Sei sulla pagina 1di 9

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

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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

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.
Hemophilic Arthropathy and Ultrasound Minno et al.

Joint hemorrhage represents the most common type of bleeding Over the last years, six US scores have been proposed for
episode in persons with hemophilia,13 and recurrent hemarth- the use in hemophilia patients,10,2125 each considering
rosis triggers chronic arthropathy, which is the most frequent different aspects of hemophilic arthropathy in different joints
chronic complication in hemophilia patients.4 In the absence of and with different scanning protocols, but all with the
an adequate prophylaxis (age at start, regimen, duration, and common purpose of implementing US for the diagnosis and
adherence) with factor VIII (FVIII, for hemophilia A) or FIX (for the surveillance of joint impairment in hemophilia
hemophilia B) concentrates, up to 85% of the patients with severe (Table 3). The possibility of detecting and scoring the major
hemophilia develop a clinically overt joint disease.57 Moreover, markers of hemophilic arthropathy (synovial hypertrophy
some recent data suggest that the rate of arthropathy is also and osteochondral changes) by US examination allows for a
signicant in patients with moderate hemophilia.8 new approach to optimize the diagnostic workow and to
In recent years, in the frame of the comprehensive care avoid additional costs and long waiting lists for imaging in
approach and a shift of the treatment paradigm to actually hemophilic patients.
preserve pristine joints or reduce joint deterioration,9 a In the present review, we will summarize literature
growing attention has been given to the periodic assessment evidence on the use of joint US for the evaluation of markers

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
of the joint status in hemophilia patients, with the aim to of disease activity (joint effusion and synovial hypertrophy)
identify early arthropathic changes and, in turn, to prevent and of degenerative damages (osteochondral changes) in
the development of a clinically overt arthropathy in children patients with hemophilia.
or to avoid/limit its progression in adolescents and adults.
However, being difcult to be detected, subclinical joint
Ultrasound Findings in Hemophilia
damages are seldom searched for and recognized.10
Gilbert orthopedic joint score and the hemophilia joint health Effusion
score (HJHS) are widely used for the clinical assessment of the In 1987, Wilson et al reported their rst experience with joint
joint status in hemophilic patients (Tables 1 and 2).5,11 In US for the assessment of 38 hemophilia patients with acute
particular, the HJHS, increasingly used in recent years,12 pro- hemarthrosis.26 Since then, several other reports have been
vides the most sensitive score for the physical examination in addressed the use of joint US in this setting. As highlighted by
this clinical setting, although it is currently validated only for Querol and Rodriguez-Merchan in a systematic review, this
children.13 However, the sensitivity and specicity of these imaging tool has been mainly used in acute clinical situations
clinical scores in the identication of early-stage and subclinical (i.e., muscle hematomas and hemarthrosis), to identify the
damages are widely challenged, and the risk to underestimate presence of blood in the joints, pinpoint its location, measure
the severity of joint deterioration cannot be ruled out.13 its size, assess its evolution, and conrm its complete disap-
Besides clinical examination, several imaging techniques pearance.20 Indeed, US has proven to be a fast and reliable
have been used to evaluate joint status and to monitor the technique to detect the presence of intra- or extra-articular
disease progression in hemophilia patients.14 Standard radi- effusion, which is a sensitive sign of a recent hemarthrosis in
ography (X-ray) is a widely available imaging tool. Although hemophilic patients.2729 Besides efcaciously differentiat-
sensitive to late arthropathic changes, usually expression of ing the size and the location of the bleeding, US is also able at
an advanced and irreversible arthropathy,15 X-ray is not able dening its relationship with adjacent anatomic structures,
to identify signs of early-stage joint disease in hemophilia its evolution, and possible complications.20
patients (synovial hypertrophy, joint effusion, and early-stage The ability of ultrasonography to distinguish between
osteochondral damages).15 Thus, the radiological Pettersson normal serous uid from hemorrhagic uid after a bleed is
score cannot be considered a reliable tool to detect subclinical one of the issues to be solved.19 In a recent study, Ceponis et al
joint impairment.16 demonstrated, for the rst time, that high-resolution muscu-
In contrast, magnetic resonance imaging (MRI) provides loskeletal US could be a valuable imaging tool to dene
detailed information concerning early- and late-stage whether acute joint/musculoskeletal pain episodes in adult
arthropathic changes and it enables the study of soft tissues hemophilia patients are secondary to bleeding episodes.27 In
in hemophilic patients.17 For this reason, MRI is currently detail, 40 episodes occurring in 30 adult hemophilic patients
accepted as the gold standard for the assessment of hemo- were evaluated, with 33 of the 40 episodes interpreted by
philic arthropathy. However, the limitations of such an patients as bleeding, 5 as arthritis-related pain, and 2 as
imaging tool include the high cost of the examination, undecided. Of the 33 events interpreted as bleeding, only 12
the limited accessibility to the machine, the need for were conrmed by US evaluation. In the remaining 21 cases
sedation in children, and the need to evaluate only one (63.4%) pain was secondary to degenerative/inammatory
joint in each examination.18 Furthermore, the implications conditions. In contrast, three of ve episodes perceived as
of minor changes picked up by MRI before being seen on arthritis-related were reclassied as bleeding. In the same
plain radiographs in terms of individual joint function clinical setting, physician assessment was incorrect in 18 of
remain to be determined.19 the 40 cases. These data clearly suggest that US could signi-
Considering the limitations of X-ray and MRI, growing cantly help in the diagnostic approach to the patient with
interest has been given to ultrasound (US) as a possible tool to hemophilia reporting an acute painful event. On the other
assess joint status and to monitor joint disease progression in hand, it must be stressed that a reliable differentiation of
hemophilic patients.20 inammatory uid from hemorrhagic effusion is not always

