Assessment of Hemophilic Arthropathy by

Ultrasound: Where Do We Stand?

Matteo Nicola Dario Di Minno, MD, PhD1,2 Pasquale Ambrosino, MD1 Gabriele Quintavalle, MD3
Antonio Coppola, MD1 Annarita Tagliaferri, MD3 Carlo Martinoli, MD4 Gianna Franca Rivolta, MD3

1 Department of Advanced Biomedical Sciences, Division of
Cardiology, Federico II University, Naples, Italy
2 Unit of Cell and Molecular Biology in Cardiovascular Diseases, Centro
Cardiologico Monzino, IRCCS, Milan, Italy
3 Regional Reference Centre for Inherited Bleeding Disorders,
University-Hospital of Parma, Parma, Italy
Address for correspondence Matteo Nicola Dario Di Minno, MD, PhD,
Department of Advanced Biomedical Sciences, Division of Cardiology,
Federico II University, Via S. Pansini 5, 80131 Naples, Italy
(e-mail: dario.diminno@hotmail.it).

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4 Department of Health Sciences (DISSAL), University of Genoa,
Genoa, Italy

Semin Thromb Hemost

Abstract Joint hemorrhages represent the most common type of bleeding episode in persons
with hemophilia, and recurrent hemarthrosis triggers chronic arthropathy, which is the
most frequent chronic complication in these patients. In recent years, in the frame of a
comprehensive care approach, a growing attention has been given to the periodic
assessment of the joint status in hemophilia patients with the aim to identify early
arthropathic changes and to prevent the development of a clinically overt arthropathy.
Besides clinical examination, X-ray and magnetic resonance imaging (MRI) are currently
used to evaluate joint status and to monitor the disease progression in hemophilia.
Considering the limitations of X-ray and MRI, growing interest has been given to
ultrasound (US) as a possible tool to assess joint status and identify early arthropathic
changes in hemophilia patients. In the present review, we summarize major literature
evidence on the use of joint US for the evaluation of markers of disease activity (joint
effusion and synovial hypertrophy) and of degenerative damages (osteochondral
changes) in patients with hemophilia. On the whole, being able to identify the presence
of intra- or extra-articular uid, US examination is the fastest and most reliable technique
to identify acute conditions, such as hemarthrosis. In addition, the information on joint
involvement provided by US in the patient follow-up may inuence treatment decisions
on a personalized basis. The use of US as part of a routine clinical examination by
Keywords hemophilia experts may optimize the diagnostic workow, avoiding additional costs
hemophilia and long waiting lists for patients referred to imaging departments. In the frame of a
hemophilic comprehensive care approach, US might represent a strategy to early detect and
arthropathy monitor synovial hypertrophy and osteochondral changes in hemophilia, thus extend-
ultrasound ing the clinical examination and helping identify joints to be studied with a second-level
imaging examination such as MRI.

Issue Theme Controversies in Inherited Copyright by Thieme Medical DOI http://dx.doi.org/

