review
How we treat delayed haemolytic transfusion reactions in
patients with sickle cell disease
Kate Gardner,1,2 Carolyn Hoppe,3 Aleksandar Mijovic2 and Swee L. Thein1,2,4
1
Molecular Haematology, Faculty of Life Sciences & Medicine, King’s College London, 2Department of Haematological Medicine,
King’s College Hospital NHS Foundation Trust, London, UK, 3Division of Hematology/Oncology, Children’s Hospital and Research
Center Oakland, Oakland, CA, and 4National Institutes of Health/National Heart Lung and Blood Institute, Sickle Cell Branch, Beth-
esda, MD, USA
Summary
Transfusion therapy is effective in the prevention and treat-
ment of many complications of sickle cell disease (SCD).
However, its benefits must be balanced against its risks,
including delayed haemolytic transfusion reactions (DHTR).
Not only is the relative rate of alloimmunization higher in
patients with SCD than in other patient populations, but
attendant risks associated with DHTR are even greater in
SCD. Clinicians’ awareness of DHTR events is poor because
symptoms of DHTR mimic acute vaso-occlusive pain and
immunohaematology findings are often negative. Transfu-
sions delivered in the acute rather than elective setting
appear to confer a higher risk of DHTR. Management of
DHTR in SCD depends on the clinical severity, ranging from
supportive care to immunosuppression, and optimization of
erythropoiesis. DHTR must be considered in any recently
transfused patient presenting with acute sickle cell pain.
Meticulous documentation of transfusion and immunohae-
matology history is key. We anticipate an increase in DHTR
events in SCD patients with the increasing use of red blood
cell transfusion therapy.
Keywords: delayed haemolytic transfusion reactions, hyper-
haemolysis, vaso-occlusive crisis, alloantibodies, sickle cell
disease.
Blood transfusion is the most effective treatment for the pre-
vention and management of many acute and chronic compli-
cations of sickle cell disease (SCD), including primary and
secondary stroke prevention, acute management of stroke,
acute chest syndrome (ACS), splenic sequestration and acute
multi-organ failure (Adams et al, 1998; DeBaun et al, 2014;
National Institutes of Health: National Heart Lung and
Correspondence: Swee L. Thein, National Heart, Lung, and Blood
Institute, NIH, Building 10-CRC/5E-5142, 10 Center Drive, Bethesda,
MD 20892, USA.
E-mails: sl.thein@nih.gov; sl.thein@kcl.ac.uk
ª 2015 John Wiley & Sons Ltd
British Journal of Haematology, 2015, 170, 745–756
Blood Institute 2014). The beneficial effects of transfusion
therapy observed in recent clinical trials are expanding their
indication and utilization, contributing to an increased use
of blood (Drasar et al, 2011; Steinberg, 2014). Nonetheless,
transfusion is not without risks; haemolytic transfusion reac-
tions and iron overload are common side effects, while trans-
mission of infections remains a significant issue in some
countries. Alloimmunization to red blood cell (RBC) anti-
gens is a major complication of transfusion and the underly-
ing cause of the majority of delayed haemolytic transfusions
reactions (DHTR). DHTR occurs from 24 h up to 21 d after
a transfusion. It is a secondary immune phenomenon, typi-
cally arising after recrudescence of an alloantibody to which
the patient had been immunized, but which later evanesced
and became undetectable by the standard compatibility tests.
However, particularly in the setting of SCD, new alloantibod-
ies are not always detected in the plasma or eluate of the
patients with an otherwise typical DHTR, invoking other
pathological mechanisms. A key challenge is that DHTR in
SCD is under-recognized, not only because it mimics the
clinical events in acute vaso-occlusive crisis (VOC), but
because serological markers of alloimmunization are often
equivocal. Furthermore, DHTR itself often triggers VOC in
SCD, which can lead to life-threatening complications. The
first DHTR cases in SCD were probably documented by Dia-
mond et al (1980), who described four patients with DHTRs
presenting as sickle cell crises. Diamond emphasized then,
that DHTR should be considered whenever a recently trans-
fused patient with SCD presents with VOC-type symptoms.
There is a current lack of evidence in the area to inform
best practice. Here, we present five real-life case scenarios
that highlight the risks and challenges in the management of
DHTRs.
Cases
Case 1
A 54-year-old multiparous British woman of African-
Caribbean origin with sickle cell anaemia (HbSS) and a
First published online 13 May 2015
doi: 10.1111/bjh.13494

Review
previous history of ACS requiring ventilator support and
RBC immunization (anti-Jkb, -McCa, -C and –E and a warm
reacting anti-HI) had a historical DHTR treated with intrave-
nous (IV) steroids. She repeatedly declined hydroxycarba-
mide therapy. She presented with acute pain typical of a
VOC, cough and fevers, and chest radiograph-documented
ACS. She was treated with IV antibiotics, oxygen and trans-
fused with two RBC units via a blood warmer under IV
methylprednisolone cover. Ten days later, she developed
increasing oxygen requirements, high fever and haemoglobin-
uria, and was transferred to critical care for non-invasive
respiratory support. A computed tomography (CT) scan of
her chest demonstrated deteriorating changes. An acute drop
in haemoglobin (Hb) to below the pre-transfusion level of
61 g/l (baseline Hb 79 g/l), along with an increase in the
HbS fraction to the pre-transfusion level of 90%, an acute
rise in lactate dehydrogenase (LDH) peaking at 3576 iu/l
(baseline 389 iu/l), and a fall in reticulocyte count to
59 9 109/l (baseline 178 9 109/l), were consistent with
DHTR (see figure 1A). She also had an acute kidney injury
(peak serum creatinine 136 lmol/l, baseline 66 lmol/l).
