review
How I manage sickle cell patients with high transcranial
doppler results
John Brewin,1 Banu Kaya2 and Subarna Chakravorty3
1
Department of Haematology, King’s College London, 2Department of Haematology, Royal London Hospital, and 3Department of Pae-
diatric Haematology, King’s College Hospital, London, UK
Summary
Stroke is one of the most severe complications to affect chil-
dren with sickle cell anaemia (SCA). Transcranial doppler
(TCD) is an accurate and non-invasive method to determine
stroke risk. Randomised controlled trials have demonstrated
the efficacy of chronic transfusion therapy in stroke preven-
tion based on risk stratification determined by TCD veloci-
ties. This has led to the regular use of TCD monitoring for
children with SCA in order to determine stroke risk. Signifi-
cant resource allocation is necessary to facilitate training,
quality assurance and failsafe arrangements for non-atten-
ders. In a subgroup of patients, chronic transfusions for
primary stroke prevention can be replaced by hydroxycar-
bamide therapy, provided careful monitoring is undertaken;
including repeat TCD studies at frequent intervals. The
authors propose an evidence-based algorithm for the man-
agement of abnormal TCD velocities and discuss the role of
this test in other clinical contexts, such as in Haemoglobin
SC disease.
Keywords: sickle cell disease, transcranial doppler, stroke,
vasculopathy.
Sickle Cell Anaemia (SCA) is one of the most common
monogenic disorders in the world, arising from a single
point mutation in the beta globin gene (HBB) and leading to
haemoglobin polymerisation and abnormal red cell confor-
mation, causing vessel occlusion and ischaemia-reperfusion
injury. It is estimated that about 100 000 people in the U.S.
and over 10 000 in the United Kingdom are affected with
either the homozygous disease state (SCA) or compound
heterozygous states with the sickle haemoglobin (HbS) col-
lectively termed Sickle Cell Disease (SCD). Globally, around
3 12 000 children are born each year with the condition
Correspondence: Subarna Chakravorty, Department of Paediatric
Haematology, King’s College Hospital, Denmark Hill, London, SE5
9RS, UK.
E-mail: subarna.chakravorty@nhs.net
ª 2017 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 179, 377–388
(Piel, 2013). Mortality due to this condition is extremely
high in the areas of the world where it is most prevalent,
such as sub-Saharan Africa (Williams, 2016). The co-opera-
tive Study of SCD analysis showed median life expectancy of
affected individuals in the USA was 45 years (Platt et al,
1994), although more recent studies have shown improve-
ments in this metric in individuals from Europe and the
USA (Gardner et al, 2016) (Elmariah et al, 2014).
Stroke in sickle cell disease
Stroke is one of the most severe complications to affect chil-
dren with SCA. In the absence of screening and primary
prevention methods, stroke occurs in 7
4% and 11% of
patients by the age of 14 years and 20 years, respectively.
The highest risk of acute ischaemic stroke (AIS) is in the
first decade of life, with an incidence of 1
02% per year
between 2 and 5 years of age. The risk of AIS then rises
again after the age of 29 years (Ohene-Frempong et al,
1998). It has long been recognised that regular red cell
transfusions significantly reduce the risk of stroke or stroke
recurrence. However, the challenge prior to the advent of
transcranial Doppler (TCD) screening was to reliably iden-
tify an at-risk population.
Traditionally, small-vessel occlusion by intravascular sick-
ling and sludging was thought to underlie stroke pathology.
However, through angiography and autopsy analyses (Merkel
et al, 1978) the role of progressive narrowing of the major
intracranial vessels, particularly the proximal segments of the
middle (MCA) and anterior (ACA) cerebral arteries became
accepted as the principal pathological mechanism. This vas-
culopathy was reflected in localised increased intra-arterial
blood flow velocities (Aaslid et al, 1982) and measurement
of this is the basis of the TCD test. Several pathophysiologi-
cal mechanisms of AIS in SCA have been proposed in recent
years, including the effect of cellular adhesion in large vessels,
hypercoagulability, endothelial cell activation, hypoxaemia
and haemolysis, leading to nitric oxide (NO) depletion and
rheology of sickled cells. Detailed discussion of stroke patho-
physiology is beyond the scope of this review and readers are
directed to two authoritative reviews on stroke pathology in
SCA (Connes et al, 2013) (Switzer et al, 2006).
First published online 2 August 2017
doi: 10.1111/bjh.14850
Review

Transcranial doppler and stroke risk identified by TCD screening, a blood transfusion programme
resulted in significant reduction of stroke risk. As screening
The association of TCD and cerebral vasculopathy in SCA
entry to the study, TCD measured the TAMMV in the MCA
patients with AIS was first described in a case report by Adams
and distal ICA only and used the previously validated thresh-
et al (1988). The authors demonstrated absent blood flow in
olds for TCD reporting: normal TCD <170 cm/s, conditional
the left MCA of a 6-year-old girl with SCA and acute stroke in
TCD >170 cm/s and <200 cm/s, and abnormal TCD
the left MCA territory, raising the possibility that this relatively
>200 cm/s (Adams et al, 1997). Those confirmed with
quick and non-invasive method, along with magnetic resonance
abnormal TCD were randomised to either receive a transfu-
imaging (MRI), could provide a more practical diagnostic alter-
sion programme, maintaining sickle haemoglobin at less than
native to angiography in children with SCA presenting with
30% or standard of care. The trial was terminated early after
AIS. The technique used Doppler sonography applied to the
it demonstrated a 92% reduction in risk of stroke in the
temporal area of the scalp and by probe manipulation, insona-
transfusion arm (odds ratio 0
08, 95% confidence interval
tion of the Internal Carotid Artery (ICA), MCA and ACA was
0
01–0
66). This led to a clinical alert by the US National
possible. Readings included peak systolic (PSV), end-diastolic
Heart, Lung and Blood Institute in 1997, recommending that
and time averaged mean of maximum velocities (TAMMV).
