Acute Hemarthrosis Research Articles

Perioperative Pain Management in Hemophilic Patient Undergoing Orthopedic Surgery: A Narrative Review

Background: Hemophilia type A and B is associated with spontaneous bleeding in muscle tissues and joints. Acute hemarthrosis, representing 70–80% of all bleedings in severe hemophilia patients, is extremely painful. When surgical procedures are needed in hemophiliac patients, perioperative management should be planned with a multidisciplinary team. Our narrative review, through a rigorous analysis of the current literature, focuses on pain management in hemophiliac patients. Methods: The report synthesizes a literature review on hemophilia, adapting PRISMA guidelines. It identifies a research question on surgical procedures and perioperative pain management. Various sources, including electronic databases, are utilized. Study inclusion criteria are defined based on the research question. Forty studies are included. A detailed study selection is illustrated. Results: Guidelines for managing acute postoperative pain in the general population advocate for a multimodal analgesic administration to enhance synergistic benefits, reduce opioid requirements, and minimize side effects. Recent recommendations from the World Federation of Hemophilia (WFH) for postoperative pain management in hemophilia patients suggest tailoring treatment based on pain levels, in coordination with anesthesiologists. Conclusions: Pain management in hemophiliac patients undergoing orthopedic interventions requires a multidisciplinary approach, with further research needed to define a reliable global standard of treatment.

Shedding light on the effects of blood on meniscus tissue: the role of mononuclear leukocytes in mediating meniscus catabolism

Traumatic meniscal injuries can cause acute pain, hemarthrosis (bleeding into the joint), joint immobility, and post-traumatic osteoarthritis (PTOA). However, the exact mechanism(s) by which PTOA develops following meniscal injuries is unknown. Since meniscus tears commonly coincide with hemarthrosis, investigating the direct effects of blood and its constituents on meniscus tissue is warranted. The goal of this study was to determine the direct effects of blood and blood components on meniscus tissue catabolism. Porcine meniscus explants or primary meniscus cells were exposed to whole blood or various fractions of blood for 3days to simulate blood exposure following injury. Explants were then washed and cultured for an additional 3days prior to collection for biochemical analyses. Whole blood increased matrix metalloproteinase (MMP) activity. Fractionation experiments revealed blood-derived red blood cells did not affect meniscus catabolism. Conversely, viable mononuclear leukocytes induced MMP activity, nitric oxide (NO) production, and loss of tissue sulfated glycosaminoglycan (sGAG) content, suggesting that these cells are mediating meniscus catabolism. These findings highlight the potential challenges of meniscus healing in the presence of hemarthrosis and the need for further research to elucidate the in vivo effects of blood and blood-derived mononuclear leukocytes due to both hemarthrosis and blood-derived therapeutics.

Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.

Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important.

Defining success in haemophilia care - Are we doing it right?

Transformational advances have occurred in the management of haemophilia in the last decade leading to much better outcomes. However, a detailed and critical examination of its assessment and reporting show gaps in many aspects. These are discussed in this review. The relevant literature related to different aspects of management of haemophilia was reviewed to identify gaps which need to be addressed. These include detection and diagnosis of haemophilia, documentation and reporting of joint bleeding, its management and methods of reporting in clinical trials and practice, aspects of personalizing care as well as access to therapeutic products and the need for and organization of comprehensive care. Current diagnostic approaches have more than doubled the identified number of persons with haemophilia (PWH) over the last 25 years but still constitute only ∼30% of the expected number. Joint bleeding is the primary indicator of disease severity and treatment efficacy, but there is lack of consistency and standardization in the way it is recorded and reported. Its continued use as an efficacy measure of modern treatments which maintain steady state factor levels or equivalence of>5% will lack sensitivity. The treatment of acute haemarthrosis has focussed on haemostasis and pain control, ignoring the role of inflammation in joint damage. Phenotypic heterogeneity of severe haemophilia has recognized clinical and laboratory variations based on haemostasis but not differences in local response to blood in the joint. At the organizational level, IU/capita provides a relevant measure of access to therapeutic products when the detection rate is ∼100% but is fallaciously low when detection rates are very low. With highly effective modern therapies for haemophilia and nearly no bleeding, the concept of comprehensive care team will need modifications. As haemophilia care advances, a deeper dive is needed into the details of various aspects its management to ensure consistency and contemporary relevance.

