Hemophilia is an inherited bleeding disorder characterized by deficiency of clotting factors, leading to increased bleeding tendencies. The most common complications are joint bleeds (hemarthroses), which cause chronic changes in joints and ultimately disability. Recurrent hemarthroses often result from chronic synovitis in target joints of patients with hemophilia, a process driven by Vascular Endothelial Growth Factor (VEGF) mediated pathological angiogenesis. Intra-articular administration of Bevacizumab, a VEGF neutralizing monoclonal antibody, may block this process and reduce the frequency of recurrent joint bleeds. This study evaluates the efficacy and safety of intra-articular Bevacizumab for preventing recurrent hemarthrosis in patients with hemophilia and chronic synovitis.

Hemophilia A is the most prevalent inherited bleeding disorder in Pakistan, accounting for approximately 69% of all hemophilia cases. A major complication is recurrent joint bleeding (hemarthrosis), which leads to chronic synovitis and progressive hemophilic arthropathy. This joint deterioration significantly impairs mobility and quality of life.

The underlying pathophysiology is driven by repeated hemarthroses, which cause increased local expression of Vascular Endothelial Growth Factor (VEGF). VEGF promotes abnormal angiogenesis and synovial proliferation, perpetuating a cycle of inflammation and bleeding, even when symptoms are not overt.

Bevacizumab is a recombinant humanized monoclonal antibody that specifically inhibits VEGF. Local intra-articular administration offers a targeted therapeutic approach to disrupt this pathogenic cycle directly at the site of pathology. By neutralizing VEGF, Bevacizumab may mitigate synovitis, reduce bleeding frequency, and slow progression of hemophilic arthropathy, while minimizing systemic exposure and associated adverse effects.

To investigate this therapeutic strategy, a two-year, open-label, single-arm clinical trial will be conducted at the Institute of Pathology and Diagnostic Medicine (IPDM), Khyber Medical University (KMU), and Hayatabad Medical Complex, Peshawar, Pakistan. A total of 25 participants with Hemophilia A and chronic synovitis in one or more target joints (knee, elbow, or ankle) will be enrolled.

All participants will receive intra-articular Bevacizumab injections following prophylactic factor replacement therapy to prevent procedure-related bleeding. The first four participants will receive 20 mg/0.8 mL per injection. If well tolerated without major toxicities, the remaining participants will receive 40 mg/1.6 mL per injection. Each injection will be administered into the target joint once every 28 days for a total of four doses.

The primary efficacy outcome will be the change in the Annualized Bleeding Rate (ABR) of the target joint, calculated from 3-month pre- and post-treatment data. Secondary outcomes will include changes in joint health assessed using the Hemophilia Joint Health Score (HJHS, Version 2.1; range 0-124, where higher scores indicate worse joint health) and synovial inflammation measured by Magnetic Resonance Imaging (MRI) with the International Prophylaxis Study Group (IPSG)-compatible scoring system.

This study may provide critical insight into a novel, VEGF-targeted strategy for managing chronic synovitis in hemophilia patients and preserving long-term joint health.

Inclusion Criteria:

• Confirmed diagnosis of Hemophilia A.
• Presence of one or more target joints (knee, elbow, ankle) with chronic synovitis and a history of >2 hemarthrosis episodes in the past 6 months.
• Target joint World Federation of Hemophilia (WFH) joint score of 2-3.
• Adequate hematological, renal, and liver function (as specified by protocol lab values).
• Ability and willingness to provide informed consent and comply with the study protocol.

Exclusion Criteria:

• HIV positive diagnosis.
• Severely damaged joints or anatomical limitations preventing safe injection.
• Contraindications to MRI.
• Uncontrolled hypertension.
• Recent major surgery/trauma (<28 days).
• Serious non-healing wound, active cardiovascular disease, or other significant comorbidities that could increase risk or interfere with the study.

Individual participant data that underlie the results reported in the primary publication (after de-identification) will be made available beginning 9 months following article publication and will remain available for a period of at least 36 months.

De-identified individual participant data will be made available 9 months after the publication of the primary results and will remain accessible for at least 36 months. Extensions may be considered upon request.

Access will be granted to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Requestors will be required to submit a proposal to the corresponding author and sign a Data Access Agreement to ensure appropriate use of the data.

This is an open-label study. No masking is used.