Seminars in Thrombosis & Hemostasis

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

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

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

Seminars in Thrombosis & Hemostasis

Hemophilic Arthropathy and Ultrasound Minno et al.

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


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



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.

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

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
synovial hypertrophy.
Bone abnormalities
(erosion, cysts,

Osteochondral Changes

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


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

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

relative to the hyaline cartilage.30 Detection of cartilage and


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


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


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

due to small differences in transducer angulation.21


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


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-

ment of subchondral cysts, whereas very well identied by

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

Seminars in Thrombosis & Hemostasis

Hemophilic Arthropathy and Ultrasound Minno et al.

because all US signals are reected back to the transducer addressed, in order to improve outcomes of prophylaxis.55
after impacting on bony structures, limiting the visualization In this respect, the US assessment as a point of care tool
to the subchondral bone surface, and hampering the assess- applied in the differential diagnosis of articular pain related to
ment of medullary bone.21,39 However, the presence of sub- a bleeding episode or to a preexisting arthropathy, performed
chondral cysts is included by Klukowska et al23 when scoring by physicians not trained in radiology,19,56 could easily
osteochondral changes. provide additional useful information. Indeed, although pro-
Doria et al have recently shown high sensitivity (> 85%) of phylaxis is able to limit joint bleeding, thus preventing joint
US for diagnosing erosions and cartilage loss, regardless the deterioration,10,55 data from MRI studies consistently suggest
severity of arthropathy, and poor sensitivity and negative that some joint damages can be identied in about 20% of
predictive values for depicting subchondral cysts in advanced cases despite treatment with clotting factor concen-
and all levels of arthropathy, respectively.39 Sierra Aisa et al, trates.33,57,58 These unexpected ndings can be explained
demonstrated a good correlation between US and MRI in the by a low compliance to the prescribed therapy or the need to
observation of erosions of joint margins and a moderate modify the treatment schedule, by increasing dosage or
agreement in the detection of cartilage loss.40 In the hemo- infusion frequency of prophylaxis regimens. Moreover, joint

