ISBT Science Series (2015) 10 (Suppl.

1), 1219

INVITED REVIEW

1A-A01-03

2015 International Society of Blood Transfusion

Handling a transfusion haemolytic reaction

Vered Yahalom1 & Orly Zelig2
1

National Blood Group Reference Laboratory (NBGRL), Magen David Adom - National Blood Services, Ramat Gan, Israel
Blood Bank, Hadassah Medical Center, Jerusalem, Israel

Haemolytic transfusion reactions (HTRs) may be immediate/acute (AHTR) usually

due to immune ABO incompatibility or delayed (DHTR) seen days to weeks following transfusion and caused by an anamnestic immune response to red cell
antigens (Kidd, Rh, Duffy and others). AHTR may cause severe morbidity and
mortality even if recognized early. Presently, there is no therapy that can reliably
treat the effects of acute haemolysis. Therefore, RBC (and other blood components) should be transfused only if clinically indicated. Strict adherence to guidelines and SOPs is essential for prevention of this avoidable severe complication.
Awareness, close observation of patients receiving transfusion, early recognition
of a transfusion reaction, prompt cessation of transfusion and appropriate supportive care are essential to minimize morbidity and mortality. Factors influencing the outcome of HTRs include antibody and antigen characteristics as well as
patient age and comorbidities. DHTRs are more frequent in patients with sickle
cell disease (SCD), thalassaemia and haematological conditions such as autoimmune haemolytic anaemia (AIHA) and myelodysplastic syndromes (MDS). In
these patients, distinction between haemolysis caused by alloantibodies or autoantibodies is challenging, especially if hyperhaemolysis is present. Investigation
of HTRs should include all aspects of the transfusion chain administrative, clinical and laboratory. In patients in whom the blood bank laboratory cannot identify a cause for haemolysis, other causes for immune and nonimmune haemolysis
should be sought. New insights into the pathogenesis of haemolysis might aid in
developing novel therapies for amelioration and treatment of HTRs. Nonetheless,
prevention of HTRs should be the major goal.
Key words: acute, delayed management, haemolytic transfusion reactions, immune

Introduction
Advances in blood collection, component preparation, testing, transfusion protocols and quality assurance systems
have improved blood safety dramatically. Nevertheless,
acute haemolytic transfusion reaction (AHTR) due to ABO
incompatibility is still a dreadful complication of transfusion. In developed countries, the reported mortality due to
fatal haemolysis is declining with an estimated mortality of
1:106 units transfused [1]. In 2012, HTRs were related to
one death and lead to major morbidity in nine patients as
Correspondence: Vered Yahalom, National Blood Group Reference
Laboratory (NBGRL), Magen David Adom - National Blood Services. Tel
Hashomer, Ramat Gan, Israel, 52621.
E-mails: veredy@mda.org.il, vered.yahalom@gmail.com

12

reported to the serious hazard of transfusion (SHOT) [2].

Eight fatalities related to HTRs were reported to the food
and drug administration (FDA). Notably, more fatalities (5/
8) were associated with non-ABO antibodies [3].
Data regarding HTRs frequency from developing countries are scarce. Acute haemolytic reaction rates of 3%
and 0
4% were reported from studies by university hospitals in Nigeria and Uganda, respectively [4, 5]. It may be
noted that in under-resourced countries, transfusions are
often administered because of a pre-existing haemolytic
condition such as malaria or Sickle cell disease (SCD).
This may suggest that in countries where resources are
limited and there are no active haemovigilance systems,
the risk of HTR is increased.
Haemolytic transfusion reaction is defined as decreased
red blood cell (RBC) survival following blood transfusion.

Handling a transfusion haemolytic reaction 13

HTR can be classified as acute (AHTR) or delayed (DHTR)

and as immune or nonimmune mediated. The clinical presentation may vary from severe reaction with multiple
organ damage that can lead to death, mainly in AHTR, to
mild and even asymptomatic especially in DHTR.
Classification of haemolytic transfusion reactions, presentation, pathogenesis, differential diagnosis and management will be addressed. Awareness, close follow-up
of patients receiving transfusion, early recognition,
prompt cessation of transfusion and appropriate supportive care are essential to minimize morbidity and mortality. However, HTRS prevention should be our main
goal.