children with SCA aged 2–16 receive TCD screening and that
However, the TAMMV measurement was considered the most
families of children at high risk discuss the risks and benefits
accurate and therefore consistently used henceforth.
of transfusions with knowledgeable clinicians (National
Following some encouraging preliminary work, a large
Heart, Lung and Blood Institute 1997). A recent analysis has
observational cohort study of 315 children with SCA was con-
shown that early TCD screening and initiation of chronic
ducted (Adams et al, 1997). This primarily measured the
transfusions has reduced the risk of overt stroke from a pre-
MCA and ICA velocities and demonstrated that those patients
viously reported value of 11% (Ohene-Frempong et al, 1998)
with TAMMV <170 cm/s had a 40-month stroke-free survival
to 1
9% by 18 years of age (Bernaudin et al, 2011).
rate of 98%. If the TAMMV were >170 cm/s but less than
A further analysis of the STOP cohort looked at repeat
200 cm/s, the rate fell to 93%, but if the TAMMV were
TCD measurements. The first important finding was that
>200 cm/s, this dramatically fell to 60%. They showed that
there was an overall conversion risk of 9
4% from ‘not
velocities >200 cm/s carried a 10% annual stroke risk, whereas
abnormal’ to abnormal TCD and that any such subsequent
conditional studies (170–199 cm/s) and normal (<170 cm/s)
abnormal TCD still represented an increased risk of stroke.
carried a 3–4% and 1% annual risk, respectively. These vali-
Secondly, they demonstrated that the younger the patient,
dated velocity parameters were therefore adopted for risk strat-
the more likely the conversion from normal or conditional
ification in stroke in SCD in clinical interventional trials.
TCD to abnormal. By sub-categorising conditional TCD to
Subsequently, the role of raised ACA velocities was interro-
low-risk (170–184 cm/s) and high-risk (185–199 cm/s), they
gated and found to have a three-fold higher stroke risk than
found that a two-year-old child with a normal TCD had
normal when raised to >170 cm/s in isolation (similar to the
<1% chance of an abnormal TCD in the next 12 months,
risk present in conditional MCA/ICA velocities). When pre-
whereas this was >70% in the high-risk conditional TCD
sent in combination with raised MCA/ICA velocities, an even
group. The usefulness of conditional TCD to predict conver-
higher risk was noted (Kwiatkowski et al, 2006).
sion was further emphasised in probability modelling; for
There remains some debate around the appropriate
example, two-year-olds with normal TCD on two occasions
thresholds for the ACA. The Stroke Prevention Trial in Sickle
had a 4% chance of conversion to abnormal in the next
Cell Anaemia (STOP) study investigators used a lower
4 years, whereas those with two high-risk conditional TCD
threshold of 170 cm/s owing to the view that ACA circula-
measurements had a 97% chance. This demonstrated the
tion is generally slower than MCA or ICA, although others
need for repeat screening of children with SCA throughout
have reported on the use of higher thresholds, such as
their childhood and argued for the closer monitoring of
200 cm/s (Bernaudin et al, 2016) (Telfer et al, 2016). Addi-
those with conditional TCD (Adams et al, 2004). It is also
tionally, raised PSV in the extra-cranial ICA (eICA), studied
important to note that intra-subject variability between two
by Doppler ultrasonography through a submandibular win-
readings based on biological, operator and machine-depen-
dow, was also shown to confer a high risk of AIS in the pres-
dent reasons can be high, hence repeat measurement of bor-
ence or absence of raised TCD velocities in the intracranial
derline results are important for accurate risk stratification
vessels (Deane et al, 2010). A recent study identified isolated
(Brambilla et al, 2007).
raised eICA to be an independent risk factor for silent cere-
Despite its proven efficacy for primary prevention of
bral infarcts (Bernaudin et al, 2015).
stroke in SCD, chronic transfusion is not without associated
costs, risks and complications. Consequently, the STOP
investigators embarked on a second randomized clinical trial,
Clinical trials in SCD
STOP 2, to determine whether transfusion therapy could be
The STOP study (Adams et al, 1998), was the first trial to safely withdrawn after at least 30 months of transfusions in
provide strong evidence that, in a cohort of ‘at risk’ patients patients who had converted to normal TCD velocities. This

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British Journal of Haematology, 2017, 179, 377–388

trial closed early due to a significant increase in risk of stroke
in participants who stopped transfusions, represented by
either reversion of TCD readings and incidence of overt
stroke, within an average time of 4
5 months of the last
transfusion (Adams & Brambilla, 2005).