Diagnostic and treatment methods of skeletal symptoms of haemophilia and education of patients regarding the disease – review study

Introduction. Haemophilia is a genetic haemorrhagic disorder that characterises with extensive and prolonged bleeding. In severe stages of the disease, joint haemorrhages may occur and eventually result in joint degeneration and haemophilic arthropathy. Aim of the study. Summary and evaluation of diagnostic and treatment methods of skeletal problems in patients with haemophilia. Review of patients’ knowledge about the disease. Material and methods. Review of the newest medical journal literature published on PubMed database. Results. Ultrasonography is a non-invasive imaging method used to diagnose acute hemarthrosis and early stages of joint damage. Magnetic resonance is a standard tool in evaluation and scoring of haemophilic arthropathy. X-rays and computed tomography can also be additionally used, but are ineffective in imaging soft tissue and cartilage. Substitution of clotting factors is a standard treatment in haemophilia which reduces the frequency of bleeding. Arthrocentesis, synovectomy for example radiosynovectomy are effective in case of joint disorders. Intra-joint injections of hyaluronic acid are also effective. In advanced stages of haemophilic arthropathy joint replacement is recommended. Majority of patients with haemophilia claim that they are sufficiently educated about their disease. Conclusion. Haemophilic arthropathy is a severe joint destructing condition that causes limited mobility, chronic pain and a reduced quality of life. Its early diagnosis and proper treatment is necessary to avoid total destruction of the affected joint. Multidisciplinary care of the patient is an approach of great importance. Education of patients about their disease and up-to-date treatment methods is necessary.

Outcome of Joint Aspiration in Acute Knee Haemarthrosis in a Haemophilic Joint: A Prospective Randomised Controlled Trial in 120 Patients in a Tertiary Haemophilia Care Centre.

Bleeding into the joints cause major morbidity in haemophilia patients. The clinical hallmark of haemophilia is haemarthrosis especially in knee, ankle and elbow joint. Current literature suggests that aspiration of an acute haemarthrosis in haemophilia may lead to further bleeding and prevent tamponade effect. But the rehabilitation gets delayed, leading to joint stiffness and the function gets deteriorated. This study was done to evaluate the efficacy of joint aspiration in the management of acute knee haemarthrosis, with regard to pain relief and functional outcome. This is a prospective, randomised controlled trial in a tertiary care haemophilia treatment centre comprising 120 haemophilic patients with unilateral acute knee haemarthrosis. Factor level was checked and appropriate factor replacement [40%] was done. The patients were randomly allocated in two groups: Group A and Group B, each consisting of 60 patients. All patients received ice application, limb immobilisation, analgesics, physiotherapy and compression bandage as the routine primary management. In addition, study Group A also received therapeutic aspiration of the knee joint at initial presentation, after the first factor infusion. All patients were clinically evaluated for pain in terms of Visual Analogue Scale (VAS score) and function in terms of Haemophilic Joint Health Score [HJHS], before and at 4h, 48h and 7days after initial factor administration. All patients showed therapeutic improvement in terms of a declining trend in VAS and HJHS scores. Pain relief (VAS Score) in Group A, was found to be significantly better compared to Group B at the end of 4h [4.80 ± 0.49 vs 6.54 ± 1.05; p < 0.001], 48h [2.48 ± 0.50 vs 3.30 ± 0.46; p < 0.001] and 7days [1.16 ± 0.37 vs 1.70 ± 0.46; p < 0.001]. Functional improvement (HJHS Score) in Group A, was found to be significantly better compared to Group B as well at the end of 4h [11.24 ± 0.77 vs 14.52 ± 0.61; p < 0.001], 48h [7.24 ± 0.65 vs 11.28 ± 0.64; p < 0.001] and 7days [2.36 ± 0.48 vs 5.52 ± 0.67; p < 0.001]. Our study recommends the use of joint aspiration as a therapeutic tool in the holistic management of acute knee haemarthrosis in addition to usual treatment of ice application, immobilization and oral tranexamic acid. Early factor replacement along with therapeutic joint aspiration is a key for better pain relief and a better functional outcome.

Look Out for Fever: Clinical Profile of Dengue in Young Adults in a Tertiary Care Center in North India.