Bleeding Disorders; Guest Editors: Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1579640.
Antonio Coppola, MD, Massimo New York, NY 10001, USA. ISSN 0094-6176.
Franchini, MD, and Annarita Tagliaferri, Tel: +1(212) 584-4662.
MD.
Hemophilic Arthropathy and Ultrasound Minno et al.
Joint hemorrhage represents the most common type of bleeding
episode in persons with hemophilia,13 and recurrent hemarth-
rosis triggers chronic arthropathy, which is the most frequent
chronic complication in hemophilia patients.4 In the absence of
an adequate prophylaxis (age at start, regimen, duration, and
adherence) with factor VIII (FVIII, for hemophilia A) or FIX (for
hemophilia B) concentrates, up to 85% of the patients with severe
hemophilia develop a clinically overt joint disease.57 Moreover,
some recent data suggest that the rate of arthropathy is also
signicant in patients with moderate hemophilia.8
In recent years, in the frame of the comprehensive care
approach and a shift of the treatment paradigm to actually
preserve pristine joints or reduce joint deterioration,9 a
growing attention has been given to the periodic assessment
of the joint status in hemophilia patients, with the aim to
identify early arthropathic changes and, in turn, to prevent
the development of a clinically overt arthropathy in children
or to avoid/limit its progression in adolescents and adults.
However, being difcult to be detected, subclinical joint
damages are seldom searched for and recognized.10
Gilbert orthopedic joint score and the hemophilia joint health
score (HJHS) are widely used for the clinical assessment of the
joint status in hemophilic patients (Tables 1 and 2).5,11 In
particular, the HJHS, increasingly used in recent years,12 pro-
vides the most sensitive score for the physical examination in
this clinical setting, although it is currently validated only for
children.13 However, the sensitivity and specicity of these
clinical scores in the identication of early-stage and subclinical
damages are widely challenged, and the risk to underestimate
the severity of joint deterioration cannot be ruled out.13
Besides clinical examination, several imaging techniques
have been used to evaluate joint status and to monitor the
disease progression in hemophilia patients.14 Standard radi-
ography (X-ray) is a widely available imaging tool. Although
sensitive to late arthropathic changes, usually expression of
an advanced and irreversible arthropathy,15 X-ray is not able
to identify signs of early-stage joint disease in hemophilia
patients (synovial hypertrophy, joint effusion, and early-stage
osteochondral damages).15 Thus, the radiological Pettersson
score cannot be considered a reliable tool to detect subclinical
joint impairment.16
In contrast, magnetic resonance imaging (MRI) provides
detailed information concerning early- and late-stage
arthropathic changes and it enables the study of soft tissues
in hemophilic patients.17 For this reason, MRI is currently
accepted as the gold standard for the assessment of hemo-
philic arthropathy. However, the limitations of such an
imaging tool include the high cost of the examination,
the limited accessibility to the machine, the need for
sedation in children, and the need to evaluate only one
joint in each examination.18 Furthermore, the implications
of minor changes picked up by MRI before being seen on
plain radiographs in terms of individual joint function
remain to be determined.19
Considering the limitations of X-ray and MRI, growing
interest has been given to ultrasound (US) as a possible tool to
assess joint status and to monitor joint disease progression in
hemophilic patients.20
Seminars in Thrombosis & Hemostasis
Over the last years, six US scores have been proposed for
the use in hemophilia patients,10,2125 each considering
different aspects of hemophilic arthropathy in different joints
and with different scanning protocols, but all with the
common purpose of implementing US for the diagnosis and
the surveillance of joint impairment in hemophilia
(Table 3). The possibility of detecting and scoring the major
markers of hemophilic arthropathy (synovial hypertrophy
and osteochondral changes) by US examination allows for a
new approach to optimize the diagnostic workow and to
avoid additional costs and long waiting lists for imaging in
hemophilic patients.
In the present review, we will summarize literature
evidence on the use of joint US for the evaluation of markers
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of disease activity (joint effusion and synovial hypertrophy)
and of degenerative damages (osteochondral changes) in
patients with hemophilia.
Ultrasound Findings in Hemophilia
Effusion
In 1987, Wilson et al reported their rst experience with joint
US for the assessment of 38 hemophilia patients with acute
hemarthrosis.26 Since then, several other reports have been
addressed the use of joint US in this setting. As highlighted by
Querol and Rodriguez-Merchan in a systematic review, this
imaging tool has been mainly used in acute clinical situations
(i.e., muscle hematomas and hemarthrosis), to identify the
presence of blood in the joints, pinpoint its location, measure
its size, assess its evolution, and conrm its complete disap-
pearance.20 Indeed, US has proven to be a fast and reliable
technique to detect the presence of intra- or extra-articular
effusion, which is a sensitive sign of a recent hemarthrosis in
hemophilic patients.2729 Besides efcaciously differentiat-
ing the size and the location of the bleeding, US is also able at
dening its relationship with adjacent anatomic structures,
its evolution, and possible complications.20
The ability of ultrasonography to distinguish between
normal serous uid from hemorrhagic uid after a bleed is
one of the issues to be solved.19 In a recent study, Ceponis et al
demonstrated, for the rst time, that high-resolution muscu-
loskeletal US could be a valuable imaging tool to dene
whether acute joint/musculoskeletal pain episodes in adult
hemophilia patients are secondary to bleeding episodes.27 In
detail, 40 episodes occurring in 30 adult hemophilic patients
were evaluated, with 33 of the 40 episodes interpreted by
patients as bleeding, 5 as arthritis-related pain, and 2 as
undecided. Of the 33 events interpreted as bleeding, only 12
were conrmed by US evaluation. In the remaining 21 cases
(63.4%) pain was secondary to degenerative/inammatory
conditions. In contrast, three of ve episodes perceived as
arthritis-related were reclassied as bleeding. In the same
clinical setting, physician assessment was incorrect in 18 of
the 40 cases. These data clearly suggest that US could signi-
cantly help in the diagnostic approach to the patient with
hemophilia reporting an acute painful event. On the other
hand, it must be stressed that a reliable differentiation of
inammatory uid from hemorrhagic effusion is not always
 Hemophilic Arthropathy and Ultrasound Minno et al.