Thus, once identified as having abnormal TCD, patients
were committed indefinitely to a transfusion programme, with
all its attendant issues. Interest naturally moved to establishing
a role for the only other disease-modifying agent licensed for
use in SCA, hydroxycarbamide (previously termed hydrox-
yurea). A few small observational studies looking at hydroxy-
carbamide prescribed for clinical severity showed a decrease in
the TCD velocities measured in these patients (Gulbis et al,
2005; Kratovil et al, 2006; Zimmerman et al, 2007). To
address this question more categorically, a large multicentre
randomised trial, TCD with Transfusions Changing to
Hydroxyurea (TWiTCH), has recently concluded (Ware et al,
2016). This study enrolled children with SCA and abnormal
TCD who had received blood transfusions for at least
12 months and had no evidence of severe intracerebral vascu-
lopathy. The study demonstrated the non-inferiority of the
hydroxycarbamide arm in maintaining TCD velocities and
continued prevention of stroke events. In support of this evi-
dence, another study (Bernaudin et al, 2016) reported on a
cohort of patients detected at risk by TCD and placed on
chronic transfusions. In this group, patients were considered
for switching to hydroxycarbamide provided normalisation of
TCD had occurred. 28
9% reverted to abnormal and transfu-
sions recommenced. This reversion was predicted by baseline
reticulocyte count prior to 3 years of age of >400 9 109/l
(P < 0
001). They performed TCD trimestrially on patients
that had been switched to hydroxycarbamide and advocate this
as an important monitoring method for any patients switch-
ing, with prompt restoration of a transfusion programme
should velocities increase again. This targeted approach could
significantly reduce the transfusion burden for these patients.
It is important to note that not all children with high
TCD readings will develop strokes. The STOP trial partici-
pants on the standard care arm with TCD velocity of
>200 cm/s had an annual stroke rate of 10% (Adams et al,
1998). The burden of transfusion-associated adverse events,
such as iron overload and alloimmunisation, is not insub-
stantial. Based on decision modelling, Mazumdar et al
(2007) demonstrated that a modified strategy of TCD screen-
ing from age 2–10 years and initiating chronic transfusion
programmes in at-risk patients until the age of 18 years only,
provided similar benefits to more intensive screening and
transfusion strategies but resulted in fewer adverse events.
Outside of the high-resourced medical services of the
West, chronic blood transfusion services present a difficult
and often impractical option. Thus, there is strong interest in
the use of hydroxycarbamide upfront for the management of
abnormal and/or conditional TCD. An international ran-
domized controlled trial, Sparing Conversion to Abnormal
TCD (SCATE), attempted to assess the efficacy of
ª 2017 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 179, 377–388
Review
hydroxycarbamide in preventing conditional TCD progress-
ing to abnormal TCD. Unfortunately, due to slow recruit-
ment, this trial was terminated prior to completion.
However, in post-hoc analysis of the 38 children who did
enrol, there was a significant reduction in conversion rates
compared with observation (Hankins et al, 2015). Two on
going trials are looking at whether hydroxycarbamide will
have a beneficial effect on TCD velocities and primary stroke
prevention as an upfront therapy in children with abnormal
TCD. These are Expanding Treatment for Existing Neurolog-
ical Disease (EXTEND; NCT02556099) (Rankine-Mullings
et al, 2016), conducted in Jamaica, and Stroke Prevention in
Nigeria (SPIN; NCT01801423) (Galadanci et al, 2015), con-
ducted in Nigeria. We await these results with great interest.
Imaging modality
Historically, validation data utilised a non-imaging TCD tech-
nique by probing the temporal acoustic windows to determine
flow velocities in the intracranial vessels (Aaslid et al, 1982).
Here, the operator ‘blindly’ identified arteries based on their
audible Doppler shift and a spectral display of the distribution
of the velocities of individual red blood cells on the TCD mon-
itor (Purkayastha & Sorond, 2012). Conversely, the TCD
imaging (TCDI) technique combined a pulsed wave Doppler
ultrasound with a colour-coded cross-sectional view of the
area of insonation, allowing for better visualisation of the
arteries. Figure 1 demonstrates a TCDI image of raised left
MCA velocity with a corresponding stenosis of the left MCA
demonstrated on magnetic resonance angiography (MRA).
The four pivotal randomised control trials investigating
stroke in SCD used non-imaging TCD (Adams et al, 1998)
(Adams & Brambilla, 2005) (Ware & Helms, 2012) (Ware
et al, 2016). TCDI has not been formally investigated in
these trials. Earlier studies had identified differences in veloc-
ity measurements between the two methods (Bulas et al,
2000). Variations in sonographer training and experience
were likely to have contributed to the initial differences
(Jones et al, 2001) and subsequent data has identified TCDI
velocities as being comparable to non-imaging techniques.
Recently, both the French National Authority for Health and
the UK Forum on Haemoglobin Disorders recommended
using the same velocity thresholds for TCDI and non-ima-
ging TCD (Bernaudin et al, 2016) (UK Forum on Hae-
moglobin Disorders 2016). The UK Haemoglobin Disorders
Peer Review programme (2014–2016) identified many ser-
vices in the UK used one or both techniques. Choice of TCD
scanning equipment was largely dependent on configuration
of services (West Midlands Quality Review Service 2016).
