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DOI: 10.1055/a-2781-8742
Extraarticular and Intraarticular Key Lesions in Knee Joints of Adult Persons with Hemophilia—A Case-Control Ultrasound Study
Authors
The authors have received funding for research carried out in this work by Baxalta, now part of Takeda and former Shire, Germany.
Abstract
Background: Persons with hemophilia (PwH) develop arthropathic changes due to recurrent hemarthroses. This study aimed to comprehensively investigate structural knee joint alterations in PwH, extended beyond synovitis and osteochondral abnormalities, and to compare findings with healthy controls (Con).
Methods: Bilateral knee ultrasound examinations were performed in 36 male PwH (severe A: 30, B: 2; moderate A: 3, B: 1; mean age: 47.1 ± 12.0) and 39 age-matched Con (mean age: 47.7 ± 12.8). A total of 26 landmarks and tissues, including synovium, osteophytes, ligaments, tendons, and bursae, were assessed quantitatively or semi-quantitatively. Clinical joint status was classified using the Hemophilia Joint Health Score, distinguishing between minorly (PwH-MI) and majorly (PwH-MA) affected joints.
Results: Synovium, osteophytes, ligaments, and bursae showed more pronounced alterations in PwH compared to Con. While the iliotibial band was slightly thicker in PwH (p = 0.023), the popliteus tendon (p = 0.001) and patellar tendon at the tibial insertion were significantly thinner. PwH-MA showed significant changes at all landmarks (p < 0.001), while PwH-MI demonstrated differences only in the lateral knee joint synovium (p = 0.006) compared to Con. Osteophytes and synovium were significantly thicker in PwH-MA than in PwH-MI.
Conclusion: The findings highlight the importance of assessing periarticular structures in PwH, as changes may contribute to functional impairments such as gait deviations. Further research is required to clarify the clinical implications.
Introduction
Hemophilia A and B are genetic disorders characterized by spontaneous or traumatic joint bleeding caused by a deficiency of coagulation factor VIII or IX, respectively. Recurrent bleedings in persons with hemophilia (PwH) lead to hemophilic arthropathy (HA), primarily affecting ankle, knee, and elbow joints.[1] These maladaptive joint remodeling processes result in pain, reduced range of motion, deformity, malalignment, and laxity.[2] Although the exact mechanisms behind the development of HA remain unclear, synovium and osteochondral tissues represent key determinants. Intraarticular hemosiderin causes synovial inflammation and joint cartilage destruction, followed by osteophyte formation.
PwH often show altered strength capacity, particularly in knee extensors and flexors. Thus, a closer look at anatomical changes is necessary to determine whether additional structures beyond the commonly assessed ones influence knee function.[3]
Joint examination not only in PwH usually contains clinical examination followed by radiography. However, radiographs cannot detect soft tissue changes, especially concerning the synovium and cartilage.[2] To visualize such “early changes” in joints and joint surrounding structures, musculoskeletal ultrasound (MSKUS) has been deployed. In osteoarthritis research, MSKUS has been proven to be more sensitive than radiographs in detecting degenerative changes such as osteophytes.[4] In hemophilia, the need for an “easy to use” instrument in clinical practice has led to the improvement of MSKUS and various examination protocols up to scores have been developed and evaluated.[5] [6] Relevant items within the scope of these scores are effusion, synovitis, cartilage abnormalities, and bone erosions.
Nevertheless, pathophysiological processes of HA, as well as osteoarthritis or rheumatoid arthritis, do not only negatively act on intraarticular structures evaluated in the aforementioned protocols. These diseases may also affect joint surrounding tissues like tendons, muscles, or ligaments, which can contribute to pain and dysfunction, as recognized in osteoarthritis research.[7] From this functional point of view, these considerations call for a more nuanced detection of joint changes to shed light on relationships of clinical- and imaging-based alterations in patients suffering from HA. By examining joint surrounding structures, which potentially impact musculoskeletal function, critical information about the development of HA could be generated and therapy could be adjusted to address the respective joint on a more global scale.
Therefore, this study aimed to investigate intraarticular (i.e., osteophytes, synovial thickening, effusion) and periarticular structures (i.e., ligaments, tendons, bursae) in knee joints of PwH and to compare them with healthy controls (Con) using ultrasound, in order to gain novel insights into the complexity of HA. Specifically, the following research questions were addressed: (1) Which intraarticular and periarticular knee structures in PwH morphologically deviate from those of healthy Con? (2) Do the extent and pattern of these alterations differ between minorly and majorly affected knee joints in PwH?