Table 1 World Federation of Hemophilia physical examination score (Gilbert score)

Pain 03 0 No pain, no functional decit, no analgesic use (except with acute hemarthrosis)
1 Mild pain, does not interfere with occupation nor with ADL,
may require occasional nonnarcotic analgesic
2 Moderate pain, partial or occasional interference with occupation or ADL,
use of nonnarcotic medications, may require occasional narcotics
3 Severe pain, interferes with occupation or ADL,
requires frequent use of nonnarcotic and narcotic medications
Bleeding 03 0 None
1 No major, 13 minor
2 12 major or 46 minor
3 3 or more major or 7 or more minor

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Physical examination
Swelling 0 or 2 0 None
2 Present
S Added after score if chronic synovitis is present
Muscle atrophy 0 or 1 0 None or minimal (< 1 cm)
1 Present
Axial deformity (measured only at knee or ankle)
Knee 02 0 Normal 07 degrees valgus
1 815 degrees valgus or 05 degrees varus
2 > 15 degrees valgus or > 5 degrees varus
Ankle 02 0 No deformity
1 Up to 10 degrees valgus or up to 5 degrees varus
2 > 10 degrees valgus or > 5 degrees varus
Crepitus on motion 0 or 1 0 None
1 Present
Range of motion 02 0 Loss of 10% of total FROM
1 Loss of 1033 1/3% of total FROM
2 Loss of > 33 1/3% of total FROM
Flexion contracture 0 or 2 0 < 15 degrees FFC
2 15 degrees or greater FFC at hip or knee or equines at ankle
Instability 02 0 None
1 Noted on examination but neither interferes with function nor requires bracing
2 Instability that creates a functional decit or requires bracing

Abbreviations: ADL, activities of daily living; FFC, xed exion contracture; FROM, full range of motion.
Note: If the limb described requires an aid to ambulation, the following letters (B, brace or orthosis; C, cane; CR, crutches; WC, wheelchair) should be
added at the end of the evaluation:

easy and in some cases it cannot be achieved based on US
ndings alone,30 thus suggesting the need for a cooperation
between US and clinical examination (presence of pain,
increased size of the joint diameter, and reduced range of
motion).31 Further, suggesting the use of US in daily clinical
practice, Aznar et al showed a discrepancy between US
ndings and self-reported bleeding episodes.31 In this recent
study, 38 hemophilia patients were included in a home-
delivered US protocol to monitor the home treatment of
hemarthrosis. In 18 patients, no hemarthrosis was reported
during an average follow-up of 18 months. In the remaining
20 patients, 37 calls for alleged hemarthrosis were reported
(16 elbows, 15 knees, and 6 ankles). In 31 cases, US conrmed
the presence of hemarthrosis, whereas, in 6 cases the US
imaging did not show the presence of intra-articular blood,
pain being more likely arthritis-related. In these cases, the
treatment with clotting factor concentrate was discontinued
after performing US with a signicant cost saving.
Overall, in spite of some inherent limitations in the frame of
home treatment, the use of US in the daily practice for the
diagnosis and management of acute hemarthrosis could opti-
mize hemophilia care.20,31 In particular, based on the two proof-

Seminars in Thrombosis & Hemostasis

Hemophilic Arthropathy and Ultrasound Minno et al.

Table 2 Hemophilia Joint Health Score 2.1

Swelling 0 No swelling
1 Mild
2 Moderate
3 Severe
Duration (swelling) 0 No swelling or < 6 mo
1 > 6 mo
Muscle Atrophy 0 None
1 Mild
2 Severe
Crepitus on motion 0 None

