We previously demonstrated in adult patients with haemophilia (PWH) that hemarthrosis is present in only ~1/3rd of acutely painful joints by using point-of-care-musculoskeletal ultrasound (MSKUS). Therefore, other unrecognized tissue abnormalities must contribute to pain. Using high resolution MSKUS, employing grey scale and power Doppler, we sought to retrospectively (i) investigate soft tissue abnormalities in painful haemophilic joints and (ii) to determine to what extent MSKUS findings, functional or radiographic joint scores correlate with biomarkers of inflammation in PWH. Findings were correlated with Hemophilia Joint Health Scores (HJHS), Pettersson scores, high sensitivity C-reactive protein and von Willebrand factor activity and antigen levels. A total of 65 MSKUS examinations for acute and chronic joint pains were performed for 34 adult haemophilia patients, mostly for chronic joint pains (72.3%). The most prominent findings (66.5%) pertained to inflammatory soft tissue changes including synovitis, tendinitis, enthesitis, bursitis and fat pad inflammation. Effusions were present in 55.5% and 46.8% of MSKUS performed for acute and chronic pain, respectively. Of those, 90.0% were bloody during acute and 47.6% during persistent pains. While inflammatory biomarkers correlated well with overall HJHS and total Pettersson scores (P < 0.05), they did not differ between those patients with synovitis and those without. MSKUS is emerging as an important modality to diagnose treatable musculoskeletal abnormalities contributing to pain in haemophilic arthropathy, and therefore seems critical for a personalized approach to haemophilia care. The role of biomarkers in this setting remains less clear and requires further investigation.

Vascular remodeling contributes to perpetuated hemophilic joint bleeding and therefore contributes to progressive arthropathy. Intra-articular or systemic administration of anti-angiogenic drugs, such as vascular endothelial growth factor antagonists, might be of benefit in such patients, but requires study.

Neoangiogenesis and vascular remodeling in the hypertrophic synovium of arthropathic hemophilic joints may disturb vascular integrity and contribute to repeated bleeding (A von Drygalski, et al. Vascular Remodeling Underlies Re-Bleeding in Hemophilic Arthropathy; ASH 2015; Abstract ID 78677). However, it is difficult to distinguish the importance of the contribution of abnormal vascular structures to hemophilic joint bleeding from the contribution of low clotting factor levels. This is because most prophylactic clotting factor replacement strategies are designed to avoid trough levels below 1-5%, but not to fully correct the factor deficiency. This report reveals the importance of aberrant angiogenesis for joint bleeding in two hemophilia patients whose clotting factor activity levels were constantly normal or near normal. The first patient had severe Hemophilia A with normalized Factor (f)VIII activity levels after liver transplantation 6 years previously. Abnormal vascularization of elbows, knees and ankles (absent bleeding) was detected by musculoskeletal ultrasound and Power Doppler (PD). Three months after the baseline exam the patient experienced severe elbow bleeding associated with new vascular changes on PD. These changes were characterized by pronounced confluent, patchy vascular signals and numerous enlarged and thickened vessels by angiography consistent with acute and chronic vascular remodeling. Bleeding could not be controlled by increasing fVIII activity to supra-normal levels, and ultimately required synovial embolization. The second patient has severe Hemophilia B and presented shortly after left knee joint replacement with fluctuating knee bleeding for many months associated with pronounced dynamic vascular changes on PD. Neither bleeding nor vascular changes were prevented by daily fIX treatment which maintained near normal plasma fIX activity levels. Within one year, additional chronic bleeding with vascular changes developed in the left elbow and left ankle and remained unresponsive to intense factor replacement. These cases provide several insights. First, vascular changes in hemophilic arthropathy persist and evolve in dynamic fashion even in the presence of normal clotting factor activities. Second, vascular disturbance and leakiness contributed to bleeding independent of clotting factor activity levels as exemplified by the first patient and as suggested by the second patient. Third, the sequence of bleeding events in the second patient suggests that at least some of the observed vascular abnormalities are mediated systemically. These observations provide clinical evidence in support of the hypothesis that neoangiogenesis and vascular remodeling contribute to hemophilic joint bleeding and should lead to new studies of the pathophysiology of vascular remodeling in such joints. Targeting angiogenesis may emerge as a new treatment strategy to enhance the effectiveness of clotting factor replacement hemophilic arthropathy. Disclosures Chang: Biogen: Research Funding. Rose:Sirtex Medical: Equity Ownership, Honoraria; XLSciTech: Consultancy; Surefire Medical: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Embolx: Consultancy. von Drygalski:Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.