Background Dengue fever (DF) is a common viral disease, clinical manifestations of which vary from influenza-like illness (DF) to life-threatening dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS). The aim of this article was to study the clinical profile of DF in young adults. Material and Methods This was an observational study conducted in the department of medicine over a period of 2 years (January 1, 2013-December 31, 2014). Patients aged between 18 and 30 years with serology proven (nonstructural protein 1 [NS1]/dengue immunoglobulin M [IgM]) DF were included in this study. The clinical and laboratory data was recorded and analyzed. Results Out of 418 cases, the incidence of DF, DHF, and DSS was 87.32, 7.66, and 5.02%, respectively. The most common presentations were fever (99.76%) followed by vomiting (29.43%), pain abdomen (17.94%), myalgias (13.16%), petechial rash (12.92%), and bleeding (10.29%). Dengue NS1 and IgM antibodies were positive in 87.3% and 88.12% of the patients, respectively. Ascites, splenomegaly, hepatomegaly, pleural effusion, gall bladder wall edema, and pericardial effusion were present in 8.13, 6.94, 6.70, 5.98, 2.63, and 0.72% of the patients, respectively. Complications included bleeding (10.29%), acute respiratory distress syndrome (1.67%), myocarditis (1.44%), seizures (1.44%), hemarthrosis (0.24%), and encephalopathy (0.24%). The mortality rate was 3.35% with death of 14 patients. Shock, bleeding, and elevated serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase levels predicted adverse outcome. Conclusion DF can present with a plethora of clinical manifestations in endemic areas. Adverse outcome is more likely if patients have elevated SGOT levels, shock, and bleeding. Continuous seroepidemiological surveillance is essential to control outbreak and minimize morbidity and mortality.

Management of Haemarthrosis in Patients On Oral Anticoagulants.

AimsOur aim was to investigate the management of patients who were admitted to hospital with an acute haemarthrosis whilst taking oral anticoagulants, and highlight the outcomes of different management strategies.MethodsA retrospective review was performed of all orthopaedic admissions over a 42-month period (January 2015–July 2018) to the Orthopaedic Department of a London District General Hospital. All patients admitted with a spontaneous joint haemarthrosis and concomitant use of oral anticoagulants was identified. Anonymised data was placed on a secure trust database.FindingsA total of 31 patients were included. 22 patients (71%) had their anticoagulant temporarily held during admission. 9 patients (32%) had their anticoagulation reversed with 10 mg of vitamin K. 5 patients had their haemarthrosis aspirated either on admission or during their hospital stay. The overall mean length of stay in patients with a haemarthrosis was 7.0 days. The mean length of stay in patients who had their anticoagulation held was 8.6 days. In contrast, patients who continued taking their anticoagulation were found to have an average length of stay of 2.3 days. No patients suffered a thrombotic event in the 60 days following discharge. No adverse events were recorded following joint aspiration.ConclusionThere is currently no consensus on the management of haemarthrosis in patients on oral anticoagulants. Continuing the anticoagulants did not increase length of hospital stay. Further research may focus on assessing the effect of management adjuncts on patient outcomes and their cost effectiveness to aid the development of local and/or national guidelines.

Point of care ultrasonography in patients with haemophilia and acute haemarthrosis: a physiotherapist and sonographer inter-professional agreement pilot study

Abstract Background Haemophilia treatment centres (HTCs) around the world are increasingly adopting point-of-care ultrasonography (POCUS) for the assessment of acute haemarthrosis and to monitor joint health. POCUS is in large part administered by physiotherapists in most comprehensive care teams. Appropriate implementation of haemophilia-specific POCUS requires an educational foundation and training to ensure competency and optimal outcomes. Inter-professional agreement and evaluation of image quality are important measures of competency and acceptable use of POCUS. Aims To determine the level of agreement between physiotherapist and sonographer-performed POCUS scans and to compare the quality of the ultrasound images obtained by physiotherapists to those obtained by the sonographer. Methods This single blind, prospective, pilot study recruited patients with haemophilia A and B who presented to clinic with a suspected acute haemarthrosis of the elbow, knee, or ankle and consented to participate. POCUS scans were performed by one trained physiotherapist and one sonographer in the haemophilia ambulatory clinic at patient presentation, one-week follow-up, and two-week follow-up. The physiotherapist participated in formal training consisting of 12 hours of online didactic modules and a two-day, 12-hour practical module with instructor-led hands-on training. For the primary objective, the outcome of interest was the binary decision on the presence or absence of blood within the joint. For the secondary objective, image quality was evaluated by the radiologist post hoc and rated as optimal, acceptable, or sub-optimal. Results Thirteen participants with haemophilia consented to the study. The results indicated an excellent level of agreement (k=0.80) with an observed agreement of 91.7%, a specific positive agreement of 94.1%, and a specific negative agreement of 85.7% for the detection of blood within the joint space. The quality of the ultrasound images obtained by the physiotherapist were rated by the radiologist as optimal (84.6%) and acceptable (15.4%). None of the images were rated as sub-optimal. Conclusion Optimal image quality and a high level of agreement between the physiotherapist and sonographer-performed POCUS for the assessment of acute hemarthrosis in people with haemophilia A and B was observed. These results suggest that, with a short formal training programme, physiotherapists can be proficient in the performance, acquisition, and interpretation of POCUS scans in patients with haemophilia.