Material and Methods
Subjects
In this case-control study, both knee joints of in total 36 patients with moderate or severe hemophilia A or B and 41 healthy, age-matched Con were examined clinically and by MSKUS. Inclusion criteria were as follows: Minimum age of 18 years for both groups and severe (factor activity <1%) or moderate (factor activity 1–5%) hemophilia A or B in PwH. Exclusion criteria for both groups comprised to not suffer from rheumatic diseases or underwent knee joint surgery within the last 6 months before examination. Likewise, PwH with bleeding events within the last 2 weeks before the examination were not included. In the case of knee arthroplasty, the affected joint was excluded. Cons were additionally excluded in case of manifest osteoarthritis. PwH were recruited through patient meetings organized in collaboration with the Department of Sports Medicine, while Cons were recruited via public calls for participation and personal contacts.
The study followed the principles of good clinical and ethical practice and the vote of the local ethic committee was obtained. According to the Declaration of Helsinki, all participants gave written informed consent after being instructed about the study’s protocol.
Clinical Joint Examination
To describe the clinical joint status, both knees of PwH and Con were examined by an experienced therapist using the Hemophilia Joint Health Score (HJHS), which represents a validated measurement tool for adult PwH.[8] Structural and functional items (e.g., range of motion, crepitation, joint circumference) were assessed and judged by score points. The maximum score for both knee joints comprises 20 points. Higher scores indicate an increased joint deficit. For in-depth subgroup analyses, knees of PwH were classified in either majorly affected and minorly affected. Majorly affected knees (PwH-MA) were defined as those with a joint score ≥ 2, while minorly affected knees (PwH-MI) had a joint score < 2.[9]
Ultrasound Examination
MSKUS was performed for each knee of PwH and Con by an experienced orthopedics blinded to the result of the HJHS score. Typical anatomical landmarks were depicted by palpation and evaluated in a quantitative or semiquantitative way. Effusion was described as 0 = no remarkable effusion, 1 = effusion depicted when upper recess was squeezed out, 2 = effusion without manipulation. The remaining tissues (i.e., synovium, ligaments, tendons, osteophytes, bursa) were measured in a standardized manner, as described in [Table 2]. A portable digital ultrasound system S8 (Sonoscape, Shenzhen, China) with a linear probe and a standard frequency of 5–15 MHz was used in a two-dimensional scan. Pictures were taken with the patient lying in supine position on a comfortable bench in a two-dimensional B-mode according to the standardized scanning methods, as described previously.[10] In each scanned region, beneath the probe lying structures were identified and measured, as listed in [Table 2].
Statistics
Statistical analyses were performed using the standard software package IBM© SPSS 29 (Armonk, NY, USA) for Windows. All statistical data were tested for normal distribution using the Kolmogorov–Smirnov test. Anthropometric data of both cohorts were compared by Student’s t-tests. In consecutive analyses, nonparametric tests were used, because not all parameters showed normal distributions. To analyze the differences of anatomical structures between PwH and Con, Mann–Whitney U tests were used. To explore the impact of the clinical situation on structural parameters, subgroup analyses were performed by dividing the clinical joint score into two halves. Subsequently, differences between PwH subgroups and Con were calculated by employing Kruskal–Wallis tests followed by post hoc tests with Bonferroni adjustment. Additionally, Spearman’s rank correlations were employed to analyze associations between age and articular and periarticular landmarks in PwH and Con. Spearman’s correlation coefficients (r s) were interpreted as follows: weak = 0.10−0.29, moderate = 0.30−0.49, strong = >0.49.[11] All statistical analyses were defined as significant with a p-value ≤ 0.05.
Results
Subjects and Clinical Joint Assessment
Examinations were performed in 36 PwH and 41 Con. Most patients had severe hemophilia A (n = 30), while only 3 PwH had moderate hemophilia A or hemophilia B (moderate B = 1, severe B = 2). The anthropometric data of both cohorts are presented in [Table 1]. Because of previously not mentioned surgery in the nearer past or the presence of osteoarthritis in Con, two participants were excluded from the final analysis. Finally, the results for knee joints of 36 PwH and 39 Con were evaluated. In some cases, several scans were not able to be carried out due to a lack of sufficient range of motion and thus could not be considered. This explains the discrepancy between the number of structures examined and the total number of knee joints assessed.
