Hemophilia Research Articles

Peculiarities of total knee arthroplasty in patients with hemophilic arthropathy

Annotation. There is a wide variety of clinical manifestations of hemophilia, but one of the most frequent is spontaneous intra-articular bleeding. It accounts for more than 90% of serious bleeding in patients with severe hemophilia. almost all patients with a severe form of hemophilia have damage to large joints in the form of hemophilic arthropathy, up to 90% of such patients require orthopedic assistance in the form of total joint replacement. The purpose of this study was to highlight one's own experience of performing total joint replacement in patients with hemophilia, their rehabilitation and hemostatic support during the stages of treatment. To perform our study, we analyzed the treatment of 34 patients with hemophilia who underwent total knee arthroplasty. Among the patients of the observation array, fibrosis of the synovial membrane of the knee joint was determined in 55.9% of cases. In 85.3% of patients, cicatricial changes in the medial and lateral surface of the patella were noted during access, which led to a decrease in patellofemoral mobility. In 17.6% of patients, during access, folds of the synovial membrane were found, which were returned to the joint cavity, which led to blockages during active movements. All patients underwent subtotal synovectomy during access to the joint. This was done not only to facilitate access to the bone structures of the knee joint, but also to prevent future bleeding. In 3 patients (8.8%) quadriceps plasty was performed to adequately expose bone tissue in the joint. In 1 patient (2.9%) in a similar situation with difficult access, we performed quadriceps dissection and osteotomy of the tibial tubercle. The conducted study indicated that total hip arthroplasty is the gold standard in the treatment of patients with hemophilic knee arthropathy. Endoprosthesis of the knee joint in patients with hemophilia can effectively reduce the arthralgic syndrome in the knee joint, increase the range of motion, and improve gait function. The use of combined replacement therapy during knee replacement surgery helps to reduce blood loss and allows patients to return to an active life. The results of knee arthroplasty in patients with hemophilia require further study in the longer term after surgery.

Metalloproteomic analysis of hemophilic arthropathy synovial tissue: insights into metal overload and pathogenesis.

Hemophilic arthropathy (HA) is a joint disease characterized by local iron overload stemming from erythrocyte rupture and closely linked to synovial lesions. However, the precise molecular characteristics of clinical HA synovial samples remain to be defined. To gain insight into HA synovial tissue lesions, we utilized a metalloprotein strategy to compare the metal and protein spectra of HA with those of osteoarthritis and rheumatoid arthritis. We collected synovial samples from patients with HA, osteoarthritis, and rheumatoid arthritis. Tissue metal and protein profiles were obtained by metallomics and proteomics, respectively. Finally, metalloproteomics strategies compared metal content, proteins, metalloproteins, and the life processes involved. Our metallomics analysis revealed an explicit increase in heavy metal content, particularly arsenic and mercury, in HA synovial samples. Through proteomics, we delineated specific metalloproteins and identified correlations between metals and pathways. These findings yield valuable insights into the pathogenesis of HA and offer potential therapeutic targets for conditions characterized by iron overload.

Rare Inherited Coagulation Deficiencies: A Single-Center Study

Background: Rare factor deficiency (RFD) is characterized by a deficiency of factor (F)I, FII, FV, FVII, FX, FXI, FXII, FXIII, or a combined deficiency of FV+FVIII or vitamin K-dependent factors. The prevalence of RFD ranges from 1/1,000,000 to 3,000,000. Combined deficiencies of vitamin K-related factors have been described in 30 families worldwide, and these patients can present with a wide range of clinical symptoms, from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Objective: This study aimed to contribute to the literature on RFD. Material and Methods: This retrospective study analyzed data from 43 children with RFD. Results: The most common factor deficiencies were FVII (n=13); whereas the other deficiencies were FI (n=1), FV (n=2), FV+FVIII (n=2), FX (n=6), FXI (n=5), FXII (n=9), FXIII (n=3), and vitamin K-dependent combined factor deficiency (n=2). Acute and severe bleeding was controlled by treatment in 6 patients, and 12 patients with recurrent bleeding symptoms received prophylaxis. RFDs were more common in regions with high rates of consanguineous marriage, and in our study, 16 (16/43) of the cases were found to have consanguineous marriages between parents. Conclusions: It is important to improve genetic counseling and access to testing for family members with RFD due to autosomal recessive inheritance. Delays in diagnosis and treatment and lack of adequate prevention are important risk factors for life-threatening bleeding.

