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Ultrasound May Be Useful to Assess Subclinical Synovial Inflammation in Hemophilia

November 30, 2023

December 2023

Ruth Jessen Hickman, MD

Ruth Jessen Hickman, MD, is a freelance medical and science writer based in Bloomington, Indiana.

A study published in Haemophilia highlights the potential utility of ultrasound screenings to assess preclinical joint damage in patients with hemophilia A.1

Dysfunction or deficiency of factor VIII, leading to hemophilia A, causes excess bleeding, primarily in the large synovial joints. Long term, this can develop into a cycle of subclinical bleeding and synovial proliferation and inflammation, which eventually leads to irreversible arthropathy. Previous studies have demonstrated that patients may develop early-stage joint damage even with little to no joint complaints or obvious joint bleeding.2-4

Thus, it is important to find other ways of identifying early-stage joint damage. For several years, researchers have been discussing the potential role of ultrasound in outcome assessment and disease monitoring of joint damage in hemophilia, but its ultimate value in clinical practice has not been clear.5

Flora H.P. van Leeuwen, an MD-PhD candidate in the Department of Radiology and Nuclear Imaging at the University of Utrecht in the Netherlands, is one of the authors on the recent study. She and her colleagues wanted to see if they could successfully detect subclinical synovial inflammation in patients with severe hemophilia A using joint ultrasound screening and a set of biomarkers that previously demonstrated potential in detecting synovitis and joint damage.1

The team studied 79 adult patients with hemophilia A (median age = 31 years) who had been receiving continuous prophylactic clotting factor treatment (78%) or on-demand treatment for bleeds. At routine clinic visits from 2019 to 2022, an experienced physiotherapist performed a physical exam and ultrasound examination of the elbows, knees, and ankles. Ultrasound results were scored as active synovial proliferation, inactive synovial proliferation, or no synovial proliferation. The researchers also tested serum and urine samples of various synovial and osteochondral biomarkers (e.g., chondroitin sulfate, osteopontin).1

The researchers found that 43% of patients had some degree of subclinical synovial proliferation assessed via ultrasound, and 22% had active (subclinical) synovial proliferation. Almost 60% of patients with synovial proliferation identified via ultrasound did not have physical exam findings such as warmth or swelling.1

Theoretically, biomarkers might provide a less subjective and perhaps more clinically readily available way to evaluate subclinical joint findings compared to ultrasound. However, in this study, the team did not find a reliable association between biomarkers and ultrasound findings.1

The cross-sectional nature of the study is an inherent limitation, as is the use of ultrasound as opposed to MRI. Synovial proliferation identified via MRI independently predicts five-year joint bleeding in hemophilia, and MRI is considered the reference standard to evaluate early joint changes in hemophilia.6 However, ultrasound compares favorably to MRI in terms of detecting synovial proliferation, and it may be more suitable for routine screening compared to MRI because of factors such as cost, availability, and speed.1,5,6

Ms. van Leeuwen noted that although some medical centers in Europe, Canada, and the U.S. routinely perform ultrasounds every one to three years in patients with severe hemophilia A, this is not yet standard. Early detection of subclinical synovial inflammation might help clinicians adapt or intensify treatment and potentially prevent irreversible joint damage. For example, some patients might benefit from an intensified prophylaxis regimen, celecoxib treatment, or both. Ms. van Leeuwen said her group would like to specifically study the effects of such treatment changes on the synovium via ultrasound.

Ms. van Leeuwen urged the hematology community to begin employing routine ultrasound to monitor joint health in patients with severe hemophilia A, although it’s not clear how often such screening should take place.

“[These patients] have subclinical synovial proliferation despite low bleeding rates and prophylaxis,” she said. “Without routine ultrasound, these subclinical findings will be missed. We may be able to prevent subclinical findings from developing into irreversible (clinical) joint damage if we detect them early.”

Any conflicts of interest declared by the authors can be found in the original article.


  1. van Bergen EDP, van Leeuwen FHP, Foppen W, et al. Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers [published online ahead of print, 2023 Sep 11]. Haemophilia. 2023. doi: 10.1111/hae.14861.
  2. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.
  3. Kraft J, Blanchette V, Babyn P, et al. Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada. J Thromb Haemost. 2012;10(12):2494- 2502.
  4. Nijdam A, Foppen W, de Kleijn P, et al. Discontinuing early prophylaxis in severe haemophilia leads to deterioration of joint status despite low bleeding rates. Thromb Haemost. 2016;115(5):931-938.
  5. Fischer K, Poonnoose P, Dunn AL, et al. Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspectiveHaemophilia. 2017;23(1):11-24.
  6. Foppen W, van der Schaaf IC, Beek FJA, et al. MRI predicts 5-year joint bleeding and development of arthropathy on radiographs in hemophilia. Blood Adv. 2020;4(1):113-121.


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