2 Inadequate storage freezing RBCs.

3 Improper administration overheating, excessive pressure on RBCs units administered through a filter or a
small intravenous cannula, co-administration with
hypotonic solutions or drugs.
4 RBC disorders in the recipient or donor haemoglobinopathies, G6PD deficiency and other congenital haemolytic anaemias.
5 Polyagglutination A spontaneous agglutination of
red cells which may result from exposure of cryptic
RBC antigens such as in T(n) activation.

Classication of HTR

Solid data on AHTR occurrence originate from countries

where active reporting systems are in place. Even
amongst these countries, reporting depends on awareness
and compliance.

Haemolytic transfusion reactions can be classified as

immune and nonimmune.
Immune reactions are commonly subclassified as follows:
1 Immediate or acute (AHTR) occurs during a blood component administration or within 24 h. It is predominantly caused by immune ABO incompatibility. The
main antibody isotype leading to intravascular haemolysis is IgM.
Most AHTRs are due to incompatible red blood cell (RBC)
administration but may occur with large volume incompatible plasma transfusion, such as following incompatible apheresis platelet transfusion (in particular group O
donor to group A recipient). There are numerous case
reports of acute haemolysis caused by non-ABO antibodies against red blood antigens including antibodies
against low frequency antibodies such as anti-Wra [6].
2 Delayed (DHTR) is seen days to weeks following transfusion. Antibodies involved are usually IgG subtypes
leading to extravascular haemolysis. They represent an
anamnestic immune response to red cell antigens (Kidd,
Duffy, Rh and others) which were not detected in the
pretransfusion specimen. DHTR resulting from primary
immunization is rare.
3 Serological DHTRs (SDTR) is detected only by laboratory investigation with no evidence or missed symptoms of haemolysis.
Other causes of immune haemolysis include the following: autoimmune haemolytic anaemia (AIHA), druginduced haemolysis which may be caused by numerous
commonly used substances as second generation cephalosporins [7], nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensives.
Nonimmune causes of HTR include the following:
1 Improper preparation high haematocrit, incomplete
removal of glycerol from frozen RBCs.

Acute haemolytic transfusion reaction

Presentation and outcome

Intravascular haemolysis may develop within minutes
from transfusion onset following transfusion of only
10 ml of incompatible blood.
Signs and symptoms of AHTR range from mild with chills,
fever, abdominal or flank pain, to severe, with hypotension,
dyspnoea, haemoglobinuria, disseminated intravascular coagulopathy (DIC), acute renal failure (ARF) and shock.
Stress and a sensation of impending doom have been
described. Dark urine secondary to haemoglobinuria may
be the presenting sign of AHTR in particular amongst
anesthetized or unconscious patients.
Acute haemolytic transfusion reaction outcome is
mainly influenced by the amount of incompatible blood
transfused. Of 36 patients who received more than 50 ml
of incompatible blood, 23(64%) manifested signs or
symptoms related to the incompatible transfusion, and 6
(17%) died. 3 (25%) of 12 patients who received 50 ml or
less of incompatible blood had associated signs or symptoms, and none died [8]. High antibody titres increase the
severity of ABO incompatibility [9]. Conversely, patients
with low titre/absent ABO antibodies might not develop
haemolysis at all [10]. Other variables that predict outcome are not well defined. Patients comorbidities, age
and appropriate timely supportive care provided are
potential factors.

Pathophysiology of immune-mediated AHTR

An immune-mediated HTR (both acute and delayed)
begins with the interaction between serum antibodies and
RBC antigens. Haemolysis may be intravascular or extra-