Familiarity with technique and ease of use, combined with
quicker achievement of competencies probably favours TCDI,
particularly when the needs of large services are to be met.
In established and experienced services, the same velocity
thresholds for risk stratification should apply to the MCA,
ACA and eICA velocities with both scanning modalities.
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Fig 1. Left: showing raised LMCA TAMMV of 291 cm/s on TCDI. Right: demonstrating corresponding Magnetic Resonance Angiography image
of LMCA stenosis. Courtesy Colin Deane, King’s College Hospital, with permission. LMCA, Left Middle Cerebral Artery; TAMMV, Time Average
Mean of Maximum Velocity; TCDI, Transcranial Doppler (Imaging).

Vessels and estimated velocity thresholds Some clinical markers have proved to be important. A
high baseline systolic blood pressure is associated with an
Early studies of TCD helped to define TAMMV of blood
increased risk of stroke (Ohene-Frempong et al, 1998;
flow, in cm/s in healthy adults and children. The MCA veloc-
DeBaun et al, 2012). Haemoglobin oxygen saturation has
ity in children was noted to be slightly higher, 79 cm/s  13
been shown to be an important determinant of cerebral
compared to adults, 62 cm/s  12 (Aaslid et al, 1982). In
artery blood flow in children with SCA and both nocturnal
contrast children with SCD had even higher velocities,
hypoxaemia (Kirkham et al, 2001) and day time desaturation
133 cm/s  19 (Adams et al, 1988). Children with angiogra-
(Quinn et al, 2009) have shown statistical association with
phy evidence of stenosis were usually >190 cm/s or <70 cm/
abnormal TCD, but not snoring, or sleep disordered breath-
s. Abnormally low velocities can represent significantly
ing (Goldstein et al, 2011).
reduced blood flow down-stream of a stenotic region, devel-
opment of collaterals and reduction of flow through a main
Genetic factors. There has been some interest in genetic vari-
artery, or presence of a large infarcted area with little meta-
ants that associate with or protect against abnormal TCD. As
bolic demand; suggesting the possibility of severe vasculopa-
with stroke occurrence, abnormal TCD readings have been
thy (Buchanan et al, 2013).
shown to be familial (Kwiatkowski et al, 2003) making
genetic factors highly likely to be relevant.
Predictors of abnormal TCD Patients with co-inheritance of alpha-thalassaemia are
recognised to have a milder phenotype of SCD. Although a few
Clinical and laboratory measurements. The causes and associ-
early studies failed to find a protective association between the
ations of the development of cerebral vasculopathy are still
presence of alpha-thalassaemia and the risk of stroke (Miller
incompletely understood. The most consistently demon-
et al, 1988; Balkaran et al, 1992), numerous subsequent studies
strated finding is an association with lower baseline haemo-
have reported a reduction in stroke and abnormal TCD results
globin, which has been demonstrated to be associated with
in the presence of alpha-thalassaemia, independent of any
AIS, silent cerebral infarcts and abnormal TCD (Ohene-
effect on haemoglobin levels (Hsu et al, 2003; Bernaudin et al,
Frempong et al, 1998; Bernaudin & Verlhac, 2008; DeBaun
2008; Belisario et al, 2010; Cox et al, 2014). Cox et al (2014)
et al, 2012). Similarly, raised markers of haemolysis are
went on to quantify the relative risk ratio of abnormally high
repeatedly found to be strongly predictive. These include
cerebral blood flow velocities with one or two alpha-thalassae-
high reticulocyte counts, high lactate dehydrogenase and high
mia deletions at 0
53 (0
35–0
8) and 0
43 (0
23–0
78) respec-
aspartate transaminase levels (O’Driscoll et al, 2008; Rees
tively. Therefore, the co-inheritance of alpha chain deletions
et al, 2008). A recent study demonstrated that an absolute
has a protective effect on development of cerebral vasculopathy
reticulocyte count >200 9 109/l in early infancy conferred a
above and beyond the effect it has on raising the haemoglobin
3 times greater risk of abnormal or conditional TCD, whilst
level and lowering levels of haemolysis.
an Hb <85 g/l had a 2
7 times increased risk of the same
The role of glucose-6-phosphate dehydrogenase (G6PD)
(Meier et al, 2016).
deficiency in abnormal TCD or stroke risk is more

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British Journal of Haematology, 2017, 179, 377–388

controversial. As a principal source of NADPH in endothelial
cells, G6PD has an important role in antioxidant formation,
which in turn promotes NO synthesis, hence a deficiency will
lead to increased oxidative stress and decreased NO levels
contributing to vascular dysfunction (Leopold et al, 2001).
Despite this plausible mechanism, no significant association
between G6PD deficiency and SCD phenotype has been
demonstrated (Rees et al, 2009; Miller et al, 2011; Belisario
et al, 2016). Similarly, Cox et al (2014) reported no evidence
of association between abnormal TCD and common G6PD
polymorphisms. Conversely, some other cohort studies have
found association (Bernaudin et al, 2008; Joly et al, 2016).