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1 Mild
2 Severe
Flexion loss 0 < 5 degrees
1 510 degrees
2 1120 degrees
3 > 20 degrees
Extension loss 0 < 5 degrees
1 510 degrees
2 1120 degrees
3 > 20 degrees
Joint pain 0 No pain through active ROM
1 No pain through active range; only pain on gentle overpressure or palpation
2 Pain through active range
Strength 0 Holds test position against gravity with maximum resistance
1 Holds test position against gravity with moderate resistance (but breaks with maximal resistance)
2 Holds test position with minimal resistance, or holds test position against gravity
3 Able to partially complete ROM against gravity, or able to move through ROM gravity eliminated,
or through partial ROM gravity eliminated
4 Trace or no muscle contraction
Global gait 0 All skills are within normal limits
1 One skill is not within normal limits
2 Two skills are not within normal limits
3 Three skills are not within normal limits
4 No skills are within normal limits

Abbreviation: ROM, range of motion.

of-concept experiences reported above,27,31 the treatment with
clotting factor concentrate could be continued even after symp-
tom relief, up to the effusion disappearance at the US examina-
tion. On the other hand, treatment with clotting factor
concentrate could be avoided in a series of cases in which the
arthritic pain has been erroneously interpreted as an acute
hemarthrosis. Although detection of joint effusion is clinically
relevant as a potential sign of acute hemarthrosis,31 it is a
transitory and rapidly changing nding and it cannot be consid-
ered a marker of arthropathy.32 Outside the context of acute
bleeding episodes, US has also proven to be an excellent
diagnostic tool to assess major markers of hemophilia-related
joint damage and blood-induced arthropathy: synovial hyper-
trophy and osteochondral changes.10 These signs of hemophilic
arthropathy are known to be encountered also in asymptomatic
joints in which just one or a few clinically overt bleeds have
previously occurred.33
Synovial Hypertrophy
The physiological function of the synovium is to digest blood
by means of the synovial cells (synoviocytes),34 but following
the exposure to repeated intra-articular bleedings, the syno-
vium hypertrophies, becomes villous, and demonstrates
increased vascularity.35,36

Seminars in Thrombosis & Hemostasis


Fig. 1 Pathophysiology of hemophilic arthropathy. IL, interleukin; MDM2, inhibitor of p53; MMP-9, matrix metallopeptidase 9; MYC, Myc transcription factor;
ROS, reactive oxygen species; SDF-1, stromal cell-derived factor 1; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
As detailed in Fig. 1, the presence of hemosiderin induces a
proinammatory status, an increase in the oxidative stress, an
induction of transcription factors and of angiogenesis mediators,
thus leading to synovial hypertrophy. This hypertrophic tissue is
able to determine cartilage damages, by means of proteolytic
enzymes, and to predispose to ensuing intra-articular bleedings.
This evidence clearly suggests that synovial tissue plays a central
role in the pathogenesis of the blood-induced joint damage by
means of an autocatalytic system, starting with synovial hyper-
trophy and leading to a progressive and irreversible damage at
the level of cartilage and of bony structures.34,35,37,38
Accordingly, all existing US protocols considered synovial
hypertrophy as one of the parameters to be taken into account
for the diagnosis and the surveillance of joint impairment in
hemophilic patients (Table 3). Synovial hypertrophy usually
appears at US as a bulk of hysoechoic/hypoechoic vegetations
located inside the joint recesses.30 However, different methods
are used to dene and categorize synovial hypertrophy. Most
protocols perform a comprehensive evaluation of the joints and
of the amount of synovial tissue.10,2123 Thus, synovial hyper-
trophy is dened as present or absent22 or quantied in different
degrees10,21,23 in most of the reported scores. Such a strategy of
detection and grading for synovial hypertrophy by US has been
used in some studies,33,39,40 consistently suggesting that US is
highly sensitive (> 92%) for detecting synovial abnormalities
with results comparable to those obtained with MRI.39,40 At
variance with the other scores, Melchiorre et al measured
synovial thickness in millimeters (mm),24 while Mua-Perja
et al expressed synovial hypertrophy in square centimeters
(cm2).25 Although the inclusion of measurements might appear
more precise, it could be actually affected by a relevant interob-
server variability. However, ad hoc designed validation studies
should be performed to further clarify this issue.
Hemophilic Arthropathy and Ultrasound Minno et al.
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Four out of the six available US scores also take into
account synovial hyperemia,2225 which is the result of
synovial neoangiogenesis and can be dened as an increased
ow signal at color-Doppler23,25 or power-Doppler.22,24 In
rheumatoid arthritis the growth of the synovium requires
angiogenesis, which increases the vascularization and the
hypertrophic synovium can form a pannus that invades and
destroys the articular cartilage and underlying bone.41
Power-Doppler US has been shown to adequately mirror
synovial vascularity and to provide an estimate of moving
fractional blood volume, thus providing a strong tool to assess
response to therapy and monitor joint disease activity.42
Considering that increased vascularity is associated with
clinically active synovitis also in other arthritides,43 it has
been supposed that power-Doppler could also be a useful tool
for diagnosing and monitoring hemophilic joint disease
activity.18
However, as suggested by some recent data33 the power-
Doppler positivity is rarely found in hemophilic patients. In
addition, in the few cases with a positive power-Doppler, only
few ags are visualized, suggesting that, at variance with
rheumatoid arthritis, this parameter cannot be considered as
a predictor of joint disease severity.
Contrasting results have been also reported about the
possibility of detecting hemosiderin deposition by US evalu-
ation. Melchiorre et al24 and Zukotynski et al21 include
hemosiderin visualization in their US scores (Table 3). In
keeping with this, Doria et al39 have recently suggested some
criteria to distinguish between hemosiderin and synovium at
US, assuming that the rst is collected in hypoechoic pockets,
has an irregular contour, is less displaceable and less com-
pressible than uid, whereas the latter is nondisplaceable,
poorly compressible, and hyperechoic in relation to uid.
Seminars in Thrombosis & Hemostasis
Hemophilic Arthropathy and Ultrasound Minno et al.