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
philia early arthropathy detection with ultrasound (HEAD- impairment can also be a consequence of multiple subclinical
US) system a single osteochondral area has been selected in bleedings, even in clinically asymptomatic joints, never
each joint as the key surface for assessing and scoring the involved with overt bleeding events. On the other hand, about
damage, speculating that one surface can be representative of 10% of individuals with severe hemophilia exhibit a mild
the diffuse osteochondral damage in hemophilic patients.10 A bleeding phenotype and they may need a less intensive
signicant correlation between US and X-ray was detected for prophylaxis regimen.59,60 On the whole, US assessment can
bone remodeling by Melchiorre et al.24 In detail, narrowing of be useful for clinical decisions in both these clinical scenarios,
joint space, erosions at joint margins, and joint deformity by objectively documenting the response to treatment or the
showed the same distribution in the US and Pettersson score. need of treatment schedule modication.
The presence of osteophytes is specically taken into Apart from early stages of arthropathic changes, US imag-
account in the US scores by Martinoli et al10 and Melchiorre ing can be also used in the clinical follow-up of the growing
et al,24 the former specically searching these formations also population of patients with late secondary (or tertiary)
at the level of the medial meniscus and at the level of the prophylaxis.61 The POTTER (Prophylaxis versus On-demand
tibiotalar joint, being these the most frequently interested Therapy Through Economic Report) study62 recently docu-
sites. Overall, we have to consider that some weight-bearing mented signicantly better joint outcomes in adult patients
areas are hidden by the presence of bony structure and US is on prophylaxis compared with on-demand treatment, as
not able to assess the whole osteochondral prole. However, revealed by orthopedic scores. Moreover, changes in Petters-
considering that hemophilia-related osteochondral changes son scores indicated that prophylaxis might actually delay
are characterized by a diffuse pattern of involvement,52 progression of arthropathy, even in patients with clinically
damages visualized by US are likely to be adequately repre- relevant joint damage. These data reect and extend to
sentative of the overall joint status. Thus, US could be adolescent and adult patients ndings previously reported
considered as a highly sensitive tool for detecting cartilage in younger patients,63 thus suggesting that US scanning might
and bone abnormalities, with a good degree of correlation help assess joint outcome in a long-term perspective and
with MRI.33 optimize the therapeutic approach also in these specic
However, the use of US for the assessment of joint
Perspectives and Conclusions
impairment is still limited in hemophilia by the intra- and
During the last years, joint US has been more and more interobserver variability of the technique, the very long
extensively used in the frame of a comprehensive care learning curve and the lack of standardization in hemophilic
approach and a shift of the treatment paradigm to actually patients.19,21 Most proposed US protocols are complex, with
preserve pristine joints or reduce joint deterioration. only trained readers being able to get an acceptable level of
Because of sensitivity in identifying also minimal and early reproducibility. In addition, some of the above mentioned
joint damages and of wide availability, US examination may scores have been designed moving by the assumption of
be a useful tool for the long-term follow-up in hemophilic clinical and pathological similarities between hemophilic
patients, also providing information for optimizing therapeu- arthropathy and other arthritides.41 They, thus, sometime