The reason for this discrepancy in findings is not clear and
further investigation is required to resolve this.
Given that the aetiology of stroke is most probably influ-
enced by many genes, each with only modest effects, success-
fully identifying polymorphisms in novel genes that show
statistically valid associations is challenging. The literature
includes numerous studies listing different associations that
are then not borne out by other studies. For example, a poly-
morphism in the promoter region of tumour necrosis factor
(TNF) (-308) gene has been shown to be associated with
stroke. However, some studies have reported the GG geno-
type to be pathological, associating specifically with large ves-
sel disease, and conferring a three-fold increased risk of
occurrence (Hoppe et al, 2007) whereas a study based on a
Brazilian cohort reported the AG/AA genotypes to be signifi-
cantly associated with stroke, but not cerebral vasculopathy
(Belisario et al, 2015). Clearly these conflicting outcomes
suggest a deeper complexity to the control of TNF expres-
sion.
There has been great interest in looking at the clinical,
laboratory and genetic factors that are associated with abnor-
mal TCD. There is good evidence to support a higher risk of
abnormal TCD for patients with low haemoglobin, high
reticulocyte count, high systolic blood pressure, and upper
and lower respiratory tract obstruction whilst presence of
alpha thalassaemia and high fetal haemoglobin levels (Som-
met et al, 2016) have a protective effect. Beyond these gener-
ally accepted markers, the evidence is largely conflicting and
unclear. Genetic associations have proved fraught with diffi-
culty. This may reflect different genetic profiles in studies
around the world as well as the added complication of look-
ing for rare events in a group where environmental events
will provide significant confounders. Further work in this
area is clearly warranted, and such resources would be of
great benefit to the clinician.
TCD in practice
Organisation of TCD services
The evidence supporting TCD as a practical, effective, and
reliable screening technique to determine risk of stroke in
children with SCD led to the UK National screening
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British Journal of Haematology, 2017, 179, 377–388
Review
guidelines being published in 2009 and subsequently updated
in 2016 (UK Forum on Haemoglobin Disorders 2016). This
gave guidance on the organisation of TCD scanning services,
scanning protocols and follow-up.
Haemoglobinopathy services in the UK are configured
into regional networks with a specialist haemoglobinopathy
centre (SHC) (NHS England 2013), which generally provide
TCD screening services to all eligible children within the net-
work. This is done either through consultations at the spe-
cialist centre where TCD services are provided at the routine
clinic visit or through the provision of specialist outreach
clinics with portable TCD services closer to home. A coordi-
nated multidisciplinary approach to monitor uptake, plan for
intervention and subsequent surveillance ensures parents and
children are appropriately supported. This is particularly
important to overcome issues around uptake of screening as
well as compliance with subsequent treatment, if any. Strin-
gent prospective follow-up with TCD in a research birth
cohort, such as the one in Creteil, France, has resulted in sig-
nificant improvement in patient outcome and a greater
understanding of neurological sequelae in SCD (Bernaudin
et al, 2011). However, similar rates of uptake and follow up
were absent in other programmes of care, notably the STOP
and STOP 2 cohort (Adams et al, 2016) and other compre-
hensive sickle centre cohorts in the US (Raphael et al, 2008),
where less than 50% of eligible patients received annual TCD
surveillance. Both provider and user factors were identified
in this shortfall in uptake of TCD monitoring despite strong
evidence of its efficacy (Reeves et al, 2015), and service
improvement initiatives have resulted in improvement in
uptake (Patik et al, 2006). UK data from the East London
and Essex Regional Haemoglobinopathy network reported an
overall improvement in TCD uptake with time in their eligi-
ble cohort of 480 patients. Between 2009 and 2013, the med-
ian interval between the first standard-risk scan and a
subsequent scan was 12 months, and that of a conditional
scan to the next scan was 3 months (Telfer et al, 2016).
Evaluation of outcomes and governance arrangements
Provision of annual TCD surveillance for all eligible children
in the UK is a key statute in the current Quality Standards
for Health Services for people with Haemoglobin Disorders
(West Midlands Quality Review Service 2014). The standards
also cover staffing, training and competencies, availability of
guidelines and fail-safe arrangements for improving adher-
ence to surveillance. A process of quality assurance (QA) to
address sonographer competencies is also recommended. A
National QA scheme is being developed in the UK and some
services are employing internal QA systems with annual anal-
ysis of scans performed by each sonographer for the regional
population to determine variances and operational errors
(UK Forum on Haemoglobin Disorders 2016). The UK Peer
Review for Haemoglobin Disorders 2014–2016 identified that
most specialist centres in the UK were able to offer a TCD
381
Review
scanning service but not all were able to demonstrate com-
pliance with all of the standards (West Midlands Quality
Review Service 2016). Annual collection of data on achieve-
ment of targets is now a commissioning requirement in the
UK (NHS England 2016) and may help to identify opera-
tional issues around delivery and help improve outcomes.
Management decisions based on TCD findings
Primary stroke prevention strategies in children with SCD
recommend TCD screening to commence at age 2 years and
continue until age 16 years (UK Forum on Haemoglobin
Disorders 2016) (Yawn & John-Sowah, 2015).