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

СПЕЦИФИКА МОЛЕКУЛЫ МОРОКТОКОГА АЛЬФА: РЕЗУЛЬТАТЫ ПРОСПЕКТИВНОГО МНОГОЦЕНТРОВОГО НАБЛЮДАТЕЛЬНОГО ИССЛЕДОВАНИЯ ЭФФЕКТИВНОСТИ И БЕЗОПАСНОСТИ У ПОДРОСТКОВ С ГЕМОФИЛИЕЙ A

The main method of treatment for hemophilia A is replacement therapy with drugs of blood coagulation factors VIII (FVIII). The active use of biotechnological methods in the production of recombinant drugs contributes to the development and registration of new FVIII drugs. The results of clinical trials of drugs in children usually include a limited number of patients for a specific period of time. Post-marketing observational studies provide additional information on the results of using a new drug in patients in clinical practice. The objectives of the study were to collect and analyze data on the efficacy and safety of domestic recombinant FVIII with a deleted B-domain, moroctocog alfa (Octofactor, GENERIUM JSC) in the treatment of adolescents aged 12–18 years with hemophilia A in routine clinical practice. Materials and methods of research: a prospective multicenter open-label observational study of the results of using the Octofactor in adolescents with hemophilia A (№ OCF-HPA-N01) included 24 male patients with severe hemophilia A aged 12 to 18 years (mean age 14,8±1,7 years), who received moroctocog alfa in routine clinical practice. Enrollment in the study was carried out after the signing of the informed consent form by the parent of the minor patient and the minor patient aged 14 to 18 years, taking into account the results of the screening examination. The follow-up period was 52±4 weeks, which, presumably, was sufficient to achieve at least 100 days of moroctocog alfa administration. To assess the effectiveness, we analyzed the incidence of spontaneous bleeding that occurred within 48–72 h after drug administration; the severity of spontaneous bleeding against the background of prophylactic treatment with moroctocog alfa, the number of injections and the dose of the study drug for prophylactic treatment, as well as for treatment at the request of one episode of bleeding, taking into account its severity; the researcher's determination of the response to treatment of acute hemarthrosis according to the scale of the World Federation of Hemophilia (2020). To assess safety, the frequency and characteristics of adverse events (AEs) associated with drug administration were analyzed, including the frequency of formation of an inhibitor to FVIII. Results: during the study, 59 bleedings were recorded, of which 21 (36%) were spontaneous and 38 (64%) were post-traumatic. Among spontaneous bleeding episodes, 5 (24%) episodes occurred within 48–72 hours after administration of the study drug. Spontaneous bleeding within 48–72 hours after administration of Octofactor was absent against the background of prophylactic treatment in most patients (81%) and was observed rarely during the observation period (1–3 times) in the remaining 19% of patients. The median number of bleeding within 48–72 h after study drug administration was 1 episode over the follow-up period. The proportion of mild to moderate bleeding was 97 [88; 100]% among all types of bleeding and 100 [84; 100]% among spontaneous bleeding within 48–72 hours after administration of the Octofactor drug. The median of a single dose of Octofactor for preventive treatment was 2000 [1500; 2000] IU or 31,7 [25,6; 38,5] IU/kg, and with treatment on demand ‒ 2000 [2000; 3000] IU or 34,1 [28,8; 38,5] IU/kg per single injection. To stop the resulting bleeding required 1 [1; 2] introduction in a single dose of 3000 [2000; 4000] IU; the average dose was 4490 ÷ 4993 IU. When doctors subjectively assess the response to treatment of acute hemarthrosis on the scale of the World Federation of Hemophilia, an excellent response was noted in 9 (27%) episodes, good and moderate ‒ in 2 (6%) and 22 (67%) episodes, respectively. Lack of response to treatment of acute hemarthrosis with moroctocog alfa was not revealed in the study. During the study, 23 AEs were recorded in 13 (54%) patients not related to the study drug. Conclusion: thus, the obtained results of the study indicates the efficacy and safety of the Octofactor both the prophylactic treatment and treatment of on-demand bleedings in 12 to 18 year old patients with severe hemophilia A.

