# Effect of Blood on Synovial Joint Tissues: Potential Role of Ferroptosis
## 2 The Etiology of Hemarthrosis  
A main characteristic of hemarthrosis includes iron deposition in both synovial and subsynovial tissues, accompanied by neutrophil and macrophage infiltration of these tissues [20]. Blood exposure and oxidative stress due to hemophilic arthropathy or trauma can alter the synovial fluid environment and induce the release of pro-inflammatory cytokines (ex. IL-6, IL-1\(\beta\), TNF\(\alpha\), IL-4, and IL-10) [21]. Recurrent bleeding increases the potential for red blood cell (RBC) lysis, further exposing the joint to elevated levels of iron following hemoglobin release. Furthermore, excess iron deposition can trigger synovial proliferation and inflammation or synovitis, which activates the immune system, leading to synovitis and angiogenesis (Figure 1) [20]. Consequently, the inflamed synovium is now at risk of repeated injury and rebleeding, leading to macrophage-like synovioocytes  
Figure 1: Human knee with and without hemophilia-induced bleeding and inflammation into the joint space after traumatic injury. releasing pro-inflammatory cytokines and matrix metalloproteinases, while fibroblast-like synoviocytes exhibit uncontrolled expansion and thickening [22]. As a result, joint cartilage becomes degraded by the new invasive synovial growth [23]. Research is ongoing to ascertain whether synovial changes due to blood-induced joint damage are independent of cartilage degradation [24]. Hemarthosis can be attributed to traumatic or nontraumatic etiologies, involving various pathological mechanisms that expose blood to the joint space [8]. Acute injuries resulting in abnormal twisting of the loaded joint often contribute to hemarthosis [25]. Specifically, ligament ruptures, articular fractures, patellar dislocations, meniscal tears, and osteochondral injuries are common traumatic events associated with bleeding [8; 26]. In a recent study, hemarthosis was observed in 98% of patients with acute knee injuries [27]. The blood that enters the joint as a result of these conditions will reach up to 100% \(v/v\) and is typically aspirated within a week if bleeding stops, compromising the structural and functional properties of surrounding tissues over time [10]. Among these injuries, partial or complete ACL tears are the predominant cause of intra-articular bleeding [15]. In a recent study, 77% of cases of acute hemarthosis were caused by ACL ruptures [28]. Further studies have shown that within 4 h of trauma-induced hemarthosis, significant degradative effects were observed in neighboring tissues including the cartilage, meniscus, and bone [29]. Damage to the joint is often accompanied by an increase in pro-inflammatory cytokine levels in the surrounding synovial fluid, indicating that these biomarkers may stem from intra-articular bleeding episodes [27]. Specifically, it has been shown that injured patients with hemarthosis exhibit elevated IL-1\(\beta\), TNF-\(\alpha\), IL-6, IL-8, MMP-3, and TIMP-1 levels in the SF post-injury [30; 31; 32]. In addition to synovial inflammatory cytokines, ECM degradative products also increase upon injury [27]. Of note, patients suffering from these traumatic incidents were observed to have a 50% higher likelihood of developing posttraumatic osteoarthritis (PTOA) within 15 years of initial injury [33]. However, precise factors contributing to PTOA pathogenesis following joint injury and concurrent hemarthosis continue to be insufficiently explored. Unlike OA whose etiology is not well known, the initiation of PTOA is well defined, which provides an opportunity for therapeutic intervention such as a disease-modifying osteoarthritis drug (DMOAD) that will disrupt the subsequential development of OA. A subset of traumatic hemarthosis involves an injury resulting from minimal trauma. In the majority of cases, the occurrence of such injuries may result in underlying bleeding diathesis [8; 34]. Postoperative hemarthosis may also occur following arthroscopic procedures, although the incidence is typically low [8; 35].