Confirmatory repeat scanning after one abnormal. An impor-
tant point to consider is that acute illness or anaemia can
temporarily increase TCD velocities due to a compensatory
increase in cardiac output in a hyperdynamic circulation.
TCD should therefore not be conducted in children who are
acutely unwell. Additionally, determination of risk stratifica-
tion criteria and the timeliness of scans are important to
limit AIS risk but must be balanced with the potential for
over-diagnosis and over-treatment. Although there has been
almost universal adoption of the threshold target of 200 cm/
s for MCA velocities for transfusion initiation, there remain
some differences within national guidelines and individual
institutions around other targets. An example of this is in
the requirement for a confirmatory scan following identifica-
tion of an abnormal TCD. The STOP protocol employed
repeat scanning to confirm risk status prior to initiation of
regular transfusion therapy (Adams et al, 1998). The current
UK guidelines recommend repeat scanning in 1 week prior
to initiation of transfusions (UK Forum on Haemoglobin
Disorders 2016). In a French series, the requirement for
repeat scanning was questioned following the development of
AIS in one patient during the interval between scans (Ber-
naudin et al, 2011). In a UK series about a quarter of chil-
dren (25
9%) who progressed from having two sequential
conditional scans to abnormal were treated with transfusion
therapy on this basis without a confirmatory or repeat
abnormal scan (Telfer et al, 2016).
Frequency of scanning in the presence of cerebral vasculopa-
thy. Another uncertainty lies around the frequency of scan-
ning following initiation of a chronic transfusion
programme. From the STOP 2 data approximately 20% of
children had a persistently elevated TCD. The likelihood of
developing stroke on transfusion in this group compared to
those who had converted to standard risk was thought to be
similar (Kwiatkowski et al, 2011). In the French series (Ber-
naudin et al, 2016) three-monthly scanning was performed
following initiation of transfusions. In this series, a return to
normal (standard risk) velocities was noted in 83
5% of
patients after a mean duration of chronic transfusion of
1
4  1
3 years. Stenosis was associated with the likelihood
382
of non-normalisation and those who remained normal on
transfusion did not revert to abnormal in the follow-up per-
iod (mean 6
1 years). Therefore, the optimal frequency of
regular repeat scanning in children with no vasculopathy
determined by MRI who revert to standard risk, is not
known. In the TWiTCH trial (Ware et al, 2016) TCD veloci-
ties were measured every 4 weeks in triplicate during screen-
ing, then at three-monthly intervals during the 24-month
follow-up period. The timing of TCD during the transfusion
programme may also be relevant. In the TWiTCH trial TCDs
were done just before transfusions to minimise the effect on
cerebral blood flow velocities immediately after a transfusion.
In clinical practice, it is also important to consistently per-
form the examination prior to transfusions. Longer follow-
up of children switched to hydroxycarbamide following an
initiation period of transfusions will help to identify the opti-
mal frequency of monitoring with TCD for those children
who are stable and remain in the standard risk category for a
sustained period.
The utility of using TCD scanning to monitor children
with established stroke and vasculopathy is unclear. In the
Stroke with Transfusions Changing to Hydroxyurea
(SWiTCH) trial (Ware & Helms, 2012), children with estab-
lished stroke had entry TCD in addition to MRA examina-
tion. In this study, most children were found to have low or
uninterpretable baseline MCA TCD velocities. These corre-
lated with worse stenosis on MRA imaging. At present, there
is no clear guidance on TCD scanning for surveillance pur-
poses in children and adults with established stroke and cere-
bral vasculopathy.
Multidisciplinary approach to decision making. Children
established on chronic transfusion programmes for stroke
prevention benefit from a multi-disciplinary approach to
their clinical management (Kassim et al, 2015). This includes
input from neuroradiologists, transfusionists, clinical nurse
specialists, clinical and educational psychologists, transplant
physicians, physical and occupational therapists working in
collaboration with the paediatric/haematology team. Adher-
ence and monitoring also often require intensive follow-up
and input from the multi-disciplinary team (Patik et al,
2006).
Child safeguarding issues around treatment options. Parental
refusal to accept chronic transfusion therapy or hydroxycar-
bamide for stroke prevention is a challenging ethical situa-
tion for medical teams. Occasionally this may rise from
religious beliefs (Catlin, 1996) or from a disagreement about
the efficacy of the suggested therapy. Information and guid-
ance regarding the ethical issues surrounding parental refusal
of therapy that may not result in an imminent threat to life
requires more bioethical research (McDougall et al, 2015). In
our practice, children whose parents refuse chronic transfu-
sion therapy are generally treated with hydroxycarbamide.
Occasionally, parents may agree on a curative therapy such
ª 2017 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 179, 377–388

as bone marrow transplantation (BMT) or may choose to
not receive any therapy at all.
Primary Stroke prevention strategies in SCD
The STOP trial provided robust data to support clinical
effectiveness of initiating a transfusion programme for pri-
mary stroke prevention in SCA (Adams et al, 1998). Subse-
quently, economic evaluation of this intervention in 2012
indicated that it had an incremental cost-effectiveness ratio
of £24 075 per quality-adjusted life-year gained, and avoided
68 strokes over the lifetime of a population of 1000 patients
(Cherry et al, 2012).
