A pathological joint-liver axis mediated by matrikine-activated CD4+ T cells.

The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+ T cells in peripheral blood and spleen. Deletion of CD4+ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4+ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4+ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4+ T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.

[Successful immunosuppressive therapy in female hemophilia A developing inhibitor after perioperative administration of factor VIII products].

A 62-year-old woman was diagnosed as a hemophilia A carrier (factor VIII activity 35%) on preoperative examination of an ovarian tumor. A total of 35,600 units of recombinant factor VIII products was administered perioperatively. On postoperative day 95, a subcutaneous hematoma formed and immunosuppressive therapy with prednisolone was started based on an APTT of 66 seconds, factor VIII (FVIII) activity of 3%, and FVIII inhibitor of 1 BU/ml. During this treatment, the patient was hospitalized due to ankle joint bleeds and required hemostatic treatment, but the inhibitor disappeared and FVIII activity recovered to 30% after postoperative day 438 with cyclophosphamide. F8 analysis revealed the patient carried a heterozygosity of p.Arg391Cys, which has previously been categorized as cross-reacting material (CRM)-positive severe hemophilia A. No high-risk mutations for inhibitor development were found. We also report the results of a desmopressin acetate hydrate test administered to the patient to prepare for future treatment in case of hemorrhage, since high-dose FVIII administration may have been a factor in inhibitor development.

Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B.

BACKGROUND: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed. OBJECTIVES: To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health-related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE. MAIN RESULTS: Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion. Prophylaxis versus on-demand therapy in people with inhibitors Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on-demand therapy in people with inhibitors. Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD -22.80, 95% CI -37.39 to -8.21), treated bleeds (MD -20.40, 95% CI -35.19 to -5.61), and annualized spontaneous bleeds (MD -15.50, 95% CI -24.06 to -6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate-certainty evidence). Fitusiran also likely reduced ABR for all bleeds (MD -28.80, 95% CI -40.07 to -17.53), treated bleeds (MD -16.80, 95% CI -25.80 to -7.80), joint bleeds (MD -12.50, 95% CI -19.91 to -5.09), and spontaneous bleeds (MD -14.80, 95% CI -24.90 to -4.71; 1 trial; 57 participants; moderate-certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on-demand therapy on AtjBR. Concizumab may reduce ABR for all bleeds (MD -12.31, 95% CI -19.17 to -5.45), treated bleeds (MD -10.10, 95% CI -17.74 to -2.46), joint bleeds (MD -9.55, 95% CI -13.55 to -5.55), and spontaneous bleeds (MD -11.96, 95% CI -19.89 to -4.03; 2 trials; 78 participants; very low-certainty evidence), but not target joint bleeds (MD -1.00, 95% CI -3.26 to 1.26). Emicizumab prophylaxis resulted in an 11.31-fold increase, fitusiran in a 12.5-fold increase, and concizumab in a 1.59-fold increase in the proportion of participants with no bleeds. HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low-certainty evidence). Non-serious adverse events were higher with non-clotting factor therapies versus on-demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab. Prophylaxis versus on-demand therapy in people without inhibitors Two trials (208 participants) compared emicizumab and fitusiran with on-demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi-weekly). Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi-weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD -20.21, 95% CI -32.12 to -8.30) and emicizumab 3.0 mg/kg bi-weekly (MD -15.30, 95% CI -30.46 to -0.14), but not with emicizumab 1.5 mg/kg/week (MD -14.60, 95% CI -29.78 to 0.58). The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi-weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on-demand therapy. Emicizumab 1.5 mg/kg/week did not improve Haem-A-QoL physical and total health scores, EQ-5D-5L VAS, or utility index scores (low-certainty evidence) when compared with on-demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi-weekly may improve HRQoL measured by the Haem-A-QoL physical health score (MD -15.97, 95% CI -29.14 to -2.80) and EQ-5D-5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low-certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem-A-QoL total score (MD -7.06, 95% CI -11.50 to -2.62) and physical health score (MD -19.75, 95% CI -25.76 to -11.94; 1 trial; 103 participants; low-certainty evidence). The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on-demand therapy (moderate-certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering. A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient-reported outcomes. No case of treatment-related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes. None of the included studies evaluated marstacimab. AUTHORS' CONCLUSIONS: Evidence from RCTs shows that prophylaxis using non-clotting factor therapies compared with on-demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non-serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long-term joint outcomes, and assessment of economic outcomes will improve evidence-based decision-making for the use of these therapies in bleed prevention.