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219

14 V. Yahalom & O. Zelig

vascular. Factors which influence haemolysis severity

include antibody class and subclass, specificity, thermal
range, complement activating efficiency and affinity.
Quantity and distribution of membrane antigens, the presence of antigen in tissue and/or fluids and activity of the
reticuloendothelial system have also been shown to be
determinants of the severity of haemolysis [11].
Acute haemolytic transfusion reaction most commonly
occurs when incompatible RBCs are transfused to a
patient with pre-existing antibodies. Antibodies that
cause AHTR are most commonly those of the ABO system, where high titre naturally occurring antibodies react
with densely expressed ABO antigens on RBCs. The complement system plays a key role in AHTR [12].
The final membrane attack complex (MAC) is inserted
in the RBC membrane. It induces osmotic lysis in which
the cell content (mainly haemoglobin) is released into the
plasma in an uncontrolled fashion.
Free plasma haemoglobin is toxic, conceivably through
the infliction of oxygen-related toxicity [13], it also acts
as nitric oxide (NO) scavenger. NO depletion causes [14]
vasoconstriction, platelet activation, leucocyte adhesion,
endothelial damage, oxygen free radical generation and
pulmonary hypertension.
The anaphylatoxins C5a and C3a (products of C5 and
C3 complement components cleavage, respectively) are
responsible for almost all the systemic effects encountered
in AHTR. They induce bronchospasm and hypotension,
stimulate the production of IL-1 and TNFa from macrophages which activates neutrophils and platelets, thus
aggravating hypotension, and enhancing the procoagulant state.

Differential diagnosis
Signs and symptoms of AHTR are common to other
causes of acute transfusion reactions. Fever with/without
chills can be seen in febrile nonhaemolytic transfusion
reaction (FNHTR) and transfusion associated sepsis (TAS).
Fever with respiratory distress might suggest transfusion
associated acute lung injury (TRALI). Haemolysis is the
hallmark of paroxysmal nocturnal haemoglobinuria (PNH)
and cold haemagglutinin disease; therefore, diagnosis of
AHTR might be more difficult to establish.
Distinguishing between the different causes of acute
transfusion reactions might not be simple as signs and
symptoms overlap, yet diagnosis of AHTR should be considered and pursued [15].

Management
Early recognition of AHTR is of paramount importance
since transfusion of only 30 ml has been reported to be

fatal [16] and transfusion of more than 50 ml is associated

with increased risk of severe morbidity and death [8].
If AHTR is suspected in a patient receiving blood, the
immediate and most critical action is prompt cessation of
transfusion followed by evaluation of hemodynamic and
respiratory status and maintaining venous access. After
ensuring that the patient is stable, verification should be
made that the blood component is compatible and designated for the specific patient. The transfusion service
should be immediately notified, and the diagnosis of
AHTR should be established or refuted.
Investigation should follow institutional standard operating procedures (SOPs) and include all aspects of the
transfusion chain:
1 Administrative: patient identity, details on blood component, blood component request and release forms,
previous patient records.
2 Laboratory testing:
a Haematological indices: haemoglobin, platelets,
coagulation parameters for DIC.
b Haemolysis markers: indirect bilirubin, lactic dehydrogenase (LDH), haptoglobin, direct antiglobulin
test (DAT).
c Renal function.
d Blood bank: repeat examination of pre- and posttransfusion samples (ABO, Rh, antibody screen,
cross-match), examination of blood bag and tubing,
further work up according to the investigation
results.
3 Clinical: patient characteristics, underlying diseases,
current admission cause, type of fluids and medications
given.
If diagnosis of AHTR is established, management
should include the following:
1 Monitoring vital signs (blood pressure/respiratory rate/
oxygen saturation.)
2 Adequate hydration to ensure hemodynamic stability
and maintain good urinary flow rate using normal saline or saline/5% dextrose.
3 Monitoring urinary output and fluid balance.
4 Examining urine sample for haemoglobinuria.
5 Monitoring laboratory parameters of renal function,
coagulation and haemolysis.
6 Other measures should be considered according to the
clinical status of the patient:
a Diuretics furosemide and/or mannitol
b Bicarbonate to increase urinary pH.
c Low dose dopamine hydrochloride
d Oxygen and mechanical ventilation support.
e Compatible blood component replacement therapy
for DIC.
Treatment should be given with attention to possible
complications such as pulmonary oedema due to volume

