NAT testing to ensure the safest possible
blood supply.
All patients are provided 3e4 log leucoreduced packed red
cells prepared using quintuple bags with integrated filter for

7. a pol l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 8 4 e1 9 0 189
pre-storage leucoreduction. This has eliminated the require-ment
of bedside filters for leucoreduction, thereby reducing
the time required for transfusion of each unit and the prob-lems
relating to clogging of filters.
For thalassemia patients, freshest possible units (prefer-ably
within one week of collection are provided. All donor
units at the department undergo extended antigen typing for
Rh and Kell antigens. Wherever possible, Rh and Kell matched
units are selected, the selection being more reliable with the
patient's Molecular grouping results available.
The facility for Saline Washing of PRCs is available and two
thalassemics are regularly receiving Washed PRCs.
We also cater to the Transfusion requirements of several
alloimmunized thalassemics, some with multiple anti-bodies
as well. In these cases, appropriate antigen matched
units are being provided. In addition, since these patients
are at a higher risk of developing new antibodies, wherever
possible Rh and Kell genotype matched blood is being
provided.
Conflicts of interest
All authors have none to declare.
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