A recent study explored the value of intensifying factor VIII prophylaxis in people with hemophilia A to prevent long-term chronic joint damage, as indicated by findings of hypertrophic synovium on ultrasound.1 The findings were published in the Journal of Thrombosis and Haemostasis.
In people with hemophilia, a single episode of joint bleeding with acute synovitis can start a chronic cycle. Subclinical bleeding can lead to chronic synovial inflammation and synovial hypertrophy. Neoangiogenesis, rebleeding, and consequent joint inflammation can lead to joint remodeling and joint space narrowing, with consequent joint instability, deformity, pain, and reduced quality of life.2
Primary prophylaxis with factor replacement therapy at a young age is key for preserving joint health in patients with hemophilia. Current guidelines recommend treatment to trough levels of factor VIII between 3% and 5%. However, some patients experience ongoing joint damage even with these standard prophylaxis regimens, including low rates of overt joint bleeding. Ultrasound is more sensitive to joint damage than clinical exam alone.2
Current guidelines recommend assessing the musculoskeletal health of patients with hemophilia at least annually, including imaging with ultrasound or MRI. However, guidelines are not explicit about how information such as synovial hypertrophy on ultrasound should be used to modify prophylaxis regimens.3
Author Ilenia Calcaterra, MD, PhD, of the Department of Clinical Medicine and Surgery of Federico II University of Naples, pointed out that this most recent study,1 led by Matteo Di Minno, MD, PhD, also of Federico II University, was partly designed with insights from the PROPEL trial, which demonstrated that intensified doses of factor VIII (to 8% to 12% trough levels) decreased bleeding rates compared with standard factor dosing.4
The researchers performed a randomized, open-label study of people with severe or moderate-to-severe hemophilia A with demonstrated hypertrophic synovium on ultrasound. Ultimately, 36 patients received factor VIII replacement in accordance with current guidelines (to trough levels of 3% to 5%), and 39 patients received factor VIII at intensified levels (to trough levels of 8% to 12%). Joint ultrasounds were performed every three months.1
In the group that received more intensive factor replacement, 25.6% achieved complete resolution of hypertrophic synovium, with an additional 10.3% achieving reduction in hypertrophic synovium by 24-month follow-up; this compared to 2.8% and 5.6%, respectively, in patients who received standard factor replacement. Via cox regression analysis, rates of reduction were roughly five times higher in the intensive factor group, and rates of complete resolution were about 10 times higher. Patient-reported outcome measures also improved, as did bleeding rates, although these were already relatively low.1
The relatively small size of the study was a potential limitation. When speaking with ASH Clinical News, Dr. Di Minno also noted that ultrasound can’t always distinguish whether fibrosis is also present, which may signal a more irreversible stage of disease, so better imaging strategies are still needed.
Dr. Di Minno sees these results as potentially practice changing, in terms of using hypertrophic synovium on ultrasound as a clear signal to escalate therapy. Added Dr. Calcaterra, “Our study might help change hematologists’ minds about the importance of looking for disease activity biomarkers [such as hypertrophic synovium].”
“This is a demonstration that one size doesn’t fit all,” Dr. Di Minno said. “If we personalize the imaging schedule and personalize the treatment, we improve the outcome. Hypertrophic synovium is one of the clinical settings that is deserving of higher protection and higher levels of factor replacement.”
Dr. Di Minno acknowledged that about 60% of patients in the intensive factor replacement group did not show joint improvements via these ultrasound findings. This prompts the need for investigation into other approaches, such as even more intensive factor replacement, at least for some individuals.
In 2023, the U.S. Food and Drug Administration approved a recombinant fusion protein designed for high and sustained levels of factor VIII replacement, ALTUVIIIO, the first treatment for hemophilia A that provides near normal levels of factor activity (over 40%). Dr. Di Minno noted that the treatment is expected to soon be available in Italy.
“We need to change our minds about the value of normalizing hemostasis and bringing trough levels closer to 40%,” Dr. Calcaterra said. “That’s an emerging topic in hemophilia treatment.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Di Minno MND, Calcaterra IL, Baldacci E, et al. Intensive FVIII replacement in hemophilia patients with hypertrophic synovium: a randomized study. J Thromb Haemost. 2025;23(2):458-465.
- Bakeer N, Saied W, Gavrilovski A, et al. Haemophilic arthropathy: diagnosis, management, and aging patient considerations. Haemophilia. 2024;30(Suppl 3):120-127.
- Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(Suppl 6):1-158.
- Klamroth R, Windyga J, Radulescu V, et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood. 2021;137(13):1818-1827.