Children with abnormal TCD velocities in the absence of
acute illness or anaemia are counselled and commenced on
red cell transfusions with an aim to reduce the pre-transfu-
sion sickle percentage to <30. The type of transfusion pro-
vided for this purpose varies greatly among institutions,
although the use of automated exchange transfusions (AET),
both in children and in adults have increased in the last dec-
ade (Kelly et al, 2016). Alternatives to automated exchange
transfusions are simple top-up transfusions or manual
exchange transfusions, and the safety, tolerability and clinical
effectiveness of all three modalities of transfusions have been
demonstrated in several studies (Koehl et al, 2016) (Mian
et al, 2015). Barriers to AET are cited as costs, availability
and lack of appropriate venous access (Koehl et al, 2016).
However, when used upfront in patients with no evidence of
prior iron overload, AET abolishes the need for additional
iron chelation therapy. Clinical efficacy of individual modali-
ties of transfusions has not been directly compared in
prospective studies. However, the STOP trials used simple
top-up transfusions to maintain pre-transfusion HbS% <30
and many subsequent studies reporting on the efficacy of
transfusion programmes in secondary stroke prevention have
used top-up as well as exchange transfusions (Aygun et al,
2009).
It is very important to ensure that children on red cell
transfusions are monitored for the efficacy of transfusions,
for example by ensuring that the pre-transfusion HbS%
remains within the target range and TCD velocities and MRI
features are monitored at regular intervals. Strict mainte-
nance of HbS% in this group of patients has proven to be
challenging, even in academic centres in the US (Aygun et al,
2012), where the average pre-transfusion HbS% was reported
to be 34%, and in the UK, where exchange transfusion pro-
grammes succeeded in achieving a mean pre-transfusion HbS
% of 50-55 (Kuo et al, 2015). Proportion of children on
transfusion whose TCD velocities remain abnormal or condi-
tional may depend on the presence of vasculopathy on MRA
at the time of transfusion initiation (Bernaudin et al, 2005),
but may also depend on the centre and stringency of mainte-
nance of transfusion parameters. Whilst in prospective
research cohorts, such as that in Creteil, France, about 20%
of children on chronic transfusion therapy will continue to
ª 2017 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 179, 377–388
Review
have abnormal TCD, mainly predicated by the presence of
associated stenoses (Bernaudin et al, 2016), other centres
have reported much higher rates of persistently abnormal
TCD velocities of up to 50% whilst on transfusions (Sheehan
et al, 2013). Interestingly, despite the difference in transfu-
sion parameters and imaging results, no children in either
centre developed a stroke whist on transfusions in 3-6 years
of follow-up.
Bone marrow transplantion for primary stroke
prevention
Several trials in BMT in SCA in Europe and USA have
included children with abnormal TCD on chronic transfu-
sions for primary stroke prevention (Bernaudin et al, 2016)
(Shenoy et al, 2016) (King et al, 2015). However, BMT in
children with isolated abnormal TCD in the absence of pro-
gressive cerebrovascular disease is not part of the accepted
clinical indication for transplant outside a trial setting
(Arnold et al, 2016). With the emerging role of hydroxycar-
bamide in primary stroke prevention in a subset of patients
who have demonstrated stable cerebrovascular disease follow-
ing a period of chronic transfusion (Ware et al, 2016) and
the wider availability of automated exchange transfusions
and iron chelation therapy, the current procedural toxicities
of BMT makes it difficult to justify this intervention in pri-
mary stroke prevention. This was also borne out at an earlier
decision analysis study where quality adjusted life years was
predicted to be the highest among patients on transfusion
and chelation therapy alone (Nietert et al, 2000), implying
that BMT for isolated abnormal TCD may not be justified,
particularly in view of the fact that 40% of patients identified
as having high risk of stroke may never have one (Cohen,
1998).
Progression of TCD abnormalities despite transfusion
therapy
A subset of patients will continue to have progressive cere-
brovascular disease despite adequate transfusion therapy for
stroke prevention and will benefit from further intensifica-
tion of therapy (Fasano et al, 2015). For children with
matched family donors, BMT may be a therapeutic option,
resulting in transfusion independence and a lower rate of
disease progression (Woodard et al, 2005; Bernaudin et al,
2007) compared to transfusion therapy alone (Hulbert et al,
2011). In a small case series of patients on chronic transfu-
sion therapy without available BMT donors, the addition of
hydroxycarbamide to transfusion resulted in disease stabilisa-
tion in 2 out of 7 patients (Brousse et al, 2013), but this
therapeutic strategy may require further investigation in a
larger cohort of patients. Surgical revascularisation
approaches are also used in children with progressive cere-
brovascular disease and Moyamoya syndrome on chronic
transfusion programmes with improved stroke-prevention
383
Review
benefit compared to chronic transfusion therapy alone (Hall
et al, 2016).
Treatment algorithm for abnormal TCD
An evidence- based approach to abnormal TCD in children
with SCA is outlined in Fig 2.
