Beyond the surface: Imaging of (sub)clinical joint changes in haemophilia

Flora H P van Leeuwen

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)


Haemophilia is an X-linked inherited coagulation disorder that results in an increased bleeding tendency. Most bleeding occurs in the large synovial joints (elbows, knees, ankles). Recurrent joint bleeding eventually leads to irreversible haemophilic arthropathy, which causes pain and reduces functionality and quality of life. Prophylactic treatment prevents most bleeding episodes. However, (subclinical) joint bleeding and inflammation still occur. Surprisingly, even in the absence of clinically overt joint bleeding, long-term progression to arthropathy is observed. Subclinical bleeding and inflammation are therefore thought to contribute to the development of arthropathy. Early detection of these subclinical processes is becoming increasingly important in the prevention of arthropathy as overt joint bleeding becomes rare with new replacement therapies. This thesis focused on the detection of subclinical bleeding, the screening for subclinical joint inflammation, and the use of ultrasound in the management of acute joint episodes.
The first part of this thesis discussed the detection of subclinical bleeding. Chapter 2 demonstrated that quantitative MRI T1 and T2 relaxometry can differentiate between haemorrhagic joint effusion with low blood concentration and synovial fluid in vitro. Chapter 3 demonstrated good feasibility and reproducibility of the T2-relaxometry method at 3 Tesla in vivo. Chapter 4 describes evidence for subclinical joint bleeding in people with severe haemophilia on long-term prophylaxis. Conventional MRI of joints without a history of bleeding showed evidence of previous subclinical bleeding in 16% of people with severe haemophilia A on prophylaxis.
The second part of this thesis focused on screening for subclinical joint inflammation. Chapters 5 and 6 are devoted to screening for (subclinical) synovial proliferation as a proxy for joint inflammation. The literature review in Chapter 5 showed that physical examination underestimates the prevalence of ultrasound-detected synovial proliferation. Therefore, ultrasound appears to have added value in screening for subclinical synovial hypertrophy. The findings in Chapter 6 support the value of ultrasound screening for subclinical synovial proliferation. The role of ultrasound is further emphasized by the failure of biochemical markers to identify ultrasound-detected subclinical synovial proliferation.
The third part of this thesis discusses the use of ultrasound in management of acute joint episodes. Although subclinical joint disease can be detected by imaging, its impact on patient management remained unclear. The cross-sectional study in Chapter 7 described that ultrasound, when added to clinical assessment, often changed the diagnosis and treatment of acute musculoskeletal complaints in people with haemophilia and von Willebrand disease (VWD). In Chapter 8, ultrasound and physical examination were used to monitor the recovery of joint bleeding in people with haemophilia and VWD. Ultrasound and physical examination provided complementary information in monitoring joint bleed recovery.
In conclusion, ultrasound should be used in haemophilia care as a screening tool for (subclinical) joint damage, as a diagnostic tool for acute joint episodes, and as a monitoring tool for recovery from joint bleeding. MRI remains the reference standard for imaging early joint changes in haemophilia and is therefore best used as a troubleshooter in difficult clinical cases and as a sensitive outcome measure in research.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
  • de Jong, Pim, Primary supervisor
  • Fischer, K, Supervisor
  • Foppen, Wouter, Co-supervisor
  • Timmer, Merel, Co-supervisor
Award date10 Jul 2024
Print ISBNs978-94-6473-491-1
Publication statusPublished - 10 Jul 2024


  • haemophilia
  • imaging
  • magnetic resonance imaging
  • ultrasound
  • joint
  • hemarthrosis
  • synovitis
  • haemophilic arthropathy


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