Correlation between Phenotype and Coagulation Factor Activity Level in Rare Bleeding Disorders: A Systematic Review.

Rare bleeding disorders (RBDs) represent 3 to 5% of congenital bleeding disorders and are primarily inherited in an autosomal recessive manner, with increased prevalence in consanguineous populations. Clinically, RBDs can be accompanied by mild to severe bleeding episodes, often assessed using bleeding assessment tools (BATs) such as the International Society on Thrombosis and Hemostasis (ISTH)-BAT. However, the correlation between bleeding severity and coagulation factor activity levels remains inconsistent. This systematic review investigates this relationship to enhance understanding and improve management strategies for patients with RBD. This review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered with the International Prospective Register for Systematic Reviews (PROSPERO) (CRD42024504537). Using the PICO (Population, Intervention, Comparator, and Outcomes) framework, the study focused on RBD patients to explore the correlation between coagulation factor activity levels and bleeding severity. A comprehensive search was conducted across PubMed, Scopus, and Web of Science until April 1, 2024, with data extracted on bleeding severity, phenotype, and coagulation factor activity levels. The analysis highlights complex and often inconsistent relationships between coagulation factor levels and the severity of bleeding. In cases of fibrinogen deficiency, three out of four studies (n = 73 of 111 cases, 66%) demonstrated a moderate to strong correlation between fibrinogen levels and bleeding severity. In prothrombin deficiency, one of two studies (n = 16 of 29 cases, 55%) found a strong correlation between FII levels and bleeding severity. Four of six studies (n = 106 of 139 cases, 76%) in FV deficiency found a weak or no correlation between factor activity and bleeding severity. In combined FV and FVIII deficiency, two of three studies (n = 26 of 60 cases, 43%) found a significant correlation between factor activity and bleeding severity. In FVII deficiency, four (of nine) studies with a study population of 325 patients (65%) found a weak correlation between factor activity and severity of bleeding. Almost all studies (five of six studies, n = 114 of 118 patients, 97%) in FX deficiency revealed a strong correlation between FX levels and bleeding severity. In FXI deficiency, most studies (five of seven studies, n = 254 patients, 93%) found a weak or no correlation between factor activity and bleeding severity or symptoms. For FXIII deficiency, there was a moderate to strong correlation between FXIII activity and bleeding severity in all three studies (n = 61 patients). In conclusion, despite current controversies, this review highlights a moderate or strong correlation between factor activity and bleeding severity in fibrinogen, FX, and FXIII deficiencies, but no correlation or weak correlation for FV, FVII, and FXI deficiencies. Further prospective studies with standardized BATs on a large number of patients are needed to better understand these relationships and optimize patient management.

Study on the value of enhanced magnetic resonance imaging in the International Prophylaxis Study Group (IPSG) score of the synovium in hemophilic arthropathy

Objective: To evaluate the value of enhanced magnetic resonance imaging (MRI) on the assessment of synovial hyperplasia and International Prophylaxis Study Group (IPSG) score of hemophilic arthropathy (HA). Methods: This was a retrospective case series study. Briefly, 54 joints of 46 male patients with hemophilia type A and diagnosed with HA in Henan Provincial People's Hospital from August 2016 to September 2017 were selected. Plain and enhanced MRI were performed at the same time. The IPSG score of synovial hyperplasia and the total joint before and after enhancement were calculated, and the enhancement rate of the synovium and muscles at the same level were also calculated. The differences in synovial hyperplasia and joint total IPSG scores before and after enhancement were compared by paired rank sum test. The correlation between enhancement joint total IPSG score, synovial IPSG score, synovial enhancement rate, total joint bleeding number, course of disease, and Hemophilia Joint Health Score (HJHS) score were analyzed by Spearman's correlation analysis. Results: Enhanced MRI could more clearly show synovial hyperplasia and ensure better accuracy of joint total IPSG score (Z=-2.24, P=0.025). The enhancement extent of synovial hyperplasia was higher than that of the same level muscle. There was no correlation between synovial enhancement rate and total number of joint bleeding, course of disease, and HJHS score. After enhancement, the joint total IPSG score was highly positively correlated with the total number of joint bleeding and the disease course (r=0.96, 0.84, P<0.001) and moderately positively correlated with the HJHS score (r=0.58, P<0.001). The enhanced synovial IPSG score showed a low positive correlation with the total number of joint bleeding and the disease course (r=0.37, 0.36, P=0.006, 0.008), but no correlation with HJHS score. Conclusion: Enhanced MRI can provide accurate imaging of synovial hyperplasia of HA and make joint IPSG score more accurate.