tic approaches and implementing or personalizing prophy- include the evaluation of poorly relevant structures and in
laxis in specic settings. Given that the pharmacokinetics some cases give an incomplete estimation of osteochondral
response to infused factor concentrates is largely heteroge- damage, limiting the clinical relevance of the US examination.
neous, with longer half-lives in adults than in children,53 To overcome this limitation, the HEAD-US protocol has
growing interest has been given to individualized approaches been specically designed to be easy to learn and use, thus
according to the specic pharmacokinetics or bleeding phe- allowing the hemophilia treating physicians to perform the
notype.54 Tailoring treatment on the basis of integrated US examination by themselves as a complementary part of
clinical (bleeding, lifestyle, joint status) and laboratory the clinical examination.10 The HEAD-US score includes a
(trough levels, pharmacokinetics) ndings is increasingly 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, 6 Pettersson H, Ahlberg A, Nilsson IM. A radiologic classication of
medial, and lateral parapatellar), and ankle (anterior and hemophilic arthropathy. Clin Orthop Relat Res 1980;(149):
posterior recesses of the tibiotalar and subtalar joints), and 153159
7 Tusell JM, Aznar JA, Querol F, Quintana M, Moreno M, Gorina E;
the assessment of the osteochondral status of the evaluated
Orthopaedic Study Group. Results of an orthopaedic survey in
joints (anterior aspect of the distal humeral epiphysis of the young patients with severe haemophilia in Spain. Haemophilia
elbow; femoral trochlea, and the anterior aspect of the talar 2002;8(Suppl 2):3842
dome). This scanning protocol is very simplied and encom- 8 Di Minno MN, Ambrosino P, Franchini M, Coppola A, Di Minno G.
passes a total of 13 scanning points for the assessment of Arthropathy in patients with moderate hemophilia a: a systematic
review of the literature. Semin Thromb Hemost 2013;39(7):723731
6 joints. However, it is able to provide comprehensive infor-
9 Colvin BT, Astermark J, Fischer K, et al; Inter Disciplinary Working
mation about osteochondral damage (expressed by chondral
Group. European principles of haemophilia care. Haemophilia
abnormalities and subchondral bone damage) and disease 2008;14(2):361374
activity (represented by the presence of joint effusion and 10 Martinoli C, Della Casa Alberighi O, Di Minno G, et al. Development
synovial hypertrophy). and denition of a simplied scanning procedure and scoring
Given the simplicity of the HEAD-US method, each joint method for Haemophilia Early Arthropathy Detection with Ultra-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
sound (HEAD-US). Thromb Haemost 2013;109(6):11701179
with its recesses can be evaluated in a few minutes, which is
11 Feldman BM, Funk SM, Bergstrom BM, et al. Validation of a new
signicantly less time compared with MRI and with some pediatric joint scoring system from the International Hemophilia
other US scanning protocols.64 In this way, during routine Prophylaxis Study Group: validity of the hemophilia joint health
clinical examination, US scanning can be performed for more score. Arthritis Care Res (Hoboken) 2011;63(2):223230
than one joint and, potentially, for all of the six major synovial 12 Oymak Y, Yildirim AT, Yaman Y, et al. The effectiveness of tools for
joints. This might allow for rening the clinical examination monitoring hemophilic arthropathy. J Pediatr Hematol Oncol
and potentially provide unexpected results, mainly in clini-
13 Nijdam A, Bladen M, Hubert N, et al. Using routine Haemophilia
cally asymptomatic joints.33 For example, in children, who Joint Health Score for international comparisons of haemophilia
have hyperlax joints and an immature skeleton, US has been outcome: standardization is needed. Haemophilia 2016;22(1):