ACL INJURY AND RETURN TO SPORT

We followed 110 patients who had sustained an acute traumatic Haemarthrosis for a mean of 60 months. The arthrometer measurements within 90 days of injury revealed the injured knee was stable in 35 patients and unstable in 75. Thirty-five unstable patients had an ACL reconstruction within 90 days of injury. Surgical procedures performed &gt;90 days after injury included ligament reconstruction in 35 patients. Factors that correlated with patients who had late surgery for a meniscal tear or an ACL reconstruction &lt; (P 0.05) were preinjury hours of sports participation, arthrometer measurements, and patient age. Follow-up data are presented for the patient’s divided into four groups: I, early stable, no reconstruction; II, early unstable, no reconstruction; III, early reconstruction; and IV, late reconstruction. No patient changed occupation because of the knee injury. Hours per year of sports participation and levels of sports participation decreased in all groups. Joint arthrosis was documented by radiograph and bone scan. Joint surface injury abnormalities observed at surgery and meniscal surgery showed greater abnormalities by radiograph and bone scan scores (P&lt; 0.05). Reconstructed patients had a higher level of arthrosis by radiograph and bone scan. Anterior cruciate ligament injuries are common. The biggest the number of these injuries occur in sports activities, mainly those that involve deceleration, torsion, shear, and jumping movements. In a study on football team injuries in Albania, reported 2.4 injuries per year on an Albanian university football squad. Many patients remain disabled for sport afterwards an ACL injury; others appear to have minimal damage. Some patients develop secondary and degenerative meniscal ttaears knee arthritis; others show little joint deterioration. Few studies have documented the incidence of late meniscal tears after an ACL injury. Due to the variability of patient impairment after ACL injury and the lack of documentation that ACL surgery prevents degenerative arthritis, controversy over indications for ligament surgery. Moreover, a large number of patients do not often follow the entire functional rehabilitation process. The purpose of this prospective study was to document the outcome of the patient with ACL injury and the search for factors identifiable immediately after the injury correlating with a greater risk of functional impairment, secondary meniscus tears and joint arthrosis.

Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia

IntroductionInterstitial, cartilage, and bone collagens have been proposed as biomarkers of joint deterioration in hemophilic arthropathy. The role of basement membrane (type IV and VIII) collagens as biomarkers of endothelial turnover in relation to acute joint bleeding is not understood. MethodsThirty‐one adult patients with hemophilia were studied prospectively for 3 years with musculoskeletal ultrasound/power Doppler (MSKUS/PD) during pain‐free intervals and painful events for joint bleed status, synovial vascular flow, and 10 plasma markers of collagen turnover. Joint health was determined using Hemophilia Joint Health Scores and Pettersson scores. In animal studies, bleeding was induced in factor VIII−/− mice by knee joint injury. Synovial vascular remodeling was assessed using MSKUS/PD and histology. Murine plasma samples were analyzed for type IV collagen turnover markers. ResultsNinety‐one patient visits were compiled. Twenty‐five were due to acute painful episodes, with 16 confirmed hemarthroses. Type IV collagen turnover markers (PRO‐C4 and C4M), and a type VIII collagen synthesis marker (PRO‐C8), were transiently elevated during acute hemarthrosis. Hemarthrosis was accompanied by increased synovial microvascular flow (MSKUS/PD), and levels of type IV collagen markers correlated with PD signals in the joint. In factor VIII‐deficient mice, plasma levels of type IV collagen turnover markers correlated negatively with synovial αSMA staining, indicating that reduced type IV collagen turnover was associated with thicker vessels. ConclusionsOur findings suggest that basement membrane turnover markers, closely linked to synovial vascular remodeling, may be systemic biomarkers of acute hemarthrosis. Vascular instability during neovascularization may be involved in the dynamics of hemarthrosis.

РЕЗУЛЬТАТЫ ОТКРЫТОГО МНОГОЦЕНТРОВОГО ПРОСПЕКТИВНОГО КЛИНИЧЕСКОГО ИССЛЕДОВАНИЯ ЭФФЕКТИВНОСТИ, БЕЗОПАСНОСТИ И ФАРМАКОКИНЕТИКИ МОРОКТОКОГА АЛЬФА У ДЕТЕЙ В ВОЗРАСТЕ ОТ 6 ДО 12 ЛЕТ С ГЕМОФИЛИЕЙ A