Features of hemostasis in patients with hemophilic arthropathy of the knee joint in the perioperative period

Features of hemostasis in patients with hemophilic arthropathy of the knee joint in the perioperative period

Assessment of haemophilic joints in a low-resourced area using clinical tools: The effect of different types of prophylaxis.

Haemophilic arthropathy (HA) is the most frequent complication in people with haemophilia (PWH). MRI is the gold standard to assess HA, however, there are limitations to its use in low-resourced areas. Primary; to compare clinical-functional, laboratory, and ultrasonographic joint scores with MRI scores to determine a reasonable alternative to MRI. Secondary; to identify the effect of various replacement therapies on the degree of joint involvement. Fifty PWH with at least one affected joint, with or without inhibitors, and receiving either on-demand treatment or secondary prophylaxis, were included. All participants had a joint assessment by clinical HJHS 2.1, functional FISH, HEAD-US, and MRI DENVER scores. Also, serum COMP level was assessed by ELISA for the PWH and 50 healthy subjects as control. The HJHS 2.1 scores had a significant positive correlation with HEAD-US and the MRI DENVER scores. The FISH score had a significant negative correlation with HJHS 2.1, HEAD-US, and MRI DENVER Scores. The serum COMP level was comparable between the PWH and the controls. The HEAD-US score had a significant positive correlation with the MRI score. All of the joints' scores for the PWH on Emicizumab prophylaxis showed significantly lower HJHS 2.1 and MRI DENVER scores but higher FISH score than the joint scores of the patients receiving other types of prophylaxis. The clinical-functional joints assessment scores (HJHS 2.1, FISH) were objective tools that correlated significantly with the HEAD-US and the Denver MRI scores. Emicizumab prophylaxis led to better joint status.

Molecular mechanism analysis of a family with hereditary coagulation FXI deficiency caused by compound heterozygous mutations.

The purpose of this study was to determine the molecular basis of a Chinese family with factor XI (FXI) deficiency. The qRT-PCR was used to detect the transcription of F11 mRNA in transfected cells. ELISAs and western blot were used to detect the expression of FXI protein in culture media and lysates. Genetic analysis revealed that the proband carried a heterozygous nonsense mutation c.1107C>A (p.Tyr351stop) in exon 10 and a heterozygous missense mutation c.1562A>G (p.Tyr503Cys) in exon 13. The expression study revealed that p.Tyr351stop mutation resulted in the degradation of F11 mRNA. The p.Tyr503Cys mutation, however, had no effects on biosynthesis and secretion of FXI protein, but it had affected the catalytic activity of FXI. The inherited FXI deficiency of this family is related to nonsense mutation p.Tyr351stop and missense mutation p.Tyr503Cys.

Distribution of Recessive Genetic Defect Carriers in Holstein Friesian Cattle: A Polish Perspective.

Genetic disorders are caused by a hereditary change in the structure of DNA that may hurt the health and life of animals. Several recessive haplotypes and a few causative mutations are known in Holstein Friesian cattle: CDH (Holstein cholesterol deficiency), haplotypes with a homozygous deficiency in Holstein (HH1, HH3, HH4, HH5, HH6, HH7), BLAD (bovine leukocyte adhesion deficiency), DUMPS (deficiency of uridine monophosphate synthase), FXI (factor XI deficiency), HHM (mule foot, syndactyly), and BC (citrullinaemia). From a breeding point of view, these genetic diseases have highly negative effects and are a significant problem for breeders, exposing them to economic losses and hurting animal welfare. This study aimed to characterize the Polish population of Holstein Friesian dairy cattle, considering the carrier status of twelve selected genetic defects. This study was based on genotype data collected from 78,884 cows and 691 bulls of the Holstein Friesian variety. The studies were performed using Illumina Infinium microarrays. Among both bulls and cows, the highest numbers of carriers were detected for HH5 (appropriately 6.7% and 5.4%). The lowest numbers of carriers were detected for DUMPS, factor XI, and HHM. The study revealed one calf suffering from cholesterol deficiency.