Given her respiratory compromise, a decision was made to
transfuse further, but with immunosuppression. Her Hb was
measured twice daily during this period to guide transfusion
management; as she continued to haemolyse, a total of six
units of RBCs were transfused incrementally over 2 d
together with 2 d each of IV methylprednisolone 500 mg/d
and IV Immunoglobulin (IVIg) 1 g/kg/d. Direct antiglobulin
test (DAT) was negative at the peak of haemolysis, but
became positive 13 d after the first transfusion. All subse-
quent RBC alloantibody screens were negative (including
RBC eluate), respiratory function slowly improved allowing
critical care discharge, but her Hb remained low at 45 g/l
(baseline Hb 79 g/l), and so further immunosuppression
with rituximab was given at 100 mg weekly for 4 weeks.
Erythropoietin (EPO) was given at 10,000 iu for 3 d per
week in combination with IV iron. Reticulocytes slowly
increased 2 weeks after the final blood transfusion, followed
by an increase in Hb a week later (Fig 1A). However, she
remained dependent on oxygen, and was discharged on regu-
lar EPO therapy and home oxygen. Hydroxycarbamide ther-
apy was subsequently commenced.
Case 2
An 18-year-old West African man on hydroxycarbamide for
multiple sickle-related complications, presented with an acute
VOC, chest and back pain. He had had a previous DHTR
episode with a history of anti-Fya antibody. A chest radio-
graph demonstrated left basal consolidation and a small
pleural effusion. He was initially treated with IV antibiotics,
but because of increasing oxygen requirements he was given
an exchange RBC transfusion (total 13 RBC units
exchanged), and subsequently transferred to critical care for
non-invasive ventilator support. Pain control was -unusually
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difficult to manage and required patient-controlled analgesia
(PCA). After achieving some respiratory improvement, he
deteriorated 5 d after his initial transfusion, with increasing
oxygen requirements, fevers, haemoglobinuria and a recru-
descence in his pain. Blood samples were grossly haemolysed
with severe anaemia (Hb 39 g/l, baseline 95 g/l), relative reti-
culocytopenia (230 9 109/l, baseline 434 9 109/l), LDH
(2418 iu/l, baseline 418 iu/l) and bilirubin (216 lmol/l, base-
line 79 lmol/l). DAT was negative with no new antibodies
identified. He was transfused a further six units of RBCs
under immunosuppressive cover, which included a total of
2 g/kg IVIg and one dose of IV methylprednisolone. A rapid
improvement was seen. To date, he has not required subse-
quent blood transfusions (Fig 1B).
Case 3
A 52-year-old Jamaican woman with HbS/b0 thalassaemia
received a two unit pre-operative RBC transfusion 6 d prior
to an elective hysterectomy. Surgery was uneventful with
minimal blood loss and she was discharged after 48 h. On
post-operative day 9 (15 d post-transfusion), she re-pre-
sented as an emergency with fever and abdominal pain. IV
antibiotics were commenced and the patient was admitted
for presumed post-operative sepsis. Laboratory results dem-
onstrated a fall in Hb to 65 g/l (baseline 86 g/l), relative
reticulocytopenia (210 9 109/l, baseline 447 9 109/l), and
rise in LDH (3664 iu/l, baseline 422 iu/l). After receiving
three units of RBCs, the patient developed haemoglobinuria
with a further drop in the post-transfusion Hb level to 61 g/l
after 5 d, this time with a reticulocytosis (789 9 109/l). A
DHTR was suspected but the DAT was negative. She
remained haemodynamically stable, reticulocytes continued
to recover and a decision was made to withhold transfusion
of RBC. Her Hb recovered without further supportive ther-
apy. Subsequent DATs were negative until 17 d post pre-
operative (initial) transfusion / 2 d post second transfusion
(IgG 1+ only); all RBC alloantibody screens, as well as RBC
eluate analysis, were negative.
Case 4
A 56-year-old British woman of Jamaican origin with HbSC
presented with left sided weakness, dysphagia and headache.
Magnetic resonance angiography of the head demonstrated
infarction in the territory of the right posterior inferior cere-
bellar artery. She was given a RBC exchange transfusion; Hb
increased from 102 to 111 g/l post-exchange (baseline Hb
108 g/l), and total HbS+HbC from 93.3% to 11.8%. Neuro-
logical symptoms swiftly improved post-exchange transfusion
to allow discharge after 10 d. She re-presented 8 d post-
transfusion with a VOC (abdominal and back pain), plus
haemoglobinuria and fever. Her Hb had dropped signifi-
cantly to 77 g/l, LDH was elevated at 1563 iu/l (baseline
419 iu/l) and total bilirubin 42 lmol/l (baseline bilirubin
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British Journal of Haematology, 2015, 170, 745–756
 13652141, 2015, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.13494 by Nigeria Hinari NPL, Wiley Online Library on [16/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Review

(A)

(B)

(C)

Fig 1. Sequence of events and intervention in the three case scenarios. (A) Case 1: 54-year-old African British woman with HbSS. As the patient con-
tinued to haemolyse, rituximab was added as third line immunosuppression. At the peak of haemolysis, the patient developed reticulocytopenia of
59 9 109/l (from a baseline of 178 9 109/l); (B) Case 2: 18-year-old West African man with HbSS; (C) Case 3: 52-year-old Jamaican woman with
HbS/b0 thalassaemia. Hb, haemoglobin; DAT, direct antiglobulin test; LDH, lactate dehydrogenase; H, total haemoglobin A; HbS%, haemoglobin S
percentage of total haemoglobin; Retics, reticulocytes; RBS, red blood cell; EPO, erythropoietin; IV, intravenous; IVIg, intravenous immunoglobulin.