Currently, the main method of treatment for hemophilia A is replacement therapy with drugs of blood coagulation factors VIII (FVIII). As a result of the development of new production technologies, recombinant FVIII are increasingly used for the treatment of hemophilia A. The justification for the use of new drugs in pediatric clinical practice requires careful preparation and clinical research studies of their efficacy and safety. The aim of this study was to evaluate the efficacy, safety and pharmacokinetics (PK) of domestic B-domain deleted recombinant factor VIII of Moroctocog alpha (Octofactor, GENERIUM JSC) in a cohort of children with hemophilia A aged 6 to 12 years in the framework of phase III clinical study of moroktocoga alpha in children 2 to 12 years old with hemophilia A. Materials and methods of the research: the age cohort of 6 to 12 years olds of an open multicenter prospective noncomparative study included 27 male children with severe hemophilia A (mean age 8,3±1,9 years). The study was carried out sequentially in 2 stages. Stage I included the study of PK parameters in 22 patients after a single study drug dose of 50 IU/kg. At stage II, the efficacy and safety of the drug was assessed in patients of stage I, as well as in additionally included 5 patients who received the study drug dose of 30±10 IU/kg per day every 2–3 days for 22±1 weeks of treatment. To assess the efficacy, we analyzed the incidence of spontaneous bleeding that occurred within 48–72 h after drug administration; the number of injections and the dose of FVIII used for prophylaxis, as well as for treatment on demand of one episode of bleeding, taking into account its severity; number of patients with severe hemophilia A with residual FVIII activity &gt;/=1% 48–72 h after drug administration; the investigator's overall assessment of response to therapy on the acute hemarthrosis response scale. The main indicators for the analysis of PK properties were the area under the «concentration-time» curve, the half-life, the elimination constant, the increase in activity, and the degree of recovery of activity. To assess safety, the frequency of formation of an inhibitor to FVIII, the dynamics of vital and laboratory parameters, the frequency and characteristics of adverse events (AEs) associated with the administration of the drug were taken into account. Results: the area under the FVIII-time activity curve in the region of 0–48 h (AUC0-48) and with exponential extrapolation to infinity (AUC0-inf) was 731,82±264,94%*h and 756,11±270,16%*h, respectively. The half-life (T1/2) was 10,32±2,27 hours. In the examined age group, 78 bleeding were recorded, of which only 27 (35%) were spontaneous, including 24 (30%) episodes that occurred during 48–72 hours after the administration of drug under investigation. Haemorrhage within 48–72 hours after administration of the Octofactor drug was absent or was observed rarely (1–3 times) against the background of prophylactic treatment in most patients (88%), the median number of bleeding within 48–72 hours after administration of the study drug was 2 episodes per observation period. The proportion of spontaneous bleeding was the smallest in patients receiving a single prophylactic doses of the study drug 2000–3000 IU (7% of all bleeding), the largest proportion of spontaneous bleeding was observed in patients receiving a single prophylactic doses of the study drug 1000–2000 IU (70% of bleeding). The average single dose of Octofactor for preventive treatment was 1290,4±458,6 IU or 39,12±7,79 IU/kg, for on-demand treatment – 1641,7±722,4 IU per single injection. Of the 78 reported bleeding episodes, 68 (87%) required the study drug administration for relief, while the remaining 10 bleedings were selfcontained. On average, to stop bleeding, it took 1,5±0,8 injections of the drug on demand, median doses were 1 [1; 2], and average doses were 2434,3±1501,7 IU. During the study, 37 AEs were recorded in 15 (56%) patients. At the same time, 36 AEs (97%) were not associated with the drug under investigation, and one AE (allergic reaction), according to the researchers, was associated with the use of the drug. Thus, the analysis of data indicates the efficacy and safety of the Octofactor drug both the prophylactic treatment and treatment of on-demand bleeding in 6 to 12 year old patients with severe hemophilia A.

Targeting Protein S Using Small Interfering RNA Is Well Tolerated and Protects Mice with Hemophilia a from Acute Hemarthrosis