Knee Arthroplasty for Ankylosis in a Patient with Severe Hemophilia A

Abstract Hemophilic arthropathy is a common complication of hemophilia A and can lead to chronic synovitis, joint damage, and eventually ankylosis. We present a case report of a 39-year-old male patient with a history of recurrent hemorrhages into the joints. He had a history of traumatic injury to both upper limbs and lower limbs. The patient was on bed rest for 6 months. Subsequently, he developed ankylosis of both elbows in 30° of flexion and ankylosis of the right (Right) knee in 40° of flexion with tricompartmental arthritis of the left knee joint. Radiologically, the left knee joint showed reduced joint space with tricompartmental arthritis. The patient was managed by the tumor prosthesis for the Rt knee. He was advised for management of the elbow joints for which he was not willing. Postoperatively, he was allowed knee range of motion exercises and walking with a walker for 4 weeks followed by a stick for 1 month. At 6-month follow-up, he was able to walk effortlessly without support. The Knee Society Score improved from 47 preoperatively to 75 at 6-month follow-up.

Laboratory and Molecular Diagnosis of Factor XI Deficiency.

The prevalence of factor XI (FXI) deficiency is 1 per 10 to 20,000 in the general population, much higher than that reported in most texts. The prevalence is higher in Ashkenazi Jews where it is about 1:20. Clinically, FXI deficiency presents as a mild bleeding disorder mostly associated with posttraumatic or postsurgical hemorrhages or unexplained minor bleeding. It is often discovered due to incidental finding of a prolonged activated partial thromboplastin time (aPTT) on routine laboratory screening. FXI deficiency is an autosomal recessive bleeding disorder with many causative F11 gene defects. Diagnosis is based on FXI activity, antigen levels, and molecular diagnostics. As FXI levels do not correlate with bleeding symptoms, identification of pathogenic genetic variants may be a more accurate predictor of bleeding risk and therefore aid in the clinical management of the patient. Two variants in the F11 gene account for most cases found in the Jewish and Arab populations. Patients with FXI deficiency can develop inhibitors to FXI although spontaneously acquired inhibitors are extremely rare. We will discuss laboratory and molecular assays used to diagnose FXI deficiency as well as interferences that can complicate diagnosis including new anticoagulants and acquired FXI inhibitors.

Performance of instrumental activities of daily living in patients with haemophilic arthropathy. A cross-sectional cohort study.

The development of haemophilic arthropathy causes joint damage that leads to functional impairment that limits the performance of activities in patients with haemophilia. The aim was to identify the best predictive model for performing instrumental activities of daily living in adult patients with haemophilia arthropathy. Cross-sectional cohort study. 102 patients were recruited. The dependent variable was the performance of instrumental activities of daily living (Lawton and Brody scale). The dependence on the performance of activities of daily living was the dependent endpoint (Barthel scale). The secondary variables were joint damage (Hemophilia Joint Health Score), pain intensity, and clinical, anthropometric, and sociodemographic variables. The degree of dependence, joint damage, pain intensity, and marital status (Cp=5.60) were the variables that best explain the variability in the performance of instrumental activities of daily living (R2 adj=0.51). Loss of predictive capacity is acceptable with good mean internal (R2 mean=0.40) and external (R2-r2=0.09) validation. According to the predictive pattern obtained, patients with haemophilia, who were married, without joint pain or damage, and independent in their day-to-day lives, had a score of 7.91 points (95% CI: 7.42; 8.39) in the performance of instrumental activities of daily living. The predictive model for the functional capacity of instrumental activities of daily living in haemophilia patients encompasses factors such as level of autonomy, joint impairment, pain severity, and marital status. Notably, despite the presence of joint damage, individuals with haemophilia exhibit a significant level of independence in carrying out both basic daily tasks and instrumental activities of daily living. Id NCT04715100.