ª 2015 John Wiley & Sons Ltd 747

British Journal of Haematology, 2015, 170, 745–756

Review
13 lmol/l). Immunohaematology results demonstrated a
positive DAT (IgG 3+ and C3d 1+) with a new anti-S anti-
body. She was haemodynamically stable, and was given one
dose of IV methylprednisolone 500 mg. Her reticulocyte
count initially remained at baseline (but subsequently
increased to 493 9 109/l (from 160 9 109/l) with Hb
improvement, allowing discharge after 1 week. A decision
was taken to initiate a post-stroke exchange transfusion pro-
gramme with S-negative blood. Subsequent blood transfu-
sions have been uneventful, not only in the elective exchange
setting, but also in acute settings, including an admission
with a large subdural haematoma.
Case 5
A 14-year-old African-American female with HbSS, presented
with acute vaso-occlusive pain localized to the chest and
abdomen. PCA led to resolution of the chest pain, but no
improvement in the abdominal pain. By day 5, the Hb level
had decreased from a baseline of 90 g/l to 70 g/l; she was
transfused RBC with an appropriate rise in Hb to 99 g/l. Six
days after transfusion, she developed fever and worsening
abdominal pain with a drop in Hb to below pre-transfusion
levels (57 g/l). The indirect antibody test (IAT) and DAT
were negative and she received a second RBC transfusion
with only a modest increment in Hb to 70 g/l followed by a
rapid decline to 45 g/l; LDH increased to 11,244 iu/l and Hb
A was not detected by Hb electrophoresis, findings consistent
with a DHTR. Methylprednisolone (2 mg/kg/d) and erythro-
poietin (750 u/kg/d) were initiated and she received one dose
of IVIg (1 g/kg). Her Hb continued to decline to a nadir of
30 g/l, serum LDH rose to 22,270 iu/l, and plasma Hb was
4.68 g/l. Repeat IAT remained negative, but polyspecific
DAT was weakly positive. However, no alloantibody was
identified by elution. The patient’s clinical status rapidly
deteriorated with development of hypertension, renal failure,
overt pancreatitis and consumptive coagulopathy. She
became unresponsive with a fixed dilated right pupil; a head
CT scan revealed a large right temporo-parietal epidural
haematoma with midline shift, requiring neurosurgical evac-
uation. An interval CT, 24 h later, showed a new right occip-
ital epidural haematoma, requiring a second neurosurgical
procedure. A total of 11 units of RBC were transfused in the
perioperative period. Despite 2 weeks of treatment with daily
methylprednisolone and erythropoietin, the patient remained
anaemic. A trial of plasma exchange followed by RBC
exchange resulted in a sustained rise in Hb levels. Methyl-
prednisolone was tapered off and the patient discharged
5 weeks later, with remarkable recovery of her physical and
cognitive function. The patient continues to receive monthly
exchange RBC transfusions with no further complications.
No alloantibodies were ever detected in this patient. In the
elective setting she was able to receive RBC transfusion with-
out complications.
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Epidemiology and risk factors for DHTR
Alloimmunization and haemolytic transfusion reactions
(HTRs) are seen in all transfused populations. In a prospec-
tive study of a non-SCD population, alloimmunization
occurred in 2.6% of recipients with no previous history of al-
loimmunization, but 8.9% of those with previously detectable
antibodies developed additional alloantibodies (Heddle et al,
1995). However, despite this high frequency of alloimmuni-
zation, only 0.05% had clinical evidence of DHTR. In SCD,
rates of alloimmunization range from 7 to 49% (Vichinsky
et al, 1990; Garratty, 1997; Aygun et al, 2002; Castro et al,
2002; Lasalle-Williams et al, 2011; Wahl et al, 2012; O’Suoji
et al, 2013). Clinically-significant DTHRs have been reported
in 4–11% of patients with SCD who receive transfusions
(King et al, 1997; Talano et al, 2003; de Montalembert et al,
2011; Vidler et al, 2015). The antigens most frequently
involved in alloimmunization in SCD belong to the Rh and
Kell blood groups, followed by Kidd, Duffy, Lewis and MNS
blood group systems (Rosse et al, 1990; Vidler et al, 2015).
Despite Rh and Kell antigen matching of transfused units,
immunization to these antigens remains high (Chou et al,
2013; Mijovic et al, 2013).