able to highlight severe joint involvement with high-grade 142147
synovial hypertrophy and cartilage abnormalities, despite a 14 Cross S, Vaidya S, Fotiadis N. Hemophilic arthropathy: a review of
imaging and staging. Semin Ultrasound CT MR 2013;34(6):
normal physical examination.65
In conclusion, being able to identify the presence of intra-
15 Doria AS. State-of-the-art imaging techniques for the evaluation of
or extra-articular uid, US examination is the fastest and haemophilic arthropathy: present and future. Haemophilia 2010;
most reliable technique for the joint assessment in acute 16(Suppl 5):107114
conditions, such as hemarthrosis. In addition, the information 16 Kilcoyne RF, Nuss R. Radiological evaluation of hemophilic
on joint involvement provided by US, in particular in children arthropathy. Semin Thromb Hemost 2003;29(1):4348
17 Funk MB, Schmidt H, Becker S, et al. Modied magnetic resonance
with absent/early arthropathic changes, could guide the
imaging score compared with orthopaedic and radiological scores
clinical management and inuence treatment decisions on for the evaluation of haemophilic arthropathy. Haemophilia 2002;
a personalized basis, in order to optimize outcomes of 8(2):98103
prophylaxis. The use of US as part of a routine clinical 18 Acharya SS, Schloss R, Dyke JP, et al. Power Doppler sonography in
examination by hemophilia experts may optimize the diag- the diagnosis of hemophilic synovitisa promising tool. J Thromb
nostic workow, avoiding additional costs, and long waiting Haemost 2008;6(12):20552061
19 Keshava SN, Gibikote S, Doria AS. Imaging Evaluation of Hemo-
lists for patients referred to imaging departments. In the
philia: Musculoskeletal Approach. Semin Thromb Hemost 2015;
frame of a comprehensive care approach, US might represent 41(8):880893
a strategy to early detect and monitor synovial hypertrophy 20 Querol F, Rodriguez-Merchan EC. The role of ultrasonography in
and osteochondral changes in hemophilia, thus integrating the diagnosis of the musculo-skeletal problems of haemophilia.
the clinical examination and helping identify joints to be Haemophilia 2012;18(3):e215e226
studied with a second-level examination, such as MRI. 21 Zukotynski K, Jarrin J, Babyn PS, et al. Sonography for assessment
of haemophilic arthropathy in children: a systematic protocol.
Haemophilia 2007;13(3):293304
22 Kidder W, Nguyen S, Larios J, Bergstrom J, Ceponis A, von Drygalski
A. Point-of-care musculoskeletal ultrasound is critical for the
References diagnosis of hemarthroses, inammation and soft tissue abnor-
1 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; malities in adult patients with painful haemophilic arthropathy.
361(9371):18011809 Haemophilia 2015;21(4):530537
2 Dalyan M, Tuncer S, Kemahli S. Hemophilic arthropathy: evalua- 23 Klukowska A, Czyrny Z, Laguna P, Brzewski M, Seran-Krol MA,
tion of clinical and radiological characteristics and disability. Turk J Rokicka-Milewska R. Correlation between clinical, radiological
Pediatr 2000;42(3):205209 and ultrasonographical image of knee joints in children with
3 Luck JV Jr, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, haemophilia. Haemophilia 2001;7(3):286292
Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg 2004; 24 Melchiorre D, Linari S, Innocenti M, et al. Ultrasound detects joint
12(4):234245 damage and bleeding in haemophilic arthropathy: a proposal of a
4 Rodriguez-Merchan EC, Jimenez-Yuste V, Aznar JA, et al. Joint score. Haemophilia 2011;17(1):112117
protection in haemophilia. Haemophilia 2011;17(Suppl 2):123 25 Mua-Perja M, Riva S, Grochowska B, Mangiaco L, Mago D,
5 Gilbert MS. Prophylaxis: musculoskeletal evaluation. Semin Hem- Gringeri A. Ultrasonography of haemophilic arthropathy. Haemo-
atol 1993;30(3, Suppl 2):36 philia 2012;18(3):364368