Data presented as mean ± standard deviation (min–max) or as proportion (%). Student’s t test. p ≤ 0.05.
Regarding the clinical joint status, PwH showed a significantly higher HJHS regarding both knees corresponding to a worse clinical joint status compared with Con (PwH = 3.1 ± 2.5, Con = 0.6 ± 0.8; p < 0.001; [Table 3]). Regarding minorly and majorly affected knees, a total of 51 knee joints were considered as PwH-MA (3.6 ± 1.9) and 21 knee joints were considered as PwH-MI (0.2 ± 2.2).
Data presented as mean ± standard deviation (min–max). Mann–Whitney U test. p ≤ 0.05.
Ultrasound Findings
As presented in detail in [Tables 4] and [5], MSKUS measurements showed significant differences for most landmarks investigated between PwH and Con and also between PwH-MA, PwH-MI, and Con. The most important results are presented briefly and systematically below. Exemplary ultrasound-based illustrations of the knee joints of PwH and Con are presented in [Figs. 1] [2] [3] [4].
Data presented as mean ± standard deviation (min–max). Mann–Whitney U test, p ≤ 0.05.
|
Anatomical structures |
Specific landmarks |
PwH-MA |
PwH-MI |
p-Value |
|---|---|---|---|---|
|
Lateral condyle of femur |
Lig. collaterale laterale (mm) |
1.55 ± 0.48 |
1.29 ± 0.18 |
† 0.198 |
|
Iliotibial band (mm) |
1.98 ± 0.48 |
1.61 ± 0.43 |
† 0.002** |
|
|
Distal edge of musculus vastus lateralis |
Synovial thickening (mm) |
1.59 ± 1.27 |
0.92 ± 0.71 |
† 0.047* |
|
Effusion (none = 0, moderate = 1, much = 2) |
0.65 ± 0.74 |
0.48 ± 0.60 (0–2) |
† 0.999 |
|
|
Lateral knee joint |
Lig. collaterale laterale (mm) |
1.78 ± 0.39 |
1.55 ± 0.35 |
† 0.081 |
|
Synovial thickening (mm) |
2.08 ± 1.64 |
1.11 ± 0.64 |
† 0.003** |
|
|
Tendon of M. popliteus (mm) |
3.69 ± 0.77 |
3.79 ± 0.76 |
† 0.999 |
|
|
Osteophytes of the femur (mm) |
3.69 ± 4.90 |
0.37 ± 1.70 |
† 0.000*** |
|
|
Osteophytes of the tibia (mm) |
1.86 ± 2.90 |
0.22 ± 1.01 |
† 0.004** |
|
|
Effusion (none = 0, moderate = 1, much = 2) |
0.52 ± 0.58 |
0.33 ± 0.58 |
† 0.999 |
|
|
Gerdy’s tubercle |
Iliotibial band (mm) |
2.77 ± 0.74 |
2.53 ± 0.62 |
† 0.839 |
|
Osteophytes femoral (mm) |
0.82 ± 2.55 |
0.40 ± 1.84 |
† 0.301 |
|
|
Osteophytes tibial (mm) |
1.49 ± 2.23 |
0.32 ± 1.29 |
† 0.008** |
|
|
Suprapatellar region |
Synovial thickening (mm) |
1.85 ± 1.70 |
0.98 ± 0.66 |
† 0.047* |
|
Effusion (none = 0, moderate = 1, much = 2) |
0.63 ± 0.75 |
0.43 ± 0.68 |
† 0.999 |
|
|
Infrapatellar area |
Patellar tendon, mid portion (mm) |
4.09 ± 0.82 |
3.81 ± 0.47 |
† 0.101 |
|
Patellar tendon, tibial insertion (mm) |
5.15 ± 0.88 |
5.00 ± 0.69 |
† 0.999 |
|
|
Bursa infrapatellaris profunda |
0.86 ± 1.54 |
0.34 ± 0.92 |
† 0.354 |
|
|
Medial condyle of femur |
Lig. collaterale |
1.93 ± 0.39 |
1.61 ± 0.35 |
† 0.002** |
|
Synovial thickening (mm) |
1.29 ± 0.87 |
0.77 ± 0.47 |
† 0.010** |
|
|
Medial knee joint |
Lig. collaterale mediale (mm) |
1.93 ± 0.41 |
1.56 ± 0.33 |
† 0.002** |
|
Mensicofemoral ligament (mm) |
1.39 ± 0.44 |
1.07 ± 0.30 |
† 0.010** |
|
|
Meniscotibial ligament (mm) |
1.25 ± 0.43 |
0.85 ± 0.23 |
† 0.000*** |
|
|
Osteophytes femoral (mm) |
1.67 ± 2.49 |
0.38 ± 1.73 |
† 0.012* |
|
|
Osteophytes tibial (mm) |
1.93 ± 2.89 |
0.45 ± 2.08 |
† 0.004** |
|
|
Medial head of tibia |
Lig. collaterale mediale (mm) |
1.85 ± 0.42 |
1.51 ± 0.30 |
† 0.003** |
|
Bursa pes anserinus |
0.25 ± 0.61 |
0.10 ± 0.46 |
† 0.486 |
Data presented as mean ± standard deviation (min–max). Kruskal–Wallis test followed by Mann–Whitney U test with Bonferroni adjustment. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001.