Arthroscopic ankle surgery in people with haemophilia.

INTRODUCTION: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. AIM: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. METHODS: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. RESULTS: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). CONCLUSION: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

Closed Suction Drainage after Total Knee Arthroplasty with Concomitant Intravenous Tranexamic Acid Administration.

Drain use in total knee arthroplasty (TKA) remains controversial. Use has been associated with increased complications, particularly postoperative transfusion, infection, increased cost, and longer hospital stays. However, studies examining drain use were performed before widespread adoption of tranexamic acid (TXA), which markedly reduces transfusion without increasing venous thromboembolism events. We aim to investigate incidence of postoperative transfusion and 90-day return to the operating room (ROR) for hemarthrosis in TKA with use of drains and concomitant intravenous (IV) TXA. Primary TKAs from a single institution were identified from August 2012 to December 2018. Inclusion criteria were primary TKA, age 18 years and over where use of TXA, drains, anticoagulant, and pre- and postsurgical hemoglobin (Hb) were documented during the patient's admission. Primary outcomes were 90-day ROR specifically for hemarthrosis and rate of postoperative transfusion. A total of 2,008 patients were included. Sixteen patients required ROR, three of which were due to hemarthrosis. Drain output was statistically higher in the ROR group (269.3 vs. 152.4 mL, p = 0.05). Five patients required transfusion within 14 days (0.25%). Patients requiring transfusion had significantly lower presurgical Hb (10.2 g/dL, p = 0.01) and 24-hour postoperative Hb (7.7 g/dL, p < 0.001). Drain output between the transfusion and no transfusion groups varied significantly (p = 0.03), with transfusion patients having higher postoperative day 1 drain output of 362.6 mL and total drain output of 376.6 mL. In this series, postoperative drain use with concomitant weight-based IV TXA is shown to be safe and efficacious. We observed exceedingly low risk of postoperative transfusion compared with prior reports of drain use alone as well as preserved low rate of hemarthrosis that has previously been positively linked to drain use.

Hemarthrosis in a Pediatric Patient With Immune Thrombocytopenia and Lyme Arthritis.

The presentation of immune thrombocytopenia is dependent on the degree of thrombocytopenia, with no to mild bleeding symptoms, primarily mucocutaneous bleeding. Severe bleeding in other organ systems is a rare complication. Spontaneous hemarthrosis is rare in patients without hemophilia. We report a child presenting with oral and cutaneous petechial lesions and left knee hemarthrosis without trauma. Laboratory findings showed severe thrombocytopenia consistent with immune thrombocytopenia. Serologic tests were consistent with Lyme disease. Hemarthrosis was presumed secondary to Lyme disease monoarticular joint inflammation with bleeding exacerbated by severe thrombocytopenia. Hemarthrosis resolved and platelet counts normalized following immunoglobulin infusion, steroid course, and antibiotics.

What is the rationale for mesenchymal stromal cells based therapies in the management of hemophilic arthropathies?

Hemophilia A and B are rare X-linked genetic bleeding disorders due to a complete or partial deficiency in the coagulation factors VIII or IX, respectively. The main treatment for hemophilia is prophylactic and based on coagulation factor replacement therapies. These treatments have significantly reduced bleeding and improved the patients' quality of life. Nevertheless, repeated joint bleedings (hemarthroses), even subclinical hemarthroses, can lead to hemophilic arthropathy (HA). This disabling condition is characterized by chronic pain due to synovial inflammation, cartilage and bone destruction requiring ultimately joint replacement. HA resembles to rheumatoid arthritis because of synovitis but HA is considered as having similarities with osteoarthritis as illustrated by the migration of immune cells, production of inflammatory cytokines, synovial hypertrophy and cartilage damage. Various drugs have been evaluated for the management of HA with limited success. The objective of the review is to discuss new therapeutic approaches with a special focus on the studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA. A systematic review of the literature has been made. Most of the studies have focused on the interest of MSCs for the delivery of missing factors VIII or IX but in some studies, more insight on the effect of MSC injection on synovial inflammation or cartilage structure were provided and put in perspective for possible clinical applications.

Predicting the development of hemophilic arthropathy in patients with hemophilia based on patient age: a retrospective single-center database study.