Nonneutralizing antibodies in Nordic persons with moderate hemophilia A and B (the MoHem study)

BackgroundThe impact of nonneutralizing antibodies (NNAs) in moderate hemophilia is elusive. ObjectivesTo explore the presence of NNAs in Nordic persons with moderate hemophilia A (MHA) and B (MHB) in relation to treatment modality, clinical outcome, history of inhibitor, and the corresponding factor VIII (FVIII)/factor IX (FIX) gene mutation. MethodsA cross-sectional multicenter study covering persons with MHA and MHB in Sweden, Finland, and Norway. Inhibitors were analyzed with the Bethesda assay, and NNAs were detected by enzyme-linked immunosorbent assay. ResultsPlasma samples from 137 MoHem study participants (median age 29 years; Q1-Q3, 15-54) were analyzed. NNAs were present in 11 of 82 (13%) of people with MHA and 7 of 55 (13%) of those with MHB irrespective of prophylactic or on-demand treatment, most frequently after 150 exposure days (EDs). Three NNA positive patients had a history of high-titer inhibitor, but current analyses were negative (<0.6 BU/mL). Baseline FVIII/FIX activity was similar among NNA positive and negative patients. Current bleeding rates were low, but patients with NNAs captured a higher Hemophilia Joint Health Score (7 [median]; Q1-Q3, 3-20 vs. 4; 1-9) (P = .02) and had more frequently undergone arthroplasty or arthrodesis (5 [33%] vs. 15 [13%]) (P = .03). ConclusionNNAs were detected in 13% of Nordic persons with MHA and MHB, most frequently after 150 EDs. Patients with NNAs had more severe hemophilic arthropathy than patients without NNAs. The relationship between NNAs and clinical outcome in hemophilia should be further explored in a large cohort including pharmacokinetics and longitudinal observations with repeated blood sampling.

Phylogenetic analysis and pathogenesis study of a new deletion mutation causing inherited FⅩ deficiency

Objective: To analyze the F10 gene mutations in a Chinese pedigree affected with the deficiency of the hereditary coagulation factor X (FX), resulting from a new deletion mutation, and to study the associated molecular pathogenesis. Methods: Next generation sequencing (NGS) was performed to screen the genetic mutations in the proband which were then verified by Sanger sequencing. The FX activity (FX∶C) of probands and their family members was detected using the blood clotting method, and the mutation sites of the family members were analyzed using Sanger sequencing. The pathogenicity of the mutation site was predicted by using the online bioinformatics software, Mutation Taster. The SWISS-MODEL software was used for stimulating the three-dimensional models of the wild-type and mutant proteins for analyzing the influence of the mutation site on the structure and function of the proteins, and for analyzing the difference between the catalytic residues of the wild-type and the mutant proteins. The level of the F10 gene mRNA was quantitatively analyzed by qRT-PCR (quantitative reverse transcription polymerase chain reaction) method by constructing plasmids, transfecting human embryonic kidney 293T cells (HEK 293T), and analyzing the splicing of the mutated site by RT-PCR method. The levels of FⅩ∶Ag in cell lysates and cell culture media (both inside and outside the cells) were detected by the ELISA (enzyme linked immunosorbent assay) method. Results: A medium-grade factor X deficiency with a 36.42% FⅩ∶C ratio was detected in the proband by the coagulation method. NGS analysis demonstrated a heterozygous deletion mutation in exon 8:c.902_919del (p.Ala301_Glu306del) in the proband. Sanger sequencing analysis indicated that some members of the family (mother and grandfather) were also carriers of the corresponding deletion mutation. Online bioinformatics software predicted the pathogenic nature of the c.902_919del mutation, with a pathogenic score of 0.999. The 3D protein structure model analysis indicated that the c.902_919del mutation resulted in the disappearance of a segment of β-fold in the protein structure, thereby shortening the preceding segment of the β-fold and a subsequent loss of hydrogen bonds between adjacent amino acids with no significant difference in the side chain conformation of the key catalytic residues compared to the wild-type. mRNA splicing analysis indicated the absence of alternative splicing changes in the mutation, and qRT-PCR results indicated the absence of a statistically significant difference between the mRNA levels of F10 gene and wild-type mRNA in cells expressing c.902_919del mutant. The ELISA results indicated that there was no statistically significant difference in the FX∶Ag levels of the mutant cell culture medium and the lysate. Conclusions: In this pedigree, the heterozygous mutation in exon 8 of F10 gene (c.902_919del, p.Ala301_Glu306del) caused the hereditary factor Ⅹ deficiency.