† = PwH-MA vs. PwH-MI, ‡ = PwH-MA vs. Con, § = PwH-MI vs. Con.
Synovium and Effusion
Synovium was significantly thicker at all landmarks assessed in PwH compared with Con and also between PwH-MA and PwH-MI (p ≤ 0.05). No differences were observed between PwH-MI and Con. Analysis of the degree of effusion showed no statistical differences in any of the regions assessed, neither between PwH and Con, nor between PwH-MA and PwH-MI.
Bone
Femoral and tibial osteophytes showed significant differences between PwH and Con laterally (p < 0.001 femoral, p < 0.001 tibial) as well as medially (p = 0.018 femoral, p = 0.007 tibial). Significant differences were also observed between PwH-MA and Con and between PwH-MA and PwH-MI, except for the femoral part of Gerdy’s tubercle (p = 0.301). No differences were detectable between PwH-MI and Con for any landmark assessed.
Ligaments
Both (medial and lateral) collateral ligaments were significantly thicker in PwH compared to Con (insertion and mid portion). Subgroup analyses revealed significant differences mainly between PwH-MA and Con. For most landmarks, there were no significant differences in the thickness of the ligaments between PwH-MA and PwH-MI and between PwH-MI and Con, with the exception of the meniscofemoral and meniscotibial ligaments. In PwH, both deep layers of the medial collateral ligament (MCL) were significantly enlarged compared to Con. Additionally, in the meniscotibial portion, PwH-MA demonstrated significantly thicker values compared to PwH-MI (p = 0.010) and Con (p < 0.001).
The MCL has two deeper layers: The meniscofemoral and the meniscotibial ligament. The proximally located meniscofemoral ligament (p < 0.001) and the meniscotibial ligament (p = 0.005) showed significantly thicker values in PwH compared with Con. Additionally, in the meniscotibial portion, a significant difference could be detected between PwH-MA and PwH-MI (p < 0.001) as well as between PwH-MA and Con (p < 0.001).
Tendons
Tendons examined include the patellar tendon in its mid portion and tibial insertion, the popliteus tendon in the femoral sulcus popliteus and the iliotibial band (ITB) at the level of the femoral condyle and its insertion at the tibial Gerdy’s tubercle.
No difference was observed in the mid-portion of the patellar tendon between PwH and Con. At its insertion at the tibial head, the patellar tendon was significantly thinner in PwH compared with Con (p = 0.003). At the tibial insertion, significant differences in the thickness between PwH-MA and Con (p = 0.042) were found. The popliteus tendon showed significantly thinner values comparing PwH with Con (p = 0.002). This difference was most notable when comparing PwH-MA and Con (p = 0.007). The ITB was measured at two landmarks: Gerdy’s tubercle and lateral condyle of the femur. Significant differences could be observed between Con and PwH in general (p = 0.031), PwH-MA (p = 0.002), and PwH-MI (p = 0.003) at the lateral condyle. At Gerdy’s tubercle, significant differences were found only between PwH-MA and Con (p = 0.025).
Bursae
The bursa beneath the pes anserinus at the medial tibia (p = 0.026) as well as the bursa infrapatellaris (p = 0.001) were significantly thicker in PwH in contrast to Con. Regarding subgroup analyses, only at the bursa infrapatellaris significant differences were observed between Con and PwH-MA (p = 0.001).