TCD in HbSC
Children with HbSC disease have a lower risk of stroke com-
pared to children with SCA, but the risk is still 50–100 times
greater than that of healthy black children (Ohene-Frempong
et al, 1998) in whom the rate of strokes is 0
0031 per 100
patient years (Broderick et al, 1993). The role of TCD in
stroke risk assessment in HbSC disease has not been estab-
lished. However, several studies have demonstrated that chil-
dren with HbSC disease have significantly lower TCD
velocities in MCA and ICA compared to children with SCA.
A recent large Brazilian study has estimated the mean MCA
TAMMV in HbSC disease to be 104 cm/s, with strong nega-
tive correlation with haemoglobin levels and haematocrit
(Vieira et al, 2017) compared to mean MCA TAMMV of
129 cm/sec in a study of 190 HbSS patients (Adams et al,
1992). A smaller study in London reported a mean MCA
Fig 2. Algorithm for the management of TCD readings in children with sickle cell anaemia. ACA, anterior cerebral artery; BMT, bone marrow
transplantation; dICA, distal internal carotid artery; eICA, extra-cranial; MCA, middle cerebral artery; MRA, magnetic resonance angiography;
MRI, magnetic resonance imaging; SCD, sickle cell disease; TCD, transcranial Doppler.
384
velocity of 94 cm/s in HbSC patients with a significant posi-
tive correlation with platelet counts. In this study, the 98th
centile measurement from a normally distributed curve was
128 cm/s and the authors recommended that velocities
higher than that should be investigated further (Deane et al,
2008). National guidelines for stroke risk monitoring in the
UK and USA do not recommend routine monitoring in
HbSC disease, (Yawn & John-Sowah, 2015) (UK Forum on
Haemoglobin Disorders 2016), but the Brazilian National
Guidelines do (Lange et al, 2012). The Brazilian guidelines
recommend the use of the STOP study velocity criteria for
stroke risk assessment in HbSC. Accordingly, variation exists
between centres in routine monitoring of asymptomatic chil-
dren with HbSC. At King’s College Hospital London, our
practice is to monitor TCD at 2, 5 and 10 years only.
TCD in adults with SCD
Incidence of acute ischaemic strokes in SCA has a bimodal
distribution with age, with the highest incidence in children
age 1–9 years followed by a second peak among adults aged
30–50 years (Ohene-Frempong et al, 1998). Therefore, the
risk of AIS in adult patients with SCA is not insubstantial. A
report in 2011 of a carefully managed birth cohort with
stroke risk surveillance and timely intervention to prevent
ª 2017 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 179, 377–388
 Review

neurovascular morbidity nonetheless demonstrated the pres-
ence of an extremely high rate of cerebrovascular disease of
about 50% by the age of 14 years (Bernaudin et al, 2011),
indicating that there is further scope to improve monitoring
and intervention in SCA to prevent cerebrovascular disease
in late childhood and early adulthood. However, whilst most
cases of stroke in childhood SCD is associated with cerebral
vasculopathy, in adults this was found to be a cause in only
41% of cases (Calvet et al, 2015). Older patients with SCD
may have other co-morbidities including hypertension, dia-
betes, hyperlipidaemia, renal dysfunction, impaired cardiac
systolic function and atrial fibrillation – recognised cardio-
vascular risk factors in adults without SCD. Nonetheless sig-
nificant numbers of adults who developed AIS in childhood
remain on chronic transfusion programmes for secondary
stroke prevention. The optimal mode of managing these
patients is unknown and warrants further research.
At present adult patients do not receive regular stroke
surveillance by TCD as there is no evidence to support the
initiation of transfusion for stroke prevention in adults and
the incidence of AIS and TCD velocities in adults are lower
than children (Valadi et al, 2006), with no determined cut
offs to assist with risk stratification.
Conclusion
Transcranial doppler monitoring and stroke risk assessment
has had a significant impact on the progression of cerebral
vasculopathy in SCD. Nonetheless, 50–60% of adolescent and
adult patients with SCA demonstrate presence of cerebral
vasculopathy in the form of acute ischaemic strokes, silent
cerebral infarcts, cerebral arterial stenosis or abnormal TCD
readings, clearly highlighting the need for the development
of further interventions to prevent the progressive neurovas-
cular decline. The institution of a TCD programme for sys-
tematic neurovascular risk monitoring for patient cohorts is
associated with operational challenges, and a multi-disciplin-
ary approach is paramount to ensure that the appropriate
intervention is offered. Efficacy of therapy also requires care-
ful assessment. Increase in uptake of hydroxycarbamide in
younger children will have a positive impact on the preva-
lence of cerebral vasculopathy in children and adults. It is
likely that novel emerging SCD therapies aiming at reduction
of vasculopathy and sickling will also have an impact on the
natural history of cerebrovascular disease in SCD. Areas of
further research include identifying genetic determinants of
TCD abnormality, careful study of biological determinants of
progressive cerebral vasculopathy and developing therapies
targeted to these biological systems.
Acknowledgments
The authors are grateful to Colin Deane of King’s College
Hospital, London for providing the transcranial doppler
images used in this paper.
Author contributions
John Brewin, Banu Kaya and Subarna Chakravorty con-
tributed equally in analysing published data, writing and
revising the manuscript.

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