Introduction &amp; Aim: Hemophilia A (HA) is an X-linked disorder caused by an absence or a reduction of coagulation factor VIII. Patients with HA often suffer from spontaneous bleeding within the musculoskeletal system, such as hemarthrosis. Hemarthrosis is caused by bleeding into joint spaces affecting the synovium, synovial blood vessels as well as cartilage and bone tissues. Current prophylactic treatments are not always effective and hemophilia patients can experience breakthrough bleeds. Recently, we demonstrated that inhibition of protein S (PS), a natural anticoagulant, controls coagulation and constitutes a potential therapeutic target in hemophilia (Blood 2018, 131:1360-1371). Here, we aim to translate our findings using small interfering RNA conjugated to an N-acetylgalactosamine (GalNAc) cluster to target Pros1 gene expression (GalNAc-PS siRNA) in vivo and exclusively in hepatocytes. siRNAs conjugated to a GalNAc cluster bind to asialoglycoprotein receptors expressed predominantly by hepatocytes thereby providing a potentially safe, specific and efficient delivery technology for therapeutic molecules. Methods &amp; Results: Forty-two days after subcutaneous (s.c.) injection of GalNAc-PS siRNA (3mg/kg), wild-type (WT) mice were alive and did not display overt disseminated intravascular coagulation (DIC). In a second study in WT mice, DIC parameters assessed fourteen days after treatment with either 5mg/kg GalNAc-PS siRNA or with vehicle were also comparable between the two groups (platelet count: 578±284 vs 725±186 G/L, p&amp;gt;0.9, n=4-6; prothrombin time: 9.0±0.4 vs 8.9±0.3 seconds, p&amp;gt;0.9, n=4-6; fibrinogen: 1.5±0.5 vs 1.8±0.4 g/L, p&amp;gt;0.85, n=5-6; thrombin anti-thrombin complexes, TAT: 71±63 vs 115±34 μg/L, p&amp;gt;0.9, n=2-4) supporting that GalNAc-PS siRNA treatment can be safe. At the same time, mice treated with GalNAc-PS siRNA displayed lower plasma PS level compared to mice receiving the vehicle (52±12 vs 100±11 %, p&amp;lt;0.001, n=6). In the liver, PS mRNA levels were reduced by 69% compared to mice treated just with the vehicle (31±10 vs 100±24 %, p&amp;lt;0.0001, n=6). Importantly, in a murine model for hemophilia A (F8-/- mice) the intrinsically-activated test using ellagic acid (INTEM) assessed by rotative thromboelastometry (ROTEM®) was improved by treatment with GalNAc-PS siRNA (5mg/kg s.c) as compared to F8-/- mice treated with the vehicle (clotting time: 281±193 vs 802±330 seconds, p&amp;lt;0.01, n=6-11; clot formation time: 109±80 vs 657±466 seconds, p&amp;lt;0.05, n=6-11; alpha angle: 70±13 vs 35±24 mm, p&amp;lt;0.1, n=6-11). To assess if targeting PS using GalNAc-siRNA-PS protects mice from acute hemarthrosis (AH), we applied an AH model to F8-/- mice. Five days after injecting a single dose of 5mg/kg GalNAc-PS s.c., right knees were injured using a 30 gauge-needle and knee diameters were measured 72 hours later. Macroscopically, vehicle treated F8-/- mice developed extensive bleeding in injured knees as compared to GalNAc-siRNA-PS treated mice. Scores for intra-articular bleeding (2.4±0.9 vs 1.0±0.7, p=0.035, n=5-9) and synovial hyperplasia (2.4±0.9 vs 0.6±0.9, p=0.027, n=5-9) were higher in F8-/- mice treated by vehicle than in those treated by GalNAc-PS-siRNA. Moreover, knee joint swelling was reduced in GalNAc-siRNA-PS treated mice compared to those treated by vehicle (0.14±0.15 vs 0.78±0.50 mm, p=0.025, n=7-10). As expected, PS plasma levels were lower in GalNAc-PS siRNA treated mice compared to those which received vehicle (63±9 vs 101±19% of WT PS antigen level, p&amp;lt;0.0001, n=7-13) with no overt DIC (platelets count: 711±149 vs 681±189 G/L, p&amp;gt;0.9, n=7-12; prothrombin time: 8.5±0.3 vs 8.4±0.3 seconds, p&amp;gt;0.9, n=4-13; fibrinogen: 2.7±0.6 vs 3.0±0.8 g/L, p=0.73, n=7-12 and TAT: 33±42 vs 45±66 μg/L, p&amp;gt;0.9, n=6-10). Conclusion: These data provide the first evidence that using a GalNAc-siRNA conjugate to modulate Pros1 gene expression is well tolerated and has the ability to reduce plasma PS level and protect F8-/- mice from AH pointing to PS targeting using GalNAc-siRNA-PS as a new valuable therapeutic approach for hemophilia. Further analysis to understand if the inhibition of PS influences also the inflammatory processes causing the hemophilic arthropathy is ongoing. Disclosures Schaeper: Silence Therapeutics GmbH: Current Employment. Dames:Silence Therapeutics: Current Employment. Eisermann:Silence Therapeutics: Current Employment.

The Efficacy of Platelet-Rich Plasma in the Treatment of Hemophilic Arthropathy

Background: The most clinical manifestation of hemophilia, as a congenital bleeding disorder, is the Intra-articular hemorrhage. The treatment of acute hemarthrosis with a sufficient amount of factor replacement will return the joint to the normal status. Objectives: This study aimed to evaluate the efficacy of platelet-rich plasma in the treatment of hemophilic arthropathy patients to reduce and improve their pain and physical function. Methods: Consecutive patients with hemophilic arthropathy were included in a self-control open-label trial in Mofid Children’s Hospital, Tehran, Iran. All participants received three platelet-rich plasma injections given two weeks apart. Also, the seriate self-reported and objective clinical outcomes were evaluated before and three months after the treatment. Results: A total of 11 patients with hemophilic arthropathy involving 14 joints received three injections of platelet-rich plasma at 2-week intervals, at our center. All patients were evaluated with a visual analog scale, the hemophilia joint health score, and the range of motion, and bleeding events, before and after the treatment. Finally, 9 boys (81.8%) and 2 girls (18.2%) completed the study. The mean age of the participants was 14.7 years (range, 9-19 years). In all patients, statistically significant improvements were noted on all evaluated measures. Conclusion: Platelet-rich plasma therapy is a reasonable and minimally invasive procedure that includes beneficial chondro-regenerative properties.