Correlation of Age with Articular and Periarticular Landmarks
An overview of results for the correlation analyses can be obtained from Supplementary Table 1. In short, synovial hypertrophy (r s = 0.420–0.648) and osteophytes (r s = 0.275–0.682) were significantly positively correlated with age in PwH, irrespective of the corresponding anatomical structure. Contrastingly, the extent of effusion (r s = −0.016 to 0.008) and bursa thickness (r s = 0.031–0.134) demonstrated no significant correlation with age in PwH. Regarding ligaments, significant correlations with age in PwH were observed for the lateral collateral ligament (LCL) at the femoral condyle (r s = 0.315, p = 0.010), the MCL and its mid portion (r s = 0.390, p = 0.001) and insertion (r s = 0.341, p = 0.005), and the meniscotibial ligament (r s = 0.346, p = 0.007). The ITB at the level of the femoral condyle (r s = 0.271, p = 0.029) was the only tendon showing a significant correlation with age in PwH.
Discussion
The aim of this study was to comprehensively examine hemophilia-related changes in knee joints of PwH compared to healthy controls using ultrasound. To conduct the examination in a more discriminatory manner, we deviated from standard protocols by focusing more specifically on distinct intraarticular and extraarticular structures. This allowed for an assessment of abnormalities of structures such as the synovium, ligaments, and tendons by comparing knees of PwH with Cons, as well as by comparing minorly and majorly affected joints of PwH.
From osteoarthritis research, it is known that both intraarticular and periarticular changes, such as ligaments and tendons, contribute to clinical impairment. To our knowledge, no study has sonographically examined ligaments or tendons in PwH, although bleedings early in life have been associated with subtle musculoskeletal and ligamentous changes in pediatric PwH.[12] [13]
Initial data revealed significant differences between PwH and Con in nearly all investigated structures ([Table 4]). More detailed analysis further showed marked differences in osteophytes, synovial hypertrophy, the LCL and MCL, and the insertion portion of the patellar tendon, some previously unknown.
In concordance with other studies, changes in synovial thickness on sonographic imaging of knee joints affected by HA were observed.[14] Notably, synovial hypertrophy appeared in even mildly affected knees, suggesting early HA development. A recent MRI study identified synovial hypertrophy as a predictor of bleeding risk over 5 years.[15] However, PwH-MI showed no differences in synovial thickness compared with Con, indicating that substantial irregularities in synovial tissue are specific to HA, because they were only detected in joints with advanced stages of joint pathology. Effusion levels were not significantly varying between PwH and Con. Our findings correspond to a study in which effusion was not approved as a specific sign of HA after an MRI assessment of the knee and ankle joints.[16] The present study could confirm these findings, as there were no differences between PwH-MI and Con.
The extent of osteophytes differed significantly comparing PwH with Con. The clinical significance of this finding can be explained by the demonstrated association between the existence of osteophytes and the experience of pain.[17] In OA research, recent results showed a correlation between knee pain and the formation of osteophytes examined with MSKUS.[18] [19] As expected, osteophytes were significantly different in length between PwH-MA and PwH-MI, but not between PwH-MI and Con. This again indicates that the presence of structural alterations, here in the form of pronounced osteophytes, is specific to patients with progressed HA, which is in concordance with other studies.[20] The extent to which correlations between HA progression and osteophyte length exist needs to be addressed in future research. However, the correlation analyses indirectly support this assumption, as the magnitude of osteophytes was significantly correlated with age. This is in line with previous research, in which sonographic findings related to osteochondral damage were more pronounced in the aging hemophilic population.[21]
Ligaments have not been routinely assessed in hemophilia imaging. In this study, the MCL and LCL were significantly thicker in PwH compared to Con. A recent animal model reported similar changes such as thickening, ossification, and loss of fiber alignment in the collateral ligaments in mice suffering from knee OA.[22] Other studies linked such ossifications to altered load transmission, joint stability, knee pain, and gait modifications.[23] [24] These findings are supported by the differences detected between PwH-MA and PwH-MI. Unlike osteophytes, ligament thickness did not differ significantly between these two groups, suggesting that changes may appear early in HA due to synovial inflammation and/or maladaptive joint loading. Seuser and his colleagues described painful, palpable points at the MCL and LCL in children without overt clinical findings, termed “silent symptoms.”[25] The exact underlying mechanisms and clinical significance of these changes remain unclear and require further investigation.