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219

Handling a transfusion haemolytic reaction 15

overload in combination with oliguric renal failure. Hyperkalemia, metabolic acidosis and uraemia may require
dialysis.
Importantly, measures to verify that other incompatible
components are not transfused and that there are no
other potential patients who may receive incompatible
units must be taken.
A case report [17] on the treatment of suspected AHTR
with the C5 inhibitor (Eculizumab) demonstrates clinical
feasibility. C1 esterase inhibitor concentrate has been
reported to ameliorate haemolysis in a case of AIHA [18].
The main causes of AHTR are errors in identification of
patients either at the time of sampling for blood typing or
while administering blood components. Errors may also
occur in the blood bank laboratory [2, 8, 16]. Emergency
situations such as multiple traumas may result in poor
adherence to SOPs thus increasing the risk for errors.

Prevention
Acute haemolytic transfusion reaction can cause severe
morbidity and mortality even if recognized early. Therefore, RBC (as other blood components) should be transfused only if clinically indicated. Prevention of HTRs
should be a major goal.
It necessitates strict adherence to guidelines and SOPs,
multidisciplinary cooperation, root cause analysis of HTRs
and appropriate education as well as implementation of
corrective actions.
Guidelines for patient identification, obtaining and
testing blood samples, distributing and administering
blood components are essential to ensure provision of the
right component to the right patient. Although self-evident, these steps are operator dependent and therefore
prone to errors.
Common practice is to begin transfusion with a low
initial infusion rate and to observe the patient closely
over the first 1530 min after initiating transfusion. This
is a simple and effective measure to increase blood transfusion safety which enables early recognition of acute
adverse effects.
Methods that may prevent human errors such as barcoded systems which facilitate transfusion only when a
correct link between the patient, tests and the blood unit
exist should be sought and if possible implemented.
Improvements in record keeping and data sharing of
patients ABO blood type and RBC antibodies are necessary [19].
Other therapeutic modalities which may prevent haemolysis include modified red cell such as pegylated RBC or
enzymatically cleaved RBC [20]. Universal donor RBC
from human-induced pluripotent stem cells [21] may
become an important resource in the future.

Delayed haemolytic transfusion reaction

Reports on DHTR rates are variable and depend on inclusion criteria and available laboratory techniques. Commonly cited estimations range between 1:2500 and
1:11 000 reaching 3:100 following multiple RBC transfusions to 15:100 and higher in susceptible patients
[22, 23].

Presentation and outcome

Delayed haemolytic transfusion reaction presentation is
variable, but in most cases, mild symptoms such as
weakness, jaundice with/without fever or exacerbation
of underlying clinical conditions are observed. Few may
present with brisk haemolysis resembling AHTR yet
haemolysis is primarily extravascular and therefore
acute renal failure and DIC are rare. Most patients with
mild to moderate DHTR will recover without major
adverse effects. Hyperhaemolysis or hyperhaemolytic
transfusion reaction (HHTR) [24] is a term used to
describe a severe form of haemolysis in which the posttransfusion haemoglobin is lower than the pretransfusion haemoglobin in the absence of bleeding or newly
formed antibodies.

Pathophysiology
In DHTR, haemolysis is mainly extravascular and thus
lacks most of the severe manifestations of AHTR. DHTR
is mediated mainly by IgG antibodies, which are weak
complement activators. They do not result in massive
activation of complement thus rarely lead to intravascular haemolysis. RBC bound IgG act as opsonins by
interacting with Fc receptors (FcRs) on phagocytes
in the reticuloendothelial system (RES) mainly in the
spleen. Antibody clearance of RBC is primarily mediated through phagocytosis although other mechanisms
have been described. Phagocytosis results in extravascular RBC destruction and prevents significant free haemoglobin
spillage
and
its
associated
clinical
consequences.
Several mechanisms [25, 26] have been suggested to
cause HHTR including macrophage activation, autoantibodies and bystander immune haemolysis in which the
recipients RBC are haemolysed with no evidence of an
antibody directed against an antigen expressed by the
recipients RBC.
Mechanisms underlying drug-induced immune haemolytic anaemia (DIIHA) are not fully elucidated and are
beyond the scope of this review. Pathogenesis is described
as drug dependent or independent via an hapten, immune
complex or autoantibody formation [27].