BACKGROUND: Patients with hemophilia (PWH) develop hemophilic arthropathy of the major joints due to recurrent hemarthrosis. This study retrospectively estimated the age at which PWH may expect to develop hemophilic arthropathy and undergo joint replacement surgery. RESEARCH DESIGN AND METHODS: Using retrospective data from PWH at a Czech orthopedic center, Kaplan Meier analyses were used to estimate the cumulative proportions of patients with hemophilic arthropathy and undergoing joint replacement surgery as a function of age. RESULTS: Based on 1028 joint examinations in 167 PWH, hemophilic arthropathy of the knees, elbows, ankles and hips was estimated to develop by a median age of 48, 51, 52 and 61 years, respectively, with ≈80% of patients having such damage by ≈70 years of age. Hemophilic arthropathy of the shoulder occurred much later (median >80 years). In patients undergoing knee or hip replacement surgery, hemophilic arthropathy of the knee and hip occurred at a median age of ≈50 and ≈60 years, respectively, with replacement surgery occurring at a median of ≈70 and >75 years. CONCLUSIONS: In PWH, the risk of developing hemophilic arthropathy accumulates continuously over the patient's lifetime, allowing predictions about the ages at which such damage and joint replacement surgery may occur.

Skeletal complications in patients with hemophilia: a single-center experience.

BACKGROUND: Arthropathy is a common complication in patients with hemophilia. We examined the prevalence of this skeletal complication in patients with hemophilia who were registered at a Comprehensive Hemophilia Center in Shiraz, Southern Iran. MATERIALS AND METHODS: In this cross-sectional study, an orthopedic specialist visited 448 patients and conducted screenings for skeletal complications. The assessment included evaluating the type of hemophilia, disease severity, treatment modality, the presence of inhibitors, and the identification of skeletal complications. RESULTS: Ninety patients with hemophilia A, with a mean age (SD) of 31.6 (14.4) years, and 10 patients with hemophilia B, with a mean age of 30.5 (20.6) years, were assessed. The most frequently affected joints were the knee and ankle joints. In the univariate analysis, patients with severe disease were more likely to exhibit synovitis, a target joint, and bone disease compared to patients with non-severe disease. Additionally, a history of treated or active hepatitis and an annual bleeding rate showed significant associations with the target joint. In the multivariable logistic regression analysis, disease severity (OR 14.43, 95% CI 1.6-129.6) and a higher age at diagnosis (OR 1.06, 95% CI 1.00-1.13) increased the likelihood of developing osteoporosis. A history of hepatitis (OR 3.67, 95% CI 1.28-10.48) was identified as an independent risk factor for the target joint. CONCLUSION: Skeletal complications are a common occurrence in hemophilia. Regular consultations with orthopedic specialists, focusing on bleeding control and hepatitis prevention, are essential for reducing the impact of this debilitating complication.

The influence of distribution, severity and volume of posttraumatic bone bruise on functional outcome after ACL reconstruction for isolated ACL injuries.

INTRODUCTION: Posttraumatic MRI of ACL tears show a high prevalence of bone bruise (BB) without macroscopic proof of chondral damage. Controversial results are described concerning the association between BB and outcome after ACL tear. Aim of this study is to evaluate the influence of distribution, severity and volume of BB in isolated ACL injuries on function, quality of life and muscle strength following ACL reconstruction (ACLR). MATERIALS AND METHODS: MRI of n = 122 patients treated by ACLR without concomitant pathologies were evaluated. BB was differentiated by four localizations: medial/lateral femoral condyle (MFC/LFC) and medial/lateral tibial plateau (MTP/LTP). Severity was graded according to Costa-Paz. BB volumes of n = 46 patients were quantified (software-assisted volumetry). Outcome was measured by Lysholm Score (LS), Tegner Activity Scale (TAS), IKDC, isokinetics and SF-36. Measurements were conducted preoperatively (t0), 6 weeks (t1), 26 weeks (t2) and 52 weeks (t3) after ACLR. RESULTS: The prevalence of BB was 91.8%. LTP was present in 91.8%, LFC 64.8%, MTP 49.2% and MFC 28.7%. 18.9% were classified Costa-Paz I, 58.2% II and 14.8% III. Total BB volume was 21.84 ± 15.27 cm3, the highest value for LTP (14.31 ± 9.93 cm3). LS/TAS/IKDC/SF-36/isokinetics improved significantly between t0-t3 (p < 0.001). Distribution, severity and volume had no influence on LS/TAS/IKDC/SF-36/isokinetics (n.s.). CONCLUSIONS: No impact of BB after ACLR on function, quality of life and objective muscle strength was shown, unaffected by concomitant pathologies. Previous data regarding prevalence and distribution is confirmed. These results help surgeons counselling patients regarding the interpretation of extensive BB findings. Long-time follow-up studies are mandatory to evaluate an impact of BB on knee function due to secondary arthritis.