It has been suggested that one possible reason for the rela-
tively high incidence of alloimmunization observed in the
SCD population is the mismatch in the RBC antigens
expressed in patients of African descent and donors of pri-
marily Northern European descent. Alloimmunization rates
are lower in patients who are transfused RBC units from eth-
nically similar donors [e.g., in Ugandan (Natukunda et al,
2010) and Jamaican (Olujohungbe et al, 2001) populations]
but the lower alloimmunization rate in SCD populations in
these countries may also be related to an overall lower expo-
sure to RBC transfusion. In the US, using a strategy of pur-
posefully sourcing black donors has reduced HTR rates
(Sosler et al, 1993; Wayne et al, 1993). More recently, Chou
et al (2013) found that a significant proportion of SCD
patients receiving phenotypic Rh- matched RBC transfusion
from exclusively African-American donors still became allo-
immunized. Molecular analyses of the RH genes in SCD
patients and African-American donors revealed remarkable
RH allelic diversity in this population and mismatch between
serological Rh phenotype and RHD or RHCE genotype due
to variant RH alleles in 87% of individuals (Chou et al,
2013). This suggests that for some SCD patients, RH geno-
typing in addition to serological typing is required to identify
compatible RBC.
Several risk factors have been identified in RBC alloimmu-
nization. First, children have been reported to have signifi-
cantly lower alloimmunization compared to older patients
even after accounting for total number of RBC units trans-
fused (Rosse et al, 1990). Second, females are also at
increased risk, owing in part to increased RBC antigen expo-
sure in pregnancy (Reisner et al, 1987; Schonewille et al,
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British Journal of Haematology, 2015, 170, 745–756

2006). Third, genotype may be a risk factor; DHTR in SCD
occurs most frequently but not exclusively in patients with
sickle cell anaemia (HbSS and HbS/b0 thalassaemia), com-
pared to HbSC patients, although this may reflect the greater
use of transfusion in the former genotypic group of patients.
However, as illustrated by Case 4, DHTR is not restricted to
sickle cell anaemia. Fourth, the risk of alloimmunization
increases with increasing number of transfusions (Rosse et al,
1990; Vichinsky et al, 1990; Bauer et al, 2007) but most al-
loimmunization occurs after fewer than 15 transfusions (Ros-
se et al, 1990). This may explain why the alloimmunization
rate in patients on chronic exchange-transfusion is not
greater than that in patients on chronic simple transfusion
(Wahl et al, 2012; Fasano et al, 2015). Fifth, the clinical con-
text of the RBC transfusion in SCD may play a role in the
development of alloimmunization and DHTR; specifically,
the risk of alloimmunization in SCD is increased if the trans-
fusion is delivered in an acute setting when the patient is in
an inflammatory state (Yazer et al, 2009; Fasano et al, 2015;
Vidler et al, 2015).
Pathophysiology
The key cause of DHTR is a recipient’s production of alloan-
tibodies against the donor’s RBC antigens after transfusion.
These alloantibodies may be either new antibodies, or eva-
nescent antibodies that were undetectable prior to transfu-
sion, but where re-exposure to a RBC antigen triggered an
anamnestic antibody response and activation of complement
(Stowell et al, 2012). Antibody evanescence, a phenomenon
crucial to the pathogenesis of DHTR in general, has been
reported for 37–51% of antibodies detected in the series
reported by Rosse et al (1990) and Harm et al (2014). The
latter group reported that in 63.6% of alloimmunized
patients, one or more alloantibodies evanesced; evanescing
antibodies were found in all blood group systems.
We use DHTR as an umbrella term, including cases with-
out serological confirmation of a new alloantibody, but with
unequivocal evidence of marked haemolysis following a
blood transfusion within the given timeframe. The terms
‘hyperhaemolytic’ transfusion reaction (HHTR) and “hyper-
haemolysis” syndrome are often used to describe cases of
more severe haemolysis, where Hb drops below pre-transfu-
sion levels due to destruction of both autologous and trans-
fused RBCs. The first cases of non-sickle HHTR were
described over 50 years ago (Stewart & Mollison, 1959; Heis-
to et al, 1960; van der Hart et al, 1963; Davey et al, 1980)
with subsequent cases in SCD (King et al, 1997; Petz et al,
1997). Petz and Garratty (2004a) found that DHTR in SCD
frequently manifested with atypical symptoms, such as pain-
ful crisis or haemoglobinuria; notably, new allo-antibodes
were never detected in 20% of cases, and in 7% they were
detected 72 h or longer after haemolysis became evident.
These authors felt that there were sufficient distinctive fea-
tures of these haemolytic episodes to be considered as an
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Review
entity, which they termed sickle cell haemolytic transfusion
reaction syndrome, rather than the somewhat confusing ‘hy-
perhaemolysis’ (Petz & Garratty, 2004a).
The pathophysiology of RBC alloimmunization in SCD
was comprehensively and recently reviewed by Yazdanbakhsh
et al (2012). Several mechanisms have been postulated to
explain haemolysis in situations of either ‘hyperhaemolysis’
(where some destruction of autologous cells is implied) and/
or haemolytic transfusions reactions without an identified
causative RBC alloantibody. Putative mechanisms include:
1 ‘Bystander haemolysis’ (King et al, 1997). Bystander haem-
olysis was first described by Petz and Garratty (2004b) as
‘immune haemolysis of cells that are negative for the anti-
gen against which the antibody is directed’.
 Complement membrane attack complex (‘MAC’) in
sickled RBC
 Sickled RBC expose cryptic antigens, high levels IgG
 Complement-mediated antibody reactions to other
transfused proteins (plasma proteins, HLA) (Garratty,
1997).
2 Auto-antibody formation (Zimring et al, 2007)
 Alloimmunization promotes autoantibody formation.
Autoantibody formation is higher in SCD than non-
SCD populations with a cumulative incidence 6–10%
(Castellino et al, 1999; Aygun et al, 2002; Garratty,
2004; Young et al, 2004; Lasalle-Williams et al, 2011).