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219

16 V. Yahalom & O. Zelig

Susceptible patient populations

Transfused RBC units are always matched for ABO and in
most instances for RhD. Alloimmunization against other
RBC antigens develops in approximately 3% of transfused
patients.
The risk of developing an antibody following transfusion varies between patients. Some patients develop antibodies (responders), whereas many others do not
(nonresponders). The mechanisms underlying responsiveness or nonresponsiveness are not fully characterized.
Genetically inherited traits such as presence of specific
MHC class II molecules have been shown to increase the
likelihood of developing particular alloantibodies (e.g.
anti-Jka with DRB1*01, anti-Fya with DRB1*04).
Increased alloimmunization rate regardless of antibody
specificity has been reported in SCD patients with HLA
DRB1*1503 [28]. Recent data suggest that HLA-DRB1*15
may also represent a susceptibility phenotype enhancing
formation of multiple RBC antibodies [29]. Conversely,
amongst patients with SCD, HLA DRB1* 0901 may confer
protection against alloantibody formation [28].
Inflammation and infection are other recipient-related
variables which may predispose to alloantibody formation
[30].
Although controversial, blood unit related factors such
as the presence of leucocytes and cytokines have been
reported to increase alloantibody production. [30, 31].
Recent publications propose that intensity of RBC
transfusions [32] or RBCs storage times between 1 and
4 weeks do not affect significantly the risk of alloimmunization [33]. Amongst multiply transfused patients, certain subgroups have been identified as particularly
susceptible for alloantibody development.
Of the most studied are patients with SCD who may
develop severe HHTR with life-threatening hyperhaemolysis [22, 25]. Discrepancies between donor and patient
population RBC phenotypes have a major role in antibody
development along with other disease and patient-related
factors. Other patients groups at risk include thalassaemia
and haematological conditions such as AIHA and MDS
[23].
The development of autoantibodies increases the risk of
forming alloantibodies and vice versa [34]. Amongst
heavily transfused patients, distinction between alloantibodies and autoantibodies can be very complex, especially if hyperhaemolysis is present.

Differential diagnosis
Differential diagnosis of DHTR includes clinical entities
that were described in the differential diagnosis of AHTR.

Special consideration should be given to drug-induced

AIHA, microangiopathic haemolytic anaemia and antibodies produced by donor passenger lymphocytes following transplantation of an ABO incompatible organ.
Some clinical settings such as liver disease, bleeding
and large haematomas may pose further diagnostic challenges. Post-transfusion babeosis or malaria may present
as fever with variable levels of haemolysis.

Management
Most patients with DHTRs will not require therapy. They
should be observed and provided adequate supportive
care while monitoring clinical and laboratory parameters.
The rare cases presenting with active intravascular
haemolysis should be treated as described above for
AHTR. Laboratory investigation should include repeat
examination of pre- and post-transfusion samples (ABO,
RhD, antibody screen and panels, cross-match, DAT). Eluates should be made and tested including from DAT negative RBCs. If offending clinically significant antibody/
antibodies are detected, transfused RBC units should be
tested for the corresponding antigen(s) to which antibodies developed. Thereafter, efforts should be made to transfuse antigen-negative RBC.
If allocation of antigen-negative units might delay
transfusion, the transfusion service should discuss transfusion alternatives with the clinicians. A multidisciplinary
medical decision should be made regarding the risk benefit ratio of transfusion vs. withholding transfusion of
incompatible units.
If severe haemolysis is ongoing despite provision of
compatible antigen-negative units, immune modifying
therapies may be considered such as corticosteroids,
intravenous immunoglobulins (IVIG) and rituximab [35]
or combination therapy of corticosteroids and IVIG [36].
Exchange transfusion is another therapeutic option in
severe cases [37].
Clinical entities which deserve special consideration
include the following:

Autoimmune haemolytic anaemia

Matching compatible blood units to patients with autoimmune haemolytic anaemia poses a real challenge. The difficulty in the laboratory stems from the fact that
autoantibodies, which are frequently panagglutinins, may
mask the presence of alloantibodies. Clinically significant
alloantibodies were found in 1245% of patients with autoantibodies.
Approaches for investigating and selecting donor RBC
units for transfusion of patients who have warm autoantibodies include the following:

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219

Handling a transfusion haemolytic reaction 17

a Autoadsorption in which the patients autologous

RBCs are used to remove autoantibody from the
patients serum and allow detection and identification
of alloantibodies in the adsorbed serum.
b Allogeneic adsorption preformed when autoadsorption tests are not feasible because of insufficient volume of the patients RBCs or recent transfusion.
c An alternative approach is to perform extensive RBC
phenotyping or genotyping of the patient and donor
units. Determining an extended phenotype in a patient
with autoantibodies may be technically impossible.
Genotyping might enable matching RBCs antigens for
antibodies which may be difficult to detect serologically.
d Testing the patients serum or diluted serum against a
red cell panel is an easy and rapid procedure which is
unreliable as important alloantibodies may be missed.
This might be used as an interim procedure in extremely urgent situations before results of adsorptions are
available.

Hyperhaemolytic transfusion reaction

Management may follow the concepts described above
for AIHA. Every effort should be made to avoid transfusion in patients with hyperhaemolysis. If life-threatening
anaemia is present, transfusion of antigen-negative units
should be given along with corticosteroids and/or IVIG
[36]. If reticulocytopenia is present, erythropoiesis-stimulating drugs may be considered. Splenectomy is a therapeutic option for persistent severe haemolysis [26].

Drug-induced immune haemolytic anaemia (DIIHA)

DIIHA should be considered in patients with anaemia and
unexplained haemolysis. Haemolysis presentation depends
on previous exposure, is variable amongst patients and
stems from the mechanism underlying DIIHA. Haemolysis
may continue for hours to months following drug discontinuation and relates to drug characteristics and DIIHA
pathogenesis.
A positive DAT with C3d (IgG) with a negative eluate
should raise the possibility of DIIHA. A positive DAT with
IgG and a positive eluate may be seen if drug-independent autoantibodies or drug-dependent antibodies (as for
penicillin compounds) develop. Most laboratories do not
perform specialized procedures required to confirm DIIHA.

Passenger lymphocyte syndrome (PLS)

In patients receiving an ABO mismatched solid organ or
hematopoietic stem cell transplantation, the development
of a positive DAT, appearance of a new antibody, anaemia and haemolysis should raise the possibility PLS. This
results from passive transfer of donor B cells which may

produce antibodies against recipient RBCs. Although

most are due to ABO antibodies, non-ABO antibodies
have also been implicated.
Haemolysis may be prolonged and severe. Transfused
RBCs should be compatible with donor and recipient
antibodies.

Prevention
An initial step to reduce immunization against RBC antigens includes restricting blood transfusions when not definitely indicated. Transfusing leucocyte reduced RBCs has
been shown to reduce alloimmunization [38]. Consideration should be given for supplying antigen negative
matched blood (Rh and Kell) for patients requiring
chronic transfusion support as advocated for SCD [25]
and AIHA. This strategy has the advantage of preventing
alloantibody production amongst responders which presently cannot be identified prior to development of antibodies. Identification of pre-existing RBC antibodies prior
to transfusion is a key factor in preventing DHTR. Some
antibodies (particularly of the Kidd system) may escape
detection as antibody titres decrease over time.
Documenting and communicating the presence of antibodies and/or the need for specialized transfusion protocol is essential for reducing DHTR in our global society
[39]. It may be achieved in certain areas through data
sharing between institutions [19] or through innovative
applications.

Summary
Acute haemolytic transfusion reaction caused by ABO
incompatibility may result in severe morbidity and mortality yet not every case is symptomatic or fatal. Upon
suspicion of AHTR, immediate cessation of transfusion
followed by adequate supportive care is the mainstay of
therapy as currently there is no specific treatment to avert
intravascular haemolysis. Severe DHTR are more prevalent amongst susceptible patients and their frequency is
higher than reported for AHTR. Therefore, all efforts
should be focused in prevention of HTRs both acute
and delayed.
Every institution involved in blood transfusion must
have guidelines and SOPs covering all aspects of the
transfusion chain beginning with blood procurement,
specimen requirements, laboratory testing, distribution of
blood components and blood administration. These
should include personnel education regarding routine
blood transfusion, adverse reactions to blood transfusion,
institutional investigation and treatment protocols, forms,
record keeping and measures to report, investigate and
manage errors and near misses.