However, considering that hemosiderin is embedded in the

ankle, hip, shoulder

synovium and it is not collected into the joint cavity as an
inert structure,36,44 other authors45 highlighted that such a

Elbow, knee,

Elbow, knee,

Elbow, knee,
Knee, ankle
distinction between hemosiderin deposition and synovium


Evaluated

cannot be made by using US. On the other hand, it is

joints

ankle

ankle
Knee
noteworthy that synovial hypertrophy is consistently recog-
nized as a major marker of blood-induced joint damage and,
in hemophilia patients, it invariably corresponds to hemosid-
Tendon, ligament,
bursa, and nerve

erin-enriched tissue (as assessed on gradient-echo MRI

The presence of the effusion is included in the scanning protocol but not considered in the scoring system because of the rapidly changing nature of the intra-articular effusion.
abnormalities

sequences). Thus, synovial hypertrophy presence might

represent a key feature, possibly related to undertreatment


due to insufcient therapy regimens or to a limited compli-
ance to treatment. However, some important issues need to
be addressed to better standardize the US assessment of

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synovial hypertrophy.
Bone abnormalities
(erosion, cysts,

Osteochondral Changes
osteophytes)

The presence of blood into the joint cavity is the factor








responsible for cartilage changes in hemophilic patients.46

In particular, by inducing a proinammatory status and an
increased oxidative stress, hemosiderin is able to determine
chondrocytes apoptosis and, in turn, a direct damage at the
Cartilage abnormalities

level of cartilage.47 In parallel, synovial hypertrophy is

hyperechogenicity,

thought to have a leading role in the development of hemo-

philic arthropathy,48,49 by means of an autocatalytic system,
(cartilage loss,








leading to a progressive and irreversible damage at the level

of cartilage and of bony structures (Fig. 1).34
thinning)

US examination of the joint surfaces reveals the subchon-

Asterisk () signies a given item is reported, and dash () signies that the item is not reported in the score.

dral bone plate as a regular continuous hyperechoic line,

covered by hypoanechoic smooth and regular linear structure
Hemosiderin

relative to the hyaline cartilage.30 Detection of cartilage and

deposition

bone abnormalities is mandatory when assessing and moni-




toring joint status in hemophilia because the presence or

absence of osteochondral abnormalities represents the
Table 3 Ultrasound evaluation of hemophilic arthropathy in different studies

watershed point for treatment failure in hemophilia.39

hyperemia

As pointed out in rheumatic diseases, US is able to detect early

Synovial

structural changes in cartilage and marginal bone erosions, with

a sensitivity superior even to X-ray.50 However, according to

Zukotynski et al, articular cartilage loss may be difcult to be
characterized by US, given the high variability of results likely
hypertrophy

due to small differences in transducer angulation.21

Synovial








Denition and quantication of osteochondral changes

widely varies among the existing US protocols.10,2125 Carti-
lage changes include progressive thinning of the cartilage up
or hemarthrosis)