Seminars in Thrombosis & Hemostasis

Hemophilic Arthropathy and Ultrasound Minno et al.

26 Wilson DJ, McLardy-Smith PD, Woodham CH, MacLarnon JC. 47 Lafeber FP, Miossec P, Valentino LA. Physiopathology of haemo-
Diagnostic ultrasound in haemophilia. J Bone Joint Surg Br philic arthropathy. Haemophilia 2008l14(Suppl 4):39
1987;69(1):103107 48 Valentino LA, Hakobyan N, Rodriguez N, Hoots WK. Pathogenesis
27 Ceponis A, Wong-Sedan I, Glass CS, von Drygalski A. Rapid of haemophilic synovitis: experimental studies on blood-induced
musculoskeletal ultrasound for painful episodes in adult haemo- joint damage. Haemophilia 2007;13(Suppl 3):1013
philia patients. Haemophilia 2013;19(5):790798 49 Valentino LA, Hakobyan N, Enockson C, et al. Exploring the
28 Robertson JD, Connolly B, Hilliard P, Wedge J, Babyn P, Carcao M. biological basis of haemophilic joint disease: experimental stud-
Acute haemarthrosis of the hip joint: rapid convalescence follow- ies. Haemophilia 2012;18(3):310318
ing ultrasound-guided needle aspiration. Haemophilia 2009; 50 Wakeeld RJ, Gibbon WW, Conaghan PG, et al. The value of
15(1):390393 sonography in the detection of bone erosions in patients with
29 Beyer R, Ingerslev J, Srensen B. Current practice in the manage- rheumatoid arthritis: a comparison with conventional radiogra-
ment of muscle haematomas in patients with severe haemophilia. phy. Arthritis Rheum 2000;43(12):27622770
Haemophilia 2010;16(6):926931 51 Grassi W, Lamanna G, Farina A, Cervini C. Sonographic imaging of
30 Bianchi S, Martinoli C, Bianchi-Zamorani M, Valle M. Ultrasound of normal and osteoarthritic cartilage. Semin Arthritis Rheum 1999;
the joints. Eur Radiol 2002;12(1):5661 28(6):398403
31 Aznar JA, Prez-Alenda S, Jaca M, et al. Home-delivered ultrasound 52 Roosendaal G, Lafeber FPJG. Blood-induced joint damage in he-