Studies suggest that alloantibody binding to the RBCs
induce conformational changes in the antigen epitope
that signal production of autoantibodies. Also, there
may be a subset of patients who are genetically predis-
posed to develop RBC autoantibodies that could reflect
an overall dysfunction of the immune system (Castelli-
no et al, 1999).
3 HLA antibody formation (Win et al, 2001): instead of
antibodies against specific RBC antigens
4 Suppression of erythropoiesis (Petz et al, 1997; Petz, 2006)
5 Instigation of an acute pain episode, RBC sickling and
consequential autologous haemolysis
6 Excessive eryptosis via exposure of phosphatidylserine (PS)
on RBC membrane signals suicidal RBC death: ‘eryptosis’
(Chadebech et al, 2009). PS exposure increases comple-
ment binding and potentiates destruction by macrophages
through PS receptors.
The concept of HHTR is particularly complicated in SCD
because of the ongoing background of chronic haemolysis
upon which an acute DHTR event occurs. Furthermore, as
DHTR itself can trigger another VOC, patients with SCD
tend to develop brisker haemolysis. In SCD the distinction
between haemolysis of ‘self’ RBCs as against ‘transfused cells’
can be traced by Hb electrophoresis that differentiates ‘self’
RBCs (HbS) from ‘transfused’ RBCs (HbA). In a classical
DHTR event, the lysis is mainly that of the transfused cells
749

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resulting in a sharp decrease in HbA% and a concomitant
increase in HbS%.
Defining and diagnosing DHTR
Definitions of DHTR vary and are ambiguous for many rea-
sons, as discussed above, but a key feature is an acute drop
in Hb in the context of a recent blood transfusion. Temporal
association with transfusion does not prove that the haemol-
ysis is a genuine transfusion reaction given the ongoing base-
line haemolysis in patients with SCD. While DHTR mimics
the events of a vaso-occlusive sickle crisis, it often triggers
another acute VOC resulting in a brisker haemolysis, that
may lead to other life-threatening complications such as
multi-organ failure, as observed in Case 5. Furthermore,
immune-haematology findings are often negative and sero-
logical findings do not necessarily correlate with clinical
severity.
The literature acknowledges the difficulties in defining
DHTR in SCD. We suggest a definition of DHTR in SCD as
a significant drop in Hb (of more than 25%) occurring
Fig 2. Proposed pathway for diagnosis and management of DHTR in SCD. SCD, sickle cell disease; VOC, vaso-occlusive crisis; Hb, haemoglobin;
DHTR, delayed haemolytic transfusion reaction; G6PD, glucose-6-phosphate dehydrogenase; DAT, direct antiglobulin test; LDH, lactate dehydro-
genase; HbA, haemoglobin A; HbS, haemoglobin S; ESA, erythropoiesis-stimulating agent.
Note: There is no one clear diagnostic test for DHTR in SCD.
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between 1 and 21 d post-transfusion. The drop in Hb is
associated with immuno-haematology evidence (new RBC
antibodies, positive DAT) with high performance liquid
chromatography evidence of destruction of transfused cells
over self RBCs (accelerated increase in HbS% and corre-
sponding fall in HbA%), evidence of prominent haemolysis
(striking rise in LDH, haemoglobinuria), and relative reticul-
ocytopenia (compared to baseline). Alternative causes of Hb
drop must be excluded, notably perioperative blood loss,
transient RBC aplasia due to infection and glucose-6-phos-
phate dehydrogenase deficiency.
Diagnosing DHTR
Delayed haemolytic transfusion reactions in SCD encom-
passes a spectrum of clinical severity, ranging from mild
cases when patients can be monitored closely as outpatients,
to fatal cases (El-Husseini & Sabry, 2010). Symptoms include
fever and pain, typically described as an acute VOC, but cru-
cially in the context of a recent RBC transfusion. On direct
questioning, patients may also report ‘dark’ or ‘Coca-Cola
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Table I. Differentiating DHTR from VOC episodes in SCD.
DHTR
Context Recent RBC transfusion (within 2–21 d)
Symptoms Pain, fever, haemoglobinuria
Reticulocytes Variable – relative reticulocytopenia or elevated
LDH Highly elevated (several times patient’s baseline LDH)
Hb quantitation Decrease in Hb to below post- and sometimes, pre-transfusion
level, rapid clearance of HbA% with concomitant
increase in HbS%
Immunohaematology DAT positive (~75%) or negative (~25%); new
RBC alloantibody detected in some cases
May require RBC eluates
DHTR, delayed haemolytic transfusion reaction; VOC, veno-occlusive crisis; SCD, sickle cell disease; RBC, red blood cell; LDH, lactate dehydroge-
nase; DAT, direct antiglobulin test.
coloured’ urine indicative of haemoglobinuria. The timing of
presentation is variable. Our cases occurred from 5 to 16 d
following a transfusion, consistent with previous reports (Ta-
lano et al, 2003; de Montalembert et al, 2011). However,
instances of very delayed HTR, occurring as late as 4 weeks
post-transfusion have been reported. We suggest an algo-
rithm and work-up for diagnosing DHTR (Fig 2) and fea-
tures that differentiate DHTR from acute VOC in SCD
(Table I).