to complete absence. In addition, loss of anechogenicity and

(synovial fluid

sharpness, hyperechogenicity, irregular prole, and calcica-

tion are an expression of cartilage irregularity and, as a
a




Effusion

consequence, they are also taken into account when catego-

rizing cartilage abnormalities (Table 3).
In contrast, bone alterations usually appear at US as an
irregularity of the hyperechoic line corresponding to the
Mua-Perja et al 2012
Zukotynski et al 2007
Melchiorre et al 2011
Klukowska et al 2001

subchondral bone.51 Most US scores only consider the pres-

Martinoli et al 2013

Kidder et al 2015

ence or the absence of such bone changes. Osteophytes, which

are expression of hypertrophic bone formation,24 can be also
detected at US because they appear as beak-shaped joint
surface projections covered by cartilage.51 As to the assess-
Author

ment of subchondral cysts, whereas very well identied by

MRI,33 they are difcult to be visualized at US examination
a

Seminars in Thrombosis & Hemostasis


because all US signals are reected back to the transducer
after impacting on bony structures, limiting the visualization
to the subchondral bone surface, and hampering the assess-
ment of medullary bone.21,39 However, the presence of sub-
chondral cysts is included by Klukowska et al23 when scoring
osteochondral changes.
Doria et al have recently shown high sensitivity (> 85%) of
US for diagnosing erosions and cartilage loss, regardless the
severity of arthropathy, and poor sensitivity and negative
predictive values for depicting subchondral cysts in advanced
and all levels of arthropathy, respectively.39 Sierra Aisa et al,
demonstrated a good correlation between US and MRI in the
observation of erosions of joint margins and a moderate
agreement in the detection of cartilage loss.40 In the hemo-
philia early arthropathy detection with ultrasound (HEAD-
US) system a single osteochondral area has been selected in
each joint as the key surface for assessing and scoring the
damage, speculating that one surface can be representative of
the diffuse osteochondral damage in hemophilic patients.10 A
signicant correlation between US and X-ray was detected for
bone remodeling by Melchiorre et al.24 In detail, narrowing of
joint space, erosions at joint margins, and joint deformity
showed the same distribution in the US and Pettersson score.
The presence of osteophytes is specically taken into
account in the US scores by Martinoli et al10 and Melchiorre
et al,24 the former specically searching these formations also
at the level of the medial meniscus and at the level of the
tibiotalar joint, being these the most frequently interested
sites. Overall, we have to consider that some weight-bearing
areas are hidden by the presence of bony structure and US is
not able to assess the whole osteochondral prole. However,
considering that hemophilia-related osteochondral changes
are characterized by a diffuse pattern of involvement,52
damages visualized by US are likely to be adequately repre-
sentative of the overall joint status. Thus, US could be
considered as a highly sensitive tool for detecting cartilage
and bone abnormalities, with a good degree of correlation
with MRI.33
Perspectives and Conclusions
During the last years, joint US has been more and more
extensively used in the frame of a comprehensive care
approach and a shift of the treatment paradigm to actually
preserve pristine joints or reduce joint deterioration.
Because of sensitivity in identifying also minimal and early
joint damages and of wide availability, US examination may
be a useful tool for the long-term follow-up in hemophilic
patients, also providing information for optimizing therapeu-
tic approaches and implementing or personalizing prophy-
laxis in specic settings. Given that the pharmacokinetics
response to infused factor concentrates is largely heteroge-
neous, with longer half-lives in adults than in children,53
growing interest has been given to individualized approaches
according to the specic pharmacokinetics or bleeding phe-
notype.54 Tailoring treatment on the basis of integrated
clinical (bleeding, lifestyle, joint status) and laboratory
(trough levels, pharmacokinetics) ndings is increasingly
Hemophilic Arthropathy and Ultrasound Minno et al.
addressed, in order to improve outcomes of prophylaxis.55
In this respect, the US assessment as a point of care tool
applied in the differential diagnosis of articular pain related to
a bleeding episode or to a preexisting arthropathy, performed
by physicians not trained in radiology,19,56 could easily
provide additional useful information. Indeed, although pro-
phylaxis is able to limit joint bleeding, thus preventing joint
deterioration,10,55 data from MRI studies consistently suggest
that some joint damages can be identied in about 20% of
cases despite treatment with clotting factor concen-
trates.33,57,58 These unexpected ndings can be explained
by a low compliance to the prescribed therapy or the need to
modify the treatment schedule, by increasing dosage or
infusion frequency of prophylaxis regimens. Moreover, joint