Tendons analogously to ligaments have not yet been studied regularly in hemophilia. In this study, the popliteus and patellar tendons, as well as the ITB at its insertion part had significantly thinner values in PwH than in Con, but not for the midportion of the patellar tendon. This corresponds to a study by Monteforte and colleagues who found thinner quadriceps and patellar tendons in patients with knee osteoarthritis.[26] These findings were confirmed in further studies, demonstrating a close relationship of the thickness of the quadriceps muscle and osteoarthritis progression, albeit using MRI and not MSKUS.[27] In hemophilia, comparable imaging assessments are lacking, although it is known that an inter-extremity difference in strength of the quadriceps exists, even in minorly affected legs.[28] A recent study identified signs of tendinopathy in PwH but suggested that these were not directly caused by the underlying disease itself. Instead, they were attributed to biomechanical changes resulting from reduced range of motion and joint rigidity.[29] The results of this study indicate that these findings are consistent in PwH, especially regarding the popliteus tendon, supporting a potential link between muscle strength and arthropathic changes. Interestingly, there was no difference between PwH-MA and PwH-MI, except for the ITB at the lateral condyle. The thicker values at their insertion point on the femoral condyle can be regarded like the thickness of the ligaments, but studies confirming this finding are lacking. Thinner tendons might be interpreted as the result of muscle affection due to reflex inhibition in HA. These results are confirmed by a study, showing dysfunctional quadriceps inhibition in patients suffering from anterior knee pain and even structural changes in the patella tendon.[30] This mechanism may lead to altered movement patterns and thus to unfavorable joint loading. The function of the popliteus muscle as a stabilizer of posterolateral rotation is described in several studies.[31] [32] Furthermore, recent data by Cabuk et al. suggest the existence of Ruffini endings in the popliteus tendon, demonstrating its proprioceptive potential.[33] In PwH, Hilberg and colleagues showed an impaired sensory function and proprioception of the lower limb.[34] [35] When taken together, these data could explain twofold: Morphologically thinner popliteus tendons in PwH are the result of decreased function induced by single or repeated hemarthroses. On the other hand, deterioration of the popliteus tendon might be a significant determinant of a patients’ sensomotoric capacity.
The differences concerning the bursa pes anserina and infrapatellaris are in line with previous osteoarthritis research,[36] confirming our hypothesis that it is important to consider additional structures to evaluate the joint state more holistically.
The stronger correlations of age with synovitis and osteophyte formation in PwH likely reflect age-related degenerative processes commonly observed in joint tissues. In contrast, only selected tendinous and ligamentous structures showed significant associations with age, possibly because age-related changes in these tissues are more subtle, depend on mechanical loading patterns, and may be less consistently detectable with imaging.
The present findings may have therapeutic implications for the management of HA. The pronounced synovial hypertrophy and osteophyte formation observed with increasing joint involvement underline the importance of early and sustained prophylactic treatment to prevent recurrent bleeding and chronic synovial inflammation. As osteophytes have been identified as significant contributors to pain in PwH, a more in-depth investigation into the mechanisms underlying osteophyte formation in this population is warranted, particularly in comparison to osteoarthritis. The identification of structural alterations in specific ligaments and tendons further suggests that periarticular soft tissues should receive more attention in functional diagnostics and imaging follow-up strategies. Further research on the influence of axial deviations, proprioceptive abilities, and weight bearing of the leg on structural changes of ligaments and tendons is therefore needed in the field of hemophilia.
Limitations
Our study has some noteworthy limitations: A lack of standardized measurements of synovial or ligamentous thickening could lead to difficulties in the comparability with other examinations. Another limitation is the often-described operator-dependency, which may lead to discrepancies in the interpretation of findings, although Naredo stated a good interobserver reliability in the sonographic assessment of rheumatology.[37] Given that only three PwH had hemophilia B, no meaningful statistical analysis could be performed based on type of hemophilia. Finally, it has to be considered that measurements in mm are lacking accuracy, limited by the technical capabilities of the sonographic machinery.