It is important to obtain previous transfusion records of
the patient and antibody testing from other centres. A sus-
pected DHTR should be promptly investigated to facilitate
future sourcing of blood should the patient require transfu-
sion. Timing of testing is important; given that clinical mani-
festations typically occur 6–10 d post-transfusion at a time
when serology may be negative, sequential testing at outpa-
tient follow-up or deterioration after discharge may capture
a positive antibody finding that was initially negative.
The full blood count in DHTR demonstrates a marked
drop in Hb. At the severe end of the spectrum (‘hyperhaem-
olysis’), Hb falls below pre-transfusion levels, implying that
both recipient and donor RBCs are lysed. Haemolytic mark-
ers, in particular LDH, become more abnormal than at base-
line. An unexplained finding is the reticulocyte count in
DHTR; not only do many patients lack a compensatory,
appropriate reticulocytosis, but many also appear to exhibit
frank reticulocytopenia in the most acute stages as demon-
strated in Cases 1 and 3. While Case 1 demonstrated absolute
reticulocytopenia, Case 3 had an inappropriately low reticu-
locyte count at peak haemolysis. As expected, reticulocytosis
heralds Hb increase and recovery from DHTR. Indeed, the
duration and severity of the DHTR may be related to the
patient’s ability to mount a reticulocyte response – Case 1
demonstrates a drawn-out DHTR period with a slow ery-
throid recovery despite EPO therapy. Hb recovery is possibly
dependent on age of the patient, with the cumulative effects
of bone marrow infarction in older patients hindering eryth-
ropoietic recovery. Other factors that may influence erythroid
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Review
VOC episodes
Any
Pain, fever
Frequently elevated from baseline unless transient RBC
aplasia from acute infection e.g. Parvovirus
Mildly elevated compared to patient’s baseline LDH
Unchanged or mild decrease from baseline (or if
transfused, appropriate increase in Hb)
DAT negative
recovery are iron deficiency (absolute or functional), inade-
quate erythropoietin response or suppression of erythropoie-
sis by pro-inflammatory cytokines (e.g. tumour necrosis
factor a, c-interferon).
Quantitation of HbA% and HbS% helps define whether
haemolysis is mainly lysis of donor cells (brisk reduction in
HbA% and swift increase in HbS%), in contrast with auto-
haemolysis. Sequential testing of HbA% and HbS% helps to
capture the trajectory of the haemolysis.
Direct antiglobulin test is imperative for all immune-
mediated haemolytic episodes. While, by definition, positive
in non-sickle DHTR in general, it was found to be negative
in 21–26% DHTR episodes (Petz & Garratty, 2004b; Vidler
et al, 2015) and in 7 of the 9 DHTR episodes in the series
reported by Talano et al (2003). Thus, while a positive
DAT is diagnostic, a negative DAT does not rule out
DHTR in SCD. If the DAT is positive, and no new alloan-
tibody is detectable in the plasma, antibody elution should
be performed in an attempt to identify the antibody. Alter-
natively, the presence of a newly detected alloantibody in
the plasma confirms the diagnosis of DHTR. If testing is
initially negative, it is important to retest to maximize the
chance of ‘capturing’ an alloantibody at peak titres. How-
ever, in ours and others’ experience, new RBC alloantibod-
ies are frequently not detected (Talano et al, 2003; de
Montalembert et al, 2011; Vidler et al, 2015). Again, this
contrasts with most non-sickle DHTRs, suggesting that
mechanisms other than antibody-mediated RBC destruction
are involved.
Patient management
Decision to treat should be guided by clinical status of the
patient and not on laboratory values – neither positive DAT
nor identification of a new alloantibody is a prerequisite for
DHTR treatment. Current management of DHTR in SCD is
empirical. There is no evidence base in SCD (other than case
series and general consensus among practitioners) in the
751

Review
management of DHTR, including no clinical trials on the use
of immunosuppressive agents (steroids, IVIg and rituximab).
Furthermore, these treatments may have particular issues for
patients with SCD, e.g., rebound pain on steroid cessation
(Darbari et al, 2008), IVIg and hyperviscosity risk (Vichinsky
et al, 2001). We suggest a combination of four strategies: (i)
supportive care (ii) optimization of erythropoiesis, (iii) con-
sideration of immunosuppression and (iv) minimizing fur-
ther RBC transfusion if possible. Throughout this process,
and until a safe Hb is achieved and sustained, laboratory
results (including Hb, reticulocyte count, LDH, and HbS/
HbA levels) must be monitored carefully. The initial aim is
to get the Hb to a clinically feasible minimum, which may
well be below the patient’s steady state Hb. A suggested path-
way for diagnosis and management of DHTR is shown in
Fig 2.
Supportive care
Patients are at risk of developing a Hb-induced tubulopathy
and associated acute kidney injury, hence maintaining fluid
balance, renal function and a good urine output, is of prime
importance. Clinicians must be vigilant for the development
of other acute sickle phenomena such as ACS, stroke and
multi-organ failure.
Directed treatments
In severe cases of HTR, where intervention is warranted, a
dual pronged treatment approach is suggested. First, some
form(s) of immunosuppression must be instituted, and sec-
ondly, erythropoiesis must be optimized.
Immunosuppression. Corticosterioids, IVIg, and rituximab
have been utilized in the treatment of DHTR/HHTR in SCD.