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
monitoring for home treatment of haemarthrosis in haemophilia mophilia. Semin Thromb Hemost 2003;29(1):3742
A. Haemophilia 2015;21(2):e147e150 53 Bjrkman S, Folkesson A, Jnsson S. Pharmacokinetics and dose
32 Lundin B, Babyn P, Doria AS, et al; International Prophylaxis Study requirements of factor VIII over the age range 3-74 years: a
Group. Compatible scales for progressive and additive MRI assess- population analysis based on 50 patients with long-term prophy-
ments of haemophilic arthropathy. Haemophilia 2005;11(2): lactic treatment for haemophilia A. Eur J Clin Pharmacol 2009;
109115 65(10):989998
33 Di Minno MN, Iervolino S, Soscia E, et al. Magnetic resonance imaging 54 Fischer K, Pouw ME, Lewandowski D, Janssen MP, van den Berg
and ultrasound evaluation of healthy joints in young subjects with HM, van Hout BA. A modeling approach to evaluate long-term
severe haemophilia A. Haemophilia 2013;19(3):e167e173 outcome of prophylactic and on demand treatment strategies for
34 Rodriguez-Merchan EC. Haemophilic synovitis: basic concepts. severe hemophilia A. Haematologica 2011;96(5):738743
Haemophilia 2007;13(Suppl 3):13 55 Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in
35 Mainardi CL, Levine PH, Werb Z, Harris ED Jr. Proliferative synovitis children with hemophilia: evidence-based achievements, old and
in hemophilia: biochemical and morphologic observations. new challenges. Semin Thromb Hemost 2012;38(1):7994
Arthritis Rheum 1978;21(1):137144 56 Martinoli C, Di Minno MN, Pasta G, Tagliaco A. Point-of-care
36 Roosendaal G, Mauser-Bunschoten EP, De Kleijn P, et al. Synovium ultrasound in haemophilic arthropathy: will the HEAD-US system
in haemophilic arthropathy. Haemophilia 1998;4(4):502505 supplement or replace physical examination? Haemophilia 2016;
37 Convery FR, Woo SL, Akeson WH, Amiel D, Malcom LL. Experi- 22(1):2021
mental hemarthrosis in the knee of the mature canine. Arthritis 57 Ng WH, Chu WC, Shing MK, et al. Role of imaging in management
Rheum 1976;19(1):5967 of hemophilic patients. AJR Am J Roentgenol 2005;184(5):
38 Roosendaal G, Vianen ME, van den Berg HM, Lafeber FP, Bijlsma 16191623
JW. Cartilage damage as a result of hemarthrosis in a human in 58 Olivieri M, Kurnik K, Puger T, Bidlingmaier C. Identication and
vitro model. J Rheumatol 1997;24(7):13501354 long-term observation of early joint damage by magnetic reso-
39 Doria AS, Keshava SN, Mohanta A, et al. Diagnostic accuracy of nance imaging in clinically asymptomatic joints in patients with
ultrasound for assessment of hemophilic arthropathy: MRI corre- haemophilia A or B despite prophylaxis. Haemophilia 2012;18(3):
lation. AJR Am J Roentgenol 2015;204(3):W33647 369374
40 Sierra Aisa C, Luca Cuesta JF, Rubio Martnez A, et al. Comparison 59 Pavlova A, Oldenburg J. Dening severity of hemophilia: more
of ultrasound and magnetic resonance imaging for diagnosis and than factor levels. Semin Thromb Hemost 2013;39(7):702710
follow-up of joint lesions in patients with haemophilia. Haemo- 60 Jayandharan GR, Srivastava A. The phenotypic heterogeneity of
philia 2014;20(1):e51e57 severe hemophilia. Semin Thromb Hemost 2008;34(1):
41 Blobel CP, Haxaire C, Kalliolias GD, DiCarlo E, Salmon J, Srivastava 128141
A. Blood-Induced Arthropathy in Hemophilia: Mechanisms and 61 Coppola A, Franchini M, Tagliaferri A. Prophylaxis in people with
Heterogeneity. Semin Thromb Hemost 2015;41(8):832837 haemophilia. Thromb Haemost 2009;101(4):674681
42 Newman JS, Laing TJ, McCarthy CJ, Adler RS. Power Doppler 62 Tagliaferri A, Feola G, Molinari AC, et al; POTTER Study Group.
sonography of synovitis: assessment of therapeutic response Benets of prophylaxis versus on-demand treatment in adoles-
preliminary observations. Radiology 1996;198(2):582584 cents and adults with severe haemophilia A: the POTTER study.
43 Rodrguez-Merchn EC. Pathogenesis, early diagnosis, and pro- Thromb Haemost 2015;114(1):3545
phylaxis for chronic hemophilic synovitis. Clin Orthop Relat Res 63 Aledort LM, Haschmeyer RH, Pettersson H; The Orthopaedic
1997;(343):611 Outcome Study Group. A longitudinal study of orthopaedic out-
44 Roosendaal G, Vianen ME, Wenting MJG, et al. Iron deposits and comes for severe factor-VIII-decient haemophiliacs. J Intern Med
catabolic properties of synovial tissue from patients with haemo- 1994;236(4):391399
philia. J Bone Joint Surg Br 1998;80(3):540545 64 Jelbert A, Vaidya S, Fotiadis N. Imaging and staging of haemophilic
45 Martinoli C, Di Minno MN, Pasta G, Tagliaco A. Haemosiderin arthropathy. Clin Radiol 2009;64(11):11191128
detection with Ultrasound: reality or myth? AJR Am J Roentgenol 65 Foppen W, van der Schaaf IC, Fischer K. Value of routine ultrasound
2016;206(Suppl 1):W30 in detecting early joint changes in children with haemophilia
46 Roosendaal G, Lafeber FP. Pathogenesis of haemophilic arthropa- using the Haemophilia Early Arthropathy Detection with Ultra-
thy. Haemophilia 2006;12(Suppl 3):117121 Sound protocol. Haemophilia 2016;22(1):121125

Seminars in Thrombosis & Hemostasis