Therapeutic effect of Intra-articular normal saline and lidocaine injection after Arthrocentesis for Knee Hemarthrosis post traumatic injury in RS Muhammadiyah Palembang (RSMP): A Case Report

Female 22 years old, come to RSMP with pain and swollen in the right knee after fall down from stairs 2 days ago. In Physical Examination found bruising around the knee with no sign of crepitation nor abnormality during ligament test. Patient than given initial treatment (analgesic and antifibrinolytic) for 1 week and X-ray examination of knee. One week later patient come with decreased but persisted pain and swollen knee. X-ray Examination suggests joint effusion. The Patient than admitted for arthrocentesis followed by Intra-articular normal saline and lidocaine injection.Bleeding into a joint is referred to as hemarthrosis and is an important cause of monoarticular joint pain and swelling. Its can be suspected based on patient history, physical exam, and multiple imaging modalities, however the best way to diagnose hemarthrosis is with arthrocentesis with synovial fluid analysis. Traumatic injury is the most common cause and the knee is a frequent site of hemarthrosis. Initial treatment of any acute hemarthrosis includes immobilization, ice, and compression. Analgesia for pain control may be required in the acute period. Arthrocentesis with aspiration from a joint can be both diagnostic and therapeutic by reducing pressure from the effusion.Intra-articular normal saline (IA-NS) injections have been utilized as a placebo in a number of researches pertaining to the management of joints problem such as knee osteoarthritis (OA). It is believed that these IA-NS injections may have a therapeutic effect that has not been quantified in the literature. Lidocaine have some mild anti-inflammatory effect during its relatively short halflife of 1.5 hours. The prompt effect of the local anesthetic providing temporary relief of symptoms can help confirm proper placement of the injection and support that the site injected was the source of the pain.

Medial Collateral Ligament Knee Injury in a Patient Receiving Rivaroxaban: A Cause of Acute Hemarthrosis

Medial collateral ligament (MCL) injury is highly common in athletes and the elderly. This ligament is in the knee region and is often at the risk of injury. Severe pain and motor limitation are the most important signs in the acute phase of the injury. In patients receiving anticoagulants, damage to the knee joint may lead to intra-articular bleeding, which exacerbates the symptoms and prolongs the recovery period. The present study aimed to describe the case of a 76-year-old woman with a sudden spin on the left knee while getting off a car. After a few minutes of walking, the patients felt pain, heard a pop-like sound on the injured knee, and was unable to walk, experiencing pain in the knee. The patient was transferred to the emergency department by the caregivers. The present case report was focused on the MCL injury in a patient receiving an anticoagulant due to atrial fibrillation.

A Study on Correlation of Magnetic Resonance Imaging and Arthroscopy in Evaluation of Anterior Cruciate Ligament Injury in Cases of Acute Traumatic Haemarthrosis of Knee: A Prospective Study

A Study on Correlation of Magnetic Resonance Imaging and Arthroscopy in Evaluation of Anterior Cruciate Ligament Injury in Cases of Acute Traumatic Haemarthrosis of Knee: A Prospective Study

Surgical approaches to hemophilic arthropathy.

: The role of the orthopedic surgeon is to use invasive and/or surgical methods to treat the musculoskeletal disorders suffered by persons with hemophilia, always within the context of a multidisciplinary team. Muscle hematomas must be diagnosed as early as possible and be subjected to continuous treatment until full resolution, as they are associated with the risk of severe complications (compartment syndromes and pseudotumors). Arthrocentesis (extraction of intra-articular blood) is recommended in cases of acute and profuse hemarthrosis. Synovectomy is mandatory in the case of synovitis. Radiosynovectomy plays a key role as it has been shown to reduce bleeding by 65%. Our department uses Yttrium-90 in knees and Rhenium-186 in elbows and ankles. Radiosynovectomy is our treatment of choice for synovitis whereas arthroscopic synovectomy is resorted to as second-line treatment. Total knee replacement (TKR) has shown itself to be effective for treating severe hemophilic arthropathy, although the infection risk in patients with hemophilia is higher than in patients with osteoarthritis (1-2 vs. 7%).