Corticosteroids: Corticosteroid therapy may be beneficial in
DHTR; however, the potential risks of steroids need to be
balanced against their potential life-saving effect and should
not be withheld in life-threatening cases. Systemic corticos-
teroids decrease the severity of ACS and vaso-occlusive
events, but when stopped abruptly, are associated with a
rebound effect. Using a tapering regimen may ameliorate the
rebound effect (as in Case 5). Neurological events have been
noted in some patients receiving steroids; however, its causal
relationship is unclear. These patients also had several co-fac-
tors including hypertension, hyperviscosity and high Hb lev-
els (Elenga et al, 2008). The potential risks of steroids need
to be balanced against their potential life-saving effect and
should not be withheld in life-threatening cases. In children,
we recommend 2 mg/kg/d of prednisolone with a maximum
dose of 60 mg/d, followed by a very slow tapering (weeks) of
steroids to prevent rebound vaso-occlusive pain events. In
adults, we have used higher steroid doses (methylpredniso-
lone 0.5 g daily) over a shorter period (up to 5 d) without
undue toxicity.
752
13652141, 2015, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.13494 by Nigeria Hinari NPL, Wiley Online Library on [16/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
IVIg and Immunomodulation: IVIg alone has been used
successfully in DHTR (Cullis et al, 1995), but more com-
monly, it is used in combination with steroids (Win et al,
2001, 2010; Scheunemann & Ataga, 2010). Severe DHTR has
been successfully managed using a combination of IVIg and
steroids, and withholding transfusion (Win et al, 2010). We
have used IVIg 1 g/kg/d for 1–2 d in both children and
adults.
Rituximab: More recently, rituximab has emerged as a
third line agent in refractory episodes of DHTR (Delmonte
et al, 2013; Noizat-Pirenne et al, 2015) or prophylactically in
polyimmunized patients with previous DHTR (Noizat-Pir-
enne et al, 2007; Bachmeyer et al, 2010). Rituximab dosing
schedules varied in the literature; we have used both low-
dose (100 mg IV once per week for 4 weeks) and standard-
dose (375 mg/m2 weekly 94). As rituximab causes significant
depletion of B lymphocytes, its use must be used judiciously
clinicians must be alert to the potential increased risk of
infection in patients who are already immunocompromized.
Optimizing erythropoiesis. Innate erythropoiesis can be maxi-
mized with a combination of an erythropoiesis-stimulating
agent (ESA) and IV iron. ESA can have particular benefit in
the DHTR setting (de Montalembert et al, 2011), even when
endogenous erythropoietin levels are elevated, because the
erythropoietin level is inappropriately low for the degree of
anaemia (Sherwood et al, 1986). In patients who develop
renal failure, higher doses of ESA, ranging from 150 to
250 u/kg/d, may be necessary and appear to be well tolerated
(Roger et al, 1991; Steinberg, 1991; Tomson et al, 1992). In a
randomized trial utilizing ESA doses up to 800 u/kg/d (Nagel
et al, 1993) in patients with renal failure, no side effects were
observed. Similarly high doses have been used effectively in
SCD cases with life-threatening DHTR (Little et al, 2006).
We suggest high-dose erythropoietin (250–800 u/kg/dose)
three times weekly, with close monitoring for hypertension,
thrombosis and bone pain. Intra-venous iron supplementa-
tion is indicated if transferrin iron saturation is <20%, due
to the inability to mobilize stored iron adequately (Nagel
et al, 1993).
Blood transfusion. Transfusion will be unavoidable in a sub-
set of cases. If the patient has life-threatening anaemia with
co-existent organ complications, e.g. ACS and respiratory
failure, further transfusion to improve oxygen delivery can
prove essential. Needless to say, blood units should be
selected as stringently as possible, although this will often
require additional donation testing or provision of blood
from frozen stocks.
Other measures. Two case reports have highlighted the use-
fulness of apheresis procedures in the management of severe
DHTR in patients with SCD. Uhlmann et al (2014) described
a modified plasma exchange procedure with return of donor
RBCs in a patient with heart failure (Uhlmann et al, 2014);
ª 2015 John Wiley & Sons Ltd
British Journal of Haematology, 2015, 170, 745–756

Kalyanaraman et al (1999) described a case with acute renal
failure following DHTR where a whole blood exchange
significantly contributed to patient recovery. Apheresis proce-
dures remain a somewhat heroic measure that should be
reserved for selected cases with DHTR in SCD.
Future patient management
Once a patient has become alloimmunized, they are at
increased risk of producing additional antibodies (Silvy et al,
2014), and thus at high risk for another DHTR. Future trans-
fusion needs must be individually determined based on the
particular risk benefit analysis for that patient.
More widely, DHTR events may be considered as a
prompt to initiate hydroxycarbamide in the patients consid-
ered ‘untransfusable’ to maximize Hb levels and hopefully
minimize transfusion needs in the longer term. This strategy
is logical but needs an evidence base to transfer the idea of
severe DHTR being an indication for hydroxycarbamide.
Going one step further, such ‘untransfusable’ patients, who
in our experience constitute 10% of alloimmunized SCD
patients (Mijovic et al, 2013), could be candidates for alloge-
neic haemopoietic stem cell transplantation However, it
should be pointed out that peri-transplant procedures may
well require blood transfusion until donor cells engraftment.