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219

18 V. Yahalom & O. Zelig

Insights into the pathogenesis of haemolysis including

the major role of the complement system, the deleterious
effects of cell-free haemoglobin, nonbound transferrin
iron and the role of inflammation in the recipient as
well as in blood components may be valuable in developing new modalities for amelioration and treatment of
HTRs.
Universal donor RBC from human-induced pluripotent
stem cells may become an important resource for ensuring compatible RBC transfusions in the future. Until these
alternatives become clinically feasible, we are dependent
on donor derived RBC transfusions with its associated
complications.

Acknowledgement
We thank Dr. Martin Ellis for reviewing the manuscript.

References
1 Carson JL, Grossman BJ, Kleinman S, et al.: Red blood cell
transfusion: a clinical practice guideline from the AABB*.
Ann Intern Med 2012; 157:4958
2 Bolton-Maggs P, Doles D, Watt A, et al.: The 2012 annual
SHOT report. http://www.shotuk.org/shot-reports/report-summary-and-supplement-2012.
3 Fatalities Reported to FDA Following Blood Collection and
Transfusion: Annual Summary for Fiscal Year 2012 http://
www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/ucm346639.htm.
4 Arewa O, Akinola N, Salawu L: Blood transfusion reactions;
evaluation of 462 transfusions at a tertiary hospital in Nigeria. Afr J Med Med Sci 2009; 38:143148
5 Waiswa MK, Moses A, Seremba E, et al.: Acute transfusion
reactions at a national referral hospital in Uganda: a prospective study. Transfusion 2014; 58:28042010
6 Boctor F: Overt immediate hemolytic transfusion reaction
attributable to anti-Wr(a). Immunohematology 2008; 24:113
115
7 Arndt P, Leger R, Garraty G: Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune
hemolytic anemia. Transfusion 2012; 52:602612
8 Janatpour KA, Kalmin ND, Jensen HM, et al.: Clinical outcomes of ABO-incompatible RBC transfusions. Am J Clin
Pathol 2008; 129:276281
9 Berseus O, Boman K, Nessen SC, et al.: Risks of hemolysis
due to anti-A and anti-B caused by the transfusion of blood
or blood components containing ABO-incompatible plasma.
Transfusion 2013; 53(Suppl 1):114S123S
10 Tormey C, Stack G: Delayed intravascular haemolysis following multiple asymptomatic ABO-incompatible red blood cell
transfusions in a patient with hepatic failure. Vox Sang 2008;
95:232235
11 Petz D, Garratty G: Immune Hemolytic Anemia, 2nd ed.
London, United Kingdom, Churchill Livingstone, 2004.