Hemophilia Joint Health Score, Functional Independence Score in Hemophilia, and Pettersson Score in Pediatric Patients With Severe Hemophilia A.

Hemophilia is an X-linked recessive disorder. Children with hemophilia go through spontaneous and trauma-provoked bleeding. Recurring joint bleeds lead to ongoing incapacity. Achieving healthy joints is the primary target of hemophilia management. The current study objective was to assess hemophilic joints in individuals with hemophilic arthropathy clinically, radiographically, and functionally. This cross-sectional study included 50 children with severe hemophilia A who were selected from the pediatric hematology clinic. All children were assessed for Hemophilia Joint Health Score (HJHS). Joint assessed functionally by Functional Independence Score in Hemophilia (FISH) and radiologically by plain radiograph and scored by the Pettersson scoring system. Data were analyzed using Statistical Package for Social Sciences. The mean age of the studied cases of hemophilia was 8.5±3.1 years. The mean FISH score among the studied patients was 26.8±4.2, the mean HJHS was 16.8±12.8, and the Pettersson score was 4.9±2.7. The number of affected joints showed a significant negative correlation to the FISH score and a significant positive correlation to HJHS. The frequency of hemarthrosis/month showed a significant positive correlation to HJHS. The number of affected joints showed a significant negative correlation to the FISH score and a significant positive correlation to HJHS. Frequency of hemarthrosis/month showed a significant positive correlation to HJHS.

Chronic pain in haemophilia: assessment and analgesic treatment.

People with haemophilia tend to experience pain from an early age because of venipuncture and hemarthrosis. If pain is not properly managed, it can become chronic and bedevil patients throughout their lives. Therapies are currently available that have been shown to effectively treat the different types of pain and their causes. Patients with haemophilia tend to experience either nociceptive or mixed pain. Identification of the cause of pain by means of imaging techniques, and understanding the characteristics, location and intensity of the pain, are essential for a more targeted therapeutic approach. Current data reveal that the most effective measures are administration of haematological and analgesic medication, intraarticular injections, and physical exercise. However, multimodal strategies such as lifestyle changes, physical modalities, psychological support and orthopaedic surgery can also prove of use. This article will look at the most effective analgesic measures used as a part of conservative clinical treatment. Collaborative studies are needed to better understand the nature of pain in the context of haemophilia.

Orthopedic surgical procedures in people with hemophilia.

People with hemophilia tend to develop joint lesions secondary to the recurrent hemarthroses typical of their condition. These usually include chronic synovitis and arthropathy chiefly affecting their ankles, knees, and elbows. In addition, muscular hematomas, albeit less frequently, may also result in complications such as acute compartment syndrome, pseudotumors, bone cysts and peripheral nerve compression. Joint lesions may require some of the following surgical interventions: arthroscopic synovectomy (in cases of synovitis), arthroscopic joint debridement, radial head resection, opening-wedge tibial osteotomy, arthrodesis, arthrodiastasis (of the ankle), tendon lengthening (hamstrings, Achilles tendon), progressive extension of the knee by placing an external fixator in cases of flexion contracture of the knee, supracondylar femoral extension osteotomy in cases of knee flexion contracture and, eventually, a total joint arthroplasty when the affected joint has been destroyed and the patient experiences severe joint pain. Total knee arthroplasty in hemophilic patients is associated with a high infection risk (7% on average). As regards the complications following muscle hematomas, acute compartment syndrome requires urgent performance of a fasciotomy when hematological treatment is incapable of resolving the problem. Surgical resection of hemophilic pseudotumors is the best solution, with those affecting the pelvis (secondary to iliopsoas hematomas) being particularly difficult to resolve. Peripheral nerve lesions can often be effectively addressed with hematological treatment, although a surgical neurolysis of the ulnar nerve is indicated if nonoperative treatment fails.

Hemostatic cover in orthopedic surgery.

Bleeding into joints, known as hemarthrosis, is the most common kind of bleeding experienced by patients with hemophilia. Repeat bleeds into the same joint lead to the so-called hemophilic arthropathy. Patients with this condition tend to require surgery earlier and most frequently than the general population. Successful hemostasis is essential to carry out such procedures. Thanks to the advances made in the treatment of hemophilia, most surgical techniques can be performed safely and reliably. The present review shall focus on the international recommendations related to the performance of these surgical procedures. We shall be examining the available treatments, including the way they should be administered as well as the requirements regarding the postoperative period and the subsequent rehabilitation program.