Strategies for prevention of DHTR in SCD
A simple, but possibly most effective, preventative strategy is
to maintain good documentation of antibody history. Some
countries in Europe, including National Health Service
Blood and Transplant in the UK, operate national central-
ized electronic database systems; in the United States, regio-
nal centralized networks have been set up to prevent
incompatible RBC transfusion to patients with evanesced
alloantibodies, who often attend more than one hospital to
receive transfusions (Harm et al, 2014). Where centralized
databases are not available, laboratory information manage-
ment systems must be carefully updated and additional mea-
sures, such as patient cards/letters or bracelets containing
information about detected antibodies, should be imple-
mented.
Strategies to prevent alloimmunization in SCD include (i)
transfusion from ethnically-matched donors and (ii)
extended RBC antigen matching. Notably, using ethnically-
matched blood may reduce rather than eliminate DHTR
given the significant RBC antigen heterogeneity in the black
population (Chou et al, 2013). This is complicated by the
high incidence of sickle cell trait in black donors; blood from
donors with sickle cell trait causes blockages of the filters
during leucodepletion (Beard et al, 2004); in addition, the
use of AS donors complicates tracking of HbS versus HbA
levels.
Prophylactic antigen matching for highly immunogenic
Rh (D, C, E, c, e) and Kell antigens has been shown to dra-
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Review
matically decrease alloimmunization rates in SCD and is rec-
ommended in most developed countries. Further extension
of antigen matching, to include Kidd, Fya and, whenever
possible, Lewis and MNS system antigens, has the potential
to reduce alloimmunization even further (Lasalle-Williams
et al, 2011). However, the cost-benefit and reproducibility of
such an approach needs to be determined. UK guidelines
recommend performing an extended RBC phenotype of
ABO, Rh, Kell, Kidd, Duffy and S/s antigens on SCD patients
prior to receiving any transfusions (Milkins et al, 2013).
With regard to antigen matching, all UK centres routinely
prophylactically match RBC units for SCD patients for ABO,
RhD, -C, -c, -E, -e and K antigens.
Molecular testing has revealed high rates of variant RHD/
RHCE alleles and consequent partial Rh antigens giving rise
to alloantibodies in patients deemed to be antigen-positive
serologically (and the antibodies are sometimes consequently
deemed to be autoantibodies as a result) (Chou et al, 2013).
These data suggest a role for genotyping, at least for those
patients with previous DHTR events, being rolled out into
clinical practice.
Special case: peri-operative transfusion
Perioperative transfusions and DHTR represents a special
case. In SCD, blood transfusion in the preoperative, elective
setting is on the increase, guided by the recent TAPS (Trans-
fusion Alternatives Preoperatively in SCD) study (Howard
et al, 2013), which found increased complications in non-
transfused patients. We note that in the TAPS trial, there
was only one incidence of alloimmunization at 3 months
follow-up from a transfusion group of 34. Lower rates of al-
loimmunization event in the TAPS trial compared to the
1995 (Vichinsky et al, 1995) study might relate to stricter
RBC matching.
Case 3 in this article, and other case reports (McGlennan
& Grundy, 2005) highlight some of the particular diagnostic
dilemmas in assessing for DHTR peri-operatively. Interpreta-
tion of blood results can be particularly confusing in those
who have had pre-operative transfusion with significant sur-
gical blood loss. Furthermore, post-operatively, the patient is
at risk for development of VOC and ACS in SCD, and this
leads many practitioners to have a low threshold for transfu-
sion. The decision to transfuse must therefore be made in the
context of consideration of DHTR as a possible differential
diagnosis in the post-operative transfusion setting.
Conclusion
Delayed haemolytic transfusion reactions in SCD continues
to challenge clinicians from diagnostic, therapeutic and pro-
phylactic perspectives. Diagnosis is best made by simply
being aware of DHTR when patients present with acute pain
following a recent transfusion; diagnosis cannot simply be
put down to uncomplicated VOC without further investiga-
753
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Review

tion. Recognition of DHTR is vital; not only is DHTR itself
potentially life-threatening, but giving a further transfusion
in this setting can prove fatal. It is notable that most trigger
transfusions for DHTR events are delivered in the acute
rather than elective setting; thus, a patient presenting acutely
again (after receiving transfusion for their first VOC) should
provide a prompt to consider DHTR. Management of DHTR
is dictated by the clinical severity. Many patients can be
managed conservatively, with close clinical and laboratory
monitoring until reticulocytes and Hb recover. If patients do
need an intervention, further blood transfusion should be
kept at the clinically feasible minimum with immunosup-
pression and optimization of erythropoiesis. While data are
limited, plasma and/or RBC exchange transfusion may also
be considered in selected cases, especially in patients who
develop additional complications that require repeated trans-
fusion.
Prevention is the key to reducing the overall burden of
DHTR in the SCD population; extended RBC phenotyping
and antigen matching of transfused units have significantly
reduced alloimmunization rates. There is growing evidence
for genetic testing of patients with SCD, particularly for
RHD and RHCE loci, which warrants further evaluation from
both clinical and cost-effectiveness standpoints. The future
may see molecular testing of both patients and donors, as
high throughput sequencing becomes less costly. This would
enable an even more individualized approach to transfusion
medicine.
Acknowledgements
We thank Dr Elliott Vichinsky (Children’s Hospital and
Research Center Oakland, Division of Hematology/Oncology,
Oakland, CA 949609, USA, for his incisive and helpful com-
ments. We also thank Claire Steward and Robin Swabey for
help in preparation of the manuscript.
Author contributions
All authors reviewed the literature, wrote and contributed to
the manuscript.
Conflict of interest
The authors declare no competing financial interest.

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