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impairment can also be a consequence of multiple subclinical
bleedings, even in clinically asymptomatic joints, never
involved with overt bleeding events. On the other hand, about
10% of individuals with severe hemophilia exhibit a mild
bleeding phenotype and they may need a less intensive
prophylaxis regimen.59,60 On the whole, US assessment can
be useful for clinical decisions in both these clinical scenarios,
by objectively documenting the response to treatment or the
need of treatment schedule modication.
Apart from early stages of arthropathic changes, US imag-
ing can be also used in the clinical follow-up of the growing
population of patients with late secondary (or tertiary)
prophylaxis.61 The POTTER (Prophylaxis versus On-demand
Therapy Through Economic Report) study62 recently docu-
mented signicantly better joint outcomes in adult patients
on prophylaxis compared with on-demand treatment, as
revealed by orthopedic scores. Moreover, changes in Petters-
son scores indicated that prophylaxis might actually delay
progression of arthropathy, even in patients with clinically
relevant joint damage. These data reect and extend to
adolescent and adult patients ndings previously reported
in younger patients,63 thus suggesting that US scanning might
help assess joint outcome in a long-term perspective and
optimize the therapeutic approach also in these specic
settings.
However, the use of US for the assessment of joint
impairment is still limited in hemophilia by the intra- and
interobserver variability of the technique, the very long
learning curve and the lack of standardization in hemophilic
patients.19,21 Most proposed US protocols are complex, with
only trained readers being able to get an acceptable level of
reproducibility. In addition, some of the above mentioned
scores have been designed moving by the assumption of
clinical and pathological similarities between hemophilic
arthropathy and other arthritides.41 They, thus, sometime
include the evaluation of poorly relevant structures and in
some cases give an incomplete estimation of osteochondral
damage, limiting the clinical relevance of the US examination.
To overcome this limitation, the HEAD-US protocol has
been specically designed to be easy to learn and use, thus
allowing the hemophilia treating physicians to perform the
US examination by themselves as a complementary part of
the clinical examination.10 The HEAD-US score includes a
systematic evaluation of the recesses of the elbow (radial,
Seminars in Thrombosis & Hemostasis
Hemophilic Arthropathy and Ultrasound Minno et al.
coronoid, annular, and olecranon), knee (suprapatellar,
medial, and lateral parapatellar), and ankle (anterior and
posterior recesses of the tibiotalar and subtalar joints), and
the assessment of the osteochondral status of the evaluated
joints (anterior aspect of the distal humeral epiphysis of the
elbow; femoral trochlea, and the anterior aspect of the talar
dome). This scanning protocol is very simplied and encom-
passes a total of 13 scanning points for the assessment of
6 joints. However, it is able to provide comprehensive infor-
mation about osteochondral damage (expressed by chondral
abnormalities and subchondral bone damage) and disease
activity (represented by the presence of joint effusion and
synovial hypertrophy).
Given the simplicity of the HEAD-US method, each joint
with its recesses can be evaluated in a few minutes, which is
signicantly less time compared with MRI and with some
other US scanning protocols.64 In this way, during routine
clinical examination, US scanning can be performed for more
than one joint and, potentially, for all of the six major synovial
joints. This might allow for rening the clinical examination
and potentially provide unexpected results, mainly in clini-
cally asymptomatic joints.33 For example, in children, who
have hyperlax joints and an immature skeleton, US has been
able to highlight severe joint involvement with high-grade
synovial hypertrophy and cartilage abnormalities, despite a
normal physical examination.65
In conclusion, being able to identify the presence of intra-
or extra-articular uid, US examination is the fastest and
most reliable technique for the joint assessment in acute
conditions, such as hemarthrosis. In addition, the information
on joint involvement provided by US, in particular in children
with absent/early arthropathic changes, could guide the
clinical management and inuence treatment decisions on
a personalized basis, in order to optimize outcomes of
prophylaxis. The use of US as part of a routine clinical
examination by hemophilia experts may optimize the diag-
nostic workow, avoiding additional costs, and long waiting
lists for patients referred to imaging departments. In the
frame of a comprehensive care approach, US might represent
a strategy to early detect and monitor synovial hypertrophy
and osteochondral changes in hemophilia, thus integrating
the clinical examination and helping identify joints to be
studied with a second-level examination, such as MRI.
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