Spontaneous Hemopericardium Complicated by Tamponade in a Child With Moderate Hemophilia A: Case-Based Review.

Hemophilia A is the most common severe innate bleeding disorder. It is an X-linked recessive inherited bleeding disorder characterized by a qualitative and/or quantitative deficiency of factor VIII. The clinical manifestation of this disease is hemorrhaging that can affect every organ, in particular joints (hemarthrosis) and muscles (hematoma). Some serious but rare hemorrhages can be life-threatening, in particular hemorrhage of the central nervous system and hemopericardium. We report a rare case of spontaneous hemopericardium complicated by tamponade in a child with moderate hemophilia A treated with Factor VIII replacement infusion and pericardial drainage, with a favorable outcome. To our knowledge, this is the second case described in the literature of spontaneous hemopericardium occurring in a child with hemophilia A. Our case suggests that a dose of 50 IU/kg/8 h of factor VIII maintained for up to one day after removal of the pericardial drain seems to be sufficient to ensure correct hemostasis, though further evidence is needed to confirm this impression.

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

BACKGROUND: Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. QUESTIONS/PURPOSES: Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? METHODS: Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits' ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). RESULTS: Intra-articular bevacizumab treatment inhibited VEGF in our rabbit model of hemophilic arthropathy. VEGF protein expression levels were lower in the mild arthropathy group that received intra-articular bevacizumab (0.89 ± 0.45) than the mild arthropathy control group (1.41 ± 0.61) (mean difference -0.52 [95% CI -0.898 to -0.143]; p = 0.02). VEGF levels were lower in the severe arthropathy group that received treatment for 16 weeks (0.94 ± 0.27) than in the control knees (1.49 ± 0.36) (mean difference -0.55 [95% CI -0.935 to -0.161]; p = 0.01). In the severe arthropathy group, the Osteoarthritis Research Society International score indicating cartilage damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than in the control group (median 17 [range 13 to 18] versus 18 [range 17 to 20]; difference of medians 1; p = 0.02). Additionally, the scores indicated synovial damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than the control group (median 5 [range 4 to 9] versus 9 [range 8 to 12]; difference of medians 4; p = 0.02). The mean of mean values for signal intensity changes was higher in the nontreated severe groups than in the group of healthy knees. The signal intensity changes were higher in the severe arthropathy control groups (Groups BC and CC) (median 311.6 [range 301.4 to 361.2] and 315.1 [range 269.7 to 460.4]) than in the mild arthropathy control group (Group AC) (median 234.1 [range 212.5 to 304.2]; difference of medians 77.5 and 81, respectively; p = 0.02 and p = 0.04, respectively). In the severe arthropathy group, discoloration caused by hemosiderin deposition in the cartilage and synovium was more pronounced than in the mild arthropathy group. In the severe arthropathy group treated with intra-articular bevacizumab, joint diameters were smaller than in the control group (Group BT median 12.7 mm [range 12.3 to 14.0] versus Group BC median 14.0 mm [range 13.1 to 14.5]; difference of medians 1.3 mm; p = 0.02). CONCLUSION: Hemarthrosis damages the synovial tissues and cartilage in the knees of rabbits, regardless of whether they are treated with intra-articular bevacizumab. However, intra-articular injection of bevacizumab may reduce cartilage and synovial damage in rabbits when treatment is initiated early during the development of hemophilic arthropathy. CLINICAL RELEVANCE: If the findings in this study are replicated in larger-animal models that consider the limitations of our work, then a trial in humans might be appropriate to ascertain whether intra-articular injection of bevacizumab could reduce cartilage damage and synovial changes in patients with hemophilia whose hemarthroses cannot otherwise be controlled.

Maladaptive lymphangiogenesis is associated with synovial iron accumulation and delayed clearance in factor VIII-deficient mice after induced hemarthrosis.