12 Stowell SR, Winkler AM, Maier CL, et al.: Initiation and regulation of complement during hemolytic transfusion reactions.
Clin Dev Immunol 2012; 2012:307093
13 Winslow RM: Oxygen: the poison is in the dose. Transfusion
2013; 53:424437
14 Rother R, Bell L, Hillmen P, et al.: The clinical sequelae of
intravascular hemolysis and extracellular plasma hemoglobin:
a novel mechanism of human disease. JAMA 2005;
293:16531662
15 Tinegate H, Birchall J, Gray A, et al.: Guideline on the investigation and management of acute transfusion reactions. Prepared by the BCSH Blood Transfusion Task Force. Br J
Haematol 2012; 159:143153
16 Sazama K: Reports of 355 transfusion-associated deaths:
1976 through 1985. Transfusion 1990; 30:583590
17 Weinstock C, Mohler R, Dorn C, et al.: ABO- Incompatible
red blood cell transfusion: successful use of eculizumab for
treatment of the acute hemolytic reaction. Vox Sang 2014;
107(Suppl. 1):29
18 Wouters D, Stephan F, Strengers P, et al.: C1-esterase inhibitor concentrate rescues erythrocytes from complement-mediated destruction in autoimmune hemolytic anemia. Blood
2013; 121:12421244
19 Delaney M, Dinwiddie S, Nester T, et al.: The immunohematologic and patient safety benefits of a centralized transfusion
database. Transfusion 2013; 53:771776
20 Goodnough L, Shander A: Current status of pharmacologic
therapies in patient blood management. Anesth Analg 2013;
116:1534
21 Zeuner A, Martelli F, Vaglio S, et al.: Concise review: stem
cell-derived erythrocytes as upcoming players in blood transfusion. Stem Cells 2012; 30:15871596
22 Miller S, Kim H, Weiner D, et al.: Red blood cell alloimmunization in sickle cell disease: prevalence in 2010. Transfusion
2013; 53:704709
23 Sanz C, Nomdedeu M, Belkaid M, et al.: Red blood cell alloimmunization in transfused patients with myelodysplastic
syndrome or chronic myelomonocytic leukemia. Transfusion
2013; 53:710715
24 Garratty G: What do we mean by Hyperhaemolysis and
what is the cause? Transfus Med 2012; 22:7779
25 Yazdanbakhsh K, Ware RE, Noizat-Pirenne F: Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management. Blood 2012; 120:528537
26 Vagace JM, Casado MS, Bajo R, et al.: Hyperhaemolysis syndrome responsive to splenectomy in a patient with db-thalassaemia: a discussion on underlying mechanisms. Blood
Transfus 2014; 12:127129
27 Garratty G: Immune hemolytic anemia associated with drug
therapy. Blood Rev; Elsevier Ltd, 2010; 24:143150
28 Hoppe C, Klitz W, Vichinsky E, et al.: HLA type and risk of
alloimmunization in sickle cell disease. Am J Hematol 2009;
84:462464
29 Schonewille H, Doxiadis I, Levering W, et al.: HLA-DRB1
associations in individuals with single and multiple clinically
relevant red blood cell antibodies. Transfusion 2014;
54:19711980

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219

Handling a transfusion haemolytic reaction 19

30 Zimring J, Hendrickson J: The role of inflammation in alloimmunization to antigens on transfused red blood cells.
Curr Opin Hematol 2008; 15:631635
31 Zimring J, Stowell S, Johnsen J, et al.: Effects of genetic, epigenetic, and environmental factors on alloimmunization to
transfused antigens: current paradigms and future considerations. Transfus Clin Biol 2012; 19:125131
32 Zalpuri S, Zwaginga J, Le Cessie S, et al.: Red-blood-cell alloimmunization and number of red-blood-cell transfusions.
Vox Sang 2012; 102:144149
33 Zalpuri S, Schonewille H, Middelburg R, et al.: Effect of storage of red blood cells on alloimmunization. Transfusion
2013; 53:27952800
34 Young P, Uzieblo A, Trulock E, et al.: Autoantibody formation after alloimmunization: are blood transfusions a risk factor for autoimmune hemolytic anemia? Transfusion 2004;
44:6772

35 Noizat-Pirenne F, Bachir D, Chadebech P, et al.: Rituximab

for prevention of delayed hemolytic transfusion reaction in
sickle cell disease. Haematologica 2007; 92:e132e135
36 Win N, Sinha S, Lee E, et al.: Treatment with intravenous
immunoglobulin and steroids may correct severe anemia in
hyperhemolytic transfusion reactions: case report and literature review. Transfus Med Rev 2010; 24:6467
37 Tormey CA, Stack G: Limiting the extent of a delayed hemolytic transfusion reaction with automated red blood cell
exchange. Arch Pathol Lab Med 2013; 137:861864
38 Blumberg N, Heal J, Gettings K: WBC reduction of RBC transfusions is associated with a decreased incidence of RBC alloimmunization. Transfusion 2003; 43:945952
39 Unni N, Peddinghaus M, Tormey C, et al.: Record fragmentation due to transfusion at multiple health care facilities: a risk
factor for delayed hemolytic transfusion reactions. Transfusion 2014; 54:98103

2015 International Society of Blood Transfusion, ISBT Science Series (2015) 10 (Suppl. 1), 1219