Joint reaction and simulated muscle forces during squatting and walking in persons with hemophilia

BackgroundPersons with hemophilia experience joint bleeding that can lead to debilitating arthropathy, most commonly seen in ankles, knees, and elbows. Arthropathy can hinder participation in daily and athletic activities. We explored how hemophilic arthropathy impacts movement patterns in walking and bilateral squatting tasks in persons with hemophilia compared to healthy controls. MethodsPersons with hemophilia and healthy controls completed walking and squatting tasks while kinematic and kinetic motion capture data were collected. The Hemophilia Joint Health Score exam was performed to measure hemophiliac arthropathy. OpenSim was used to model muscle and joint reaction forces and calculate moments and angles. Peak values were compared using Cohen's d to estimate effect sizes of hemophilia on movement parameters. FindingsNine persons with hemophilia and eight age-matched controls were analyzed. Temporal-spatial metrics were similar between hemophilia and control groups in both tasks. In walking, persons with hemophilia had higher peak ankle dorsiflexion angles, vertical ground reaction force weight acceptance peaks, and hip extension and flexion moments compared to controls. In squatting, persons with hemophilia had lower knee extension moments, ankle joint reaction force, and knee extensor forces, but had higher hip extension moments. InterpretationTemporal-spatial metric similarity between hemophilia and controls suggests that kinetic and kinematic analyses are needed to identify movement pattern differences. These data identify potential compensatory strategies at the hip that may be used by persons with hemophilia to mitigate impact on the knee and ankle. Future work will confirm these data in a larger sample size and be used to develop physical therapy strategies.

Total Knee Replacement as Treatment for Hemophilic Arthropathy: A Case Series.

Background and objectives Hemophilic arthropathy is a known complication of patients with hemophilia, with the knee as the commonest joint affected. Patients with this condition have severe pain and restricted joint mobility, affecting their activities of daily living. Total knee replacement can increase these patients' quality of life. Nevertheless, this surgery has a high risk of complications due to the nature of the underlying hemophilia. In this study, we present the short-term outcome of a case series of six patients with hemophilic arthropathy who underwent total knee replacement at a hospital with hematology support performed by an experienced arthroplasty surgeon. Patients and method This study reviewed and included eight consecutive total knee replacements in six patients with hemophilic arthropathy performed by a single board-certified arthroplasty surgeon from 2019 to 2023. The demographic profile of the patients, pre- and postoperative range of movement, and short-term outcome scores were summarized. Results The mean preoperative flexion contracture was 10.6° (range: 5°-30°), and it was 0.7° (range: 0°-5°) postoperatively. The mean preoperative flexion of the knee was 78.1° (range: 45°-110°) and 98.8° postoperatively. At six-month follow-up, the average Knee Society Score expectation, satisfaction, and functional scores had improved from 8.3 to 13.8 points, 20 to 38.5 points, and 42.8 to 80.5 points, respectively. Conclusion This study suggests that short-term results of total knee replacement in patients with hemophilic arthropathy are favorable, with increased range of movement and quality of life. We also conclude that surgery should be performed by an experienced surgeon with the support of a dedicated hematology unit.

Levels of Tumor Necrosis Factor Alpha and Serum Ferritin in Patients with Hemophilia and Correlation with Clinical Data and Joint Arthropathy