BACKGROUND: Mechanisms of iron clearance from hemophilic joints are unknown. OBJECTIVES: To better understand mechanisms of iron clearance following joint bleeding in a mouse model of hemophilia. METHODS: Hemarthrosis was induced by subpatellar puncture in factor VIII (FVIII)-deficient (FVII-/-) mice, +/- periprocedural recombinant human FVIII, and hypocoagulable (HypoBALB/c) mice. HypoBALB/c mice experienced transient FVIII deficiency (anti-FVIII antibody) at the time of injury combined with warfarin-induced hypocoagulability. Synovial tissue was harvested weekly up to 6 weeks after injury for histological analysis, ferric iron and macrophage accumulation (CD68), blood and lymphatic vessel remodeling (αSMA; LYVE1). Synovial RNA sequencing was performed for FVIII-/- mice at days 0, 3, and 14 after injury to quantify expression changes of iron regulators and lymphatic markers. RESULTS: Bleed volumes were similar in FVIII-/- and HypoBALB/c mice. However, pronounced and prolonged synovial iron accumulation colocalizing with macrophages and impaired lymphangiogenesis were detected only in FVIII-/- mice and were prevented by periprocedural FVIII. Gene expression changes involved in iron handling (some genes with dual roles in inflammation) and lymphatic markers supported proinflammatory milieu with iron retention and disturbed lymphangiogenesis. CONCLUSION: Accumulation and delayed clearance of iron-laden macrophages were associated with defective lymphangiogenesis after hemarthrosis in FVIII-/- mice. The absence of such findings in HypoBALB/c mice suggests that intact lymphatics are required for removal of iron-laden macrophages and that these processes depend on FVIII availability. Studies to elucidate the biological mechanisms of disturbed lymphangiogenesis in hemophilia appear critical to develop new therapeutic targets.

Topical administration of tranexamic acid reduces postoperative blood loss and inflammatory response in knee arthroscopic arthrolysis: a retrospective comparative study.

BACKGROUND: Knee arthroscopic arthrolysis serves as an effective treatment for knee arthrofibrosis. However, hemarthrosis is the most common complication in arthroscopic surgery, which has potential adverse effects on postoperative rehabilitation. The purpose of this study was to evaluate the effects of topical tranexamic acid (TXA) in knee arthroscopic arthrolysis. METHODS: A total of 87 patients with knee arthrofibrosis who underwent arthroscopic arthrolysis from September 2019 to June 2021 were eligible for this retrospective review. Patients in the TXA group (n = 47) received topical administration of TXA (50 mL, 10 mg/mL) at the end of the surgery, and patients in the control group (n = 40) received no TXA. The postoperative drainage volumes, hematologic levels, inflammatory marker levels, knee range of motion (ROM), visual analog scale (VAS) pain scores, Lysholm knee scores and complications were compared between the two groups. The curative effect of each group was calculated according to Judet's criteria. RESULTS: The mean drainage volumes on postoperative day (POD) 1 and POD 2, and total drainage volume were significantly lower in the TXA group than in the control group (P < 0.001 for all). The TXA group had significantly lower postoperative CRP and IL-6 levels on POD 1 and POD 2, and at postoperative week (POW) 1 and POW 2 than the control group. The VAS pain scores in the TXA group were significantly lower on POD 1 and POD 2, and at POW 1 and POW 2 than those in the control group (P < 0.001 for all). Patients in the TXA group showed better postoperative ROM and Lysholm knee scores at POW 1 and POW 2. No patient had any complications such as deep venous thrombosis (DVT) or infection. The excellent and good rates of knee arthroscopic arthrolysis were comparable between the two groups at the sixth postoperative month (P = 0.536). CONCLUSIONS: Topical administration of TXA in knee arthroscopic arthrolysis can reduce postoperative blood loss and inflammatory response, alleviate early postoperative pain, increase early postoperative knee ROM, and improve early postoperative knee function without increased risks.

Biologics, Stem Cells, Growth Factors, Platelet-Rich Plasma, Hemarthrosis, and Scaffolds May Enhance Anterior Cruciate Ligament Surgical Treatment.

Biologics including mesenchymal stem cells (MSCs), growth factors, and platelet-rich plasma may enhance anterior cruciate ligament (ACL) reconstruction and even ACL primary repair. In addition, hemarthrosis after acute ACL injury represents a source of biologic factors. MSCs can differentiate into both fibroblasts and osteoblasts, potentially providing a transition between the ligament or graft and bone. MSCs also produce cytokines and growth factors necessary for cartilage, bone, ligament, and tendon regeneration. MSC sources including bone marrow, synovium, adipose tissue, ACL-remnant, patellar tendon, and umbilical cord. Also, scaffolds may represent a tool for ACL tissue engineering. A scaffold should be porous, which allows cell growth and flow of nutrients and waste, should be biocompatible, and might have mechanical properties that match the native ACL. Scaffolds have the potential to deliver bioactive molecules or stem cells. Synthetic and biologically derived scaffolds are widely available. ACL reconstruction with improved outcome, ACL repair, and ACL tissue engineering are promising goals. LEVEL OF EVIDENCE: Level V, expert opinion.