Study Reveals Prevalence of Subclinical Synovial Proliferation in Hemophilia A


The findings highlight the critical role that subclinical synovial proliferation plays in the progression of hemophilic arthropathy.

Doctor Conducting Ultrasound | Image credit: Africa Studio –

Doctor Conducting Ultrasound | Image credit: Africa Studio –

Individuals with severe hemophilia A and arthropathy experience progressive joint damage and chronic pain. New research suggests that subclinical bleeding and inflammation play a role in the progression of this condition. The study also states that early detection of synovial proliferation through routine ultrasound examinations may offer valuable insights for guiding treatment changes and preventing the advancement of arthropathy.

The team of investigators evaluated the prevalence of active and inactive subclinical synovial proliferation and explored potential biochemical markers for identifying patients with active synovial proliferation. Their cross-sectional study, published in Haemophilia, involved patients with severe hemophilia A born between 1970 and 2006 (N = 79; median age, 31 [range, 16.5-50.8] years). Patients were evaluated during routine clinic visits and those with a history of inhibitors or recent joint bleeding were excluded from the study. Over the previous 5 years, the annualized median joint bleeding rate was 0.6 (0.2-1.1).

Examinations focused on the elbows, knees, and ankles, as assessed by ultrasound and physical examination, to identify subclinical synovial proliferation. Active and inactive synovial proliferation were differentiated using predefined criteria.

Additionally, the investigators examined various blood and urine biochemical markers, including serum osteopontin, sVCAM-1, Coll2-1, COMP, CS846, TIMP, and urinary CTX-II, to determine their correlation with active synovial proliferation.

The investigators observed that both active (22%) and inactive (22%) subclinical synovial proliferation were prevalent among the study participants, indicating that even patients with access to prophylaxis are susceptible to subclinical synovial proliferation. When examining specific joints, this active synovial proliferation was found in 21 of 474 joints evaluated, accounting for 4% (95% CI, 3%-7%) of the total joints studied.

Similarly, inactive synovial proliferation was identified in 17 of the 79 patients (22%; 95% CI, 13%-32%). When analyzed at the joint level, this inactive synovial proliferation was present in 27 of 474 joints (6%; 95% CI, 4%-8%) of the total joints assessed. The team acknowledged this could have remained unnoticed without routine ultrasound examinations.

Further examination of patients with active synovial proliferation revealed 14 of them exhibited physical abnormalities during the clinical examination, highlighting the importance of combining clinical and imaging assessments for a comprehensive evaluation.

Only 7 patients among those with active synovial proliferation displayed hyperemia, or increased blood flow when assessed through ultrasound, which suggests that relying solely on hyperemia as an indicator may lead to the underestimation of active synovial proliferation in some cases.

The study also noted that in 20 patients, synovial proliferation detected through ultrasound did not manifest with warmth or swelling during physical examination, emphasizing the need for a multidimensional approach to diagnosis and monitoring.

When the potential of biochemical markers was investigated to identify patients with active subclinical synovial proliferation, the data did not reveal any significant correlations between these markers and active synovial proliferation. According to the study, this indicates that although biochemical markers may hold promise in various aspects of hemophilia research, they may not be reliable indicators of active subclinical synovial proliferation.

These findings highlight the critical role that subclinical synovial proliferation plays in the progression of hemophilic arthropathy.

“Subclinical synovial proliferation, including active synovial proliferation, was prevalent in this Dutch cohort of patients with severe hemophilia A who visited the clinic for routine follow-up and reported no recent joint bleeds, emphasizing the importance of ultrasound screening to detect subclinical synovial proliferation,” the investigators wrote.


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. Haemophilia. Published online September 11, 2023. doi:10.1111/hae.14861

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