Conclusion
MSKUS can be used to detect typical changes in HA that go beyond the protocols most commonly used at present. The results confirm well-documented pathophysiological mechanisms in HA, for example, synovial hypertrophy. On the other hand, the data provide novel insights into which structures are affected and morphologically altered in PwH, in addition to those already established. Significantly thinner tendons in affected joints led to the consideration that muscle weakness or a lack in proprioception may play a role in the development of HA, which is further substantiated by the findings of thicker ligaments and probably thicker bursa identified by MSKUS.
Based on the data, we recommend to consider ligamentous and tendinous structures in imaging diagnostics and research especially by using MSKUS in assessing HA with special focus on functional impairments.
Contributorsʼ Statement
M.H. and S.H. performed the data collection. M.H., S.H. and A.S. performed the data analysis. M.H., A.S. and T.H. drafted the manuscript. J.H. and F.T. provided scientific expertise. M.H., S.H. and T.H. designed and T.H. supervised the study. All authors read and approved the final manuscript.
Conflict of Interest
S. Herzig was employed by the Department of Sports Medicine during the design, conduct, and analysis of the study, but is now employed by Chugai Pharma Germany GmbH. M. Hoffmeister has received travel expenses and speaker honoraria from Takeda. T. Hilberg has received research funding from Biotest, Chugai, Intersero, Novo Nordisk, Roche, Sobi and Takeda as well as travel expenses, speaker or scientific advisory board honoraria from Bayer, Biotest, Chugai, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi and Takeda. The remaining authors stated that they had no interests which might be perceived as posing a conflict or bias.
Acknowledgment
The authors would like to thank the volunteers for participating in this study. This study was kindly supported by Baxalta, now part of Takeda and former Shire, Germany.
Ethics Approval Statement
This study was approved by the local Ethical Review Boards (University of Wuppertal MS/BB). All participants provided written informed consent.
Patient Consent Statement
Informed consent was obtained from all individual participants included in the study.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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- 20 Melchiorre D, Linari S, Innocenti M. et al. Haemophilia 2011; 17 (01) 112-117
- 21 Fang Y, Guo Y, Qin T, Luan Y, Zhang C. J Ultrasound Med 2023; 42 (04) 859-868
- 22 Ramos-Mucci L, Javaheri B. R v't H et al. Arthritis Res Ther 2020; 22 (01) 171
- 23 Poulet B, Hamilton RW, Shefelbine S, Pitsillides AA. Arthritis Rheum 2011; 63 (01) 137-147
- 24 Kim HA, Kim I, Song YW. et al. Osteoarthr Cartil 2011; 19 (12) 1422-1428
- 25 Seuser A. Hamostaseologie 2012; 32 Suppl (01) S52-S61
- 26 Monteforte P, Sessarego P, Rovetta G. G Ital Med Lav Ergon 2008; 30 (01) 75-77
- 27 Dannhauer T, Sattler M, Wirth W, Hunter DJ, Kwoh CK, Eckstein F. Magma 2014; 27 (04) 339-347
- 28 Brunner A, Stäuber F, Göhler S. et al. Haemophilia 2013; 19 (02) 267-274
- 29 Donati D, Spinnato P, Valdrè L. et al. J Clin Med. 2023 12. (13)
- 30 Davi SM, Lepley AS, Denegar CR, DiStefano LJ, Edgar CM, Lepley LK. J Athl Train 2020; 55 (06) 608-614
- 31 Nielsen S, Helmig P. Archiv Orthopadische Unfall-Chirurgie 1986; 104 (06) 357-362
- 32 Nyland J, Lachman N, Kocabey Y, Brosky J, Altun R, Caborn D. J Orthop Sports Phys Ther 2005; 35 (03) 165-179
- 33 Çabuk H, Kuşku ÇF. Clin Anatomy 2016; 29 (06) 789-795
- 34 Hilberg T, Herbsleb M, Gabriel HH, Jeschke D, Schramm W. Haemophilia 2001; 7 (06) 582-588
- 35 Hilberg T, Herbsleb M, Puta C, Gabriel HHW, Schramm W. Haemophilia 2003; 9 (01) 86-93
- 36 Hill CL, Gale DR, Chaisson CE. et al. Arthritis Rheum 2003; 48 (10) 2836-2844
- 37 Naredo E, Möller I, Moragues C. et al. Ann Rheum Dis 2006; 65 (01) 14-19
Correspondence
Publication History
Received: 23 August 2025
Accepted after revision: 07 January 2026
Article published online:
27 January 2026
© 2026. Thieme. All rights reserved.
Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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