Abstract Background Hemophilic arthropathy still represents a major concern especially in resource- limited settings, despite major advances in the management of patients with hemophilia worldwide. TNF-α has been enrolled in the pathophysiology of chronic hemophilic arthropathy. Aim: To evaluate levels of TNF-α and ferritin in patients with hemophilia in relation to hemophilic arthropathy. Methodology We conducted a 6-months comparative cross-sectional study including 38 hemophiliacs with arthropathy (HA+) and without arthropathy (HA−), who are mild, moderate and sever hemophilia; as well as 53 age- and sex-matched healthy control. Patients with a history of acute bleeding or inflammatory conditions in the previous four weeks were excluded from the study. We assessed every patient annual bleeding rate(ABR) measured serum levels of ferritin and TNF-α by using enzyme linked immune-sorbent assay (ELISA). joint status was assessed clinically by the Hemophilia joint health score (HJHS), and radiologically by the six major joints ultrasound (US) Results The median (IQR) age of hemophiliacs was 11.8 (9-16.1) years opposed to 11 (8-13) years in the control group (p = 0.435). Most patients (97.3%) received regular low dose prophylaxis. The median (IQR) HJHS among (HA−) was 0 (0 - 1) versus 18 (9 - 22) in (HA+) group (p &amp;lt; 0.001), and HJHS correlated well with the US score (p &amp;lt; 0.001, p &amp;lt; 0.001 and p = 0.005 for knee, ankle and elbow joints respectively). The annual bleeding rate (ABR) was comparable between both hemophilia groups with median (IQR) 0.88 (0- 2.25) in HA− group versus 1.25 (0.5- 1.75) in HA+ patients (p = 0.571). There was no significant difference in ferritin levels among hemophiliacs with median (IQR) in (HA+) and (HA-) of 40 (35-70) ng/ml and 30 (30-50) ng/ml respectively. On the other hand, TNF-α levels was significantly higher in hemophiliacs compared to control (p &amp;lt; 0.001); with median (IQR) 500 (390 -780) in HA− patients, 485 (385 -580) in HA+ group and 65 (50 - 95) for healthy controls. In a post-hoc analysis TNF-α levels were comparable among patients with and without arthropathy (p = 0.56). Conclusion Hemophiliacs display higher TNF-α levels when compared to healthy controls, which may be a useful surrogate biomarker for bleeding episodes.

Utilizing artificial intelligence for the detection of hemarthrosis in hemophilia using point-of-care ultrasonography

BackgroundRecurrent hemarthrosis and resultant hemophilic arthropathy are significant causes of morbidity in persons with hemophilia, despite the marked evolution of hemophilia care. Prevention, timely diagnosis, and treatment of bleeding episodes are key. However, a physical examination or a patient’s assessment of musculoskeletal pain may not accurately identify a joint bleed. This difficulty is compounded as hemophilic arthropathy progresses. ObjectivesOur system aims to utilize artificial intelligence and ultrasonography (US; point-of-care and handheld) to enable providers, and ultimately patients, to detect joint bleeds at the bedside and at home. We aimed to develop and assess the reliability of artificial intelligence algorithms in detecting and segmenting synovial recess distension (SRD; an indicator of disease activity) on US images of adult and pediatric knee, elbow, and ankle joints. MethodsA total of 12,145 joint exams, comprising 61,501 US images from 7 international healthcare centers, were collected. The dataset included healthy participants and adult and pediatric persons with hemophilia, with and without SRD. Images were manually labeled by 2 experts and used to train binary convolutional neural network classifiers and segmentation models. Metrics to evaluate performance included accuracy, sensitivity, specificity, and area under the curve. ResultsThe algorithms exhibited high performance across all joints and all cohorts. Specifically, the knee model showed an accuracy of 97%, sensitivity of 96%, specificity of 97%, and an area under the curve of 0.97 in SRD. High Dice coefficients (80%-85%) were achieved in segmentation tasks across all joints. ConclusionThis technology could assist with the early detection and management of hemarthrosis in hemophilia.

Clinical and Humanistic Burden of Non-inhibitor HaemophiliaA in Five European Countries: Insights from the CHESSII Study.

HaemophiliaA (HA) is a congenital bleeding disorder caused by a deficiency/absence of factorVIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESSII) study. CHESSII was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18years) individuals with haemophiliaA or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.

Immersive visualization of movement in patients with hemophilic ankle arthropathy. Multicenter, single-blind, randomized clinical trial.

To evaluate the efficacy of immersive movement observation in adult patients with haemophilic ankle arthropathy. Multicentre, single-blind, randomized clinical trial. 48 patients with haemophilia. Patients were randomly allocated to 2 groups (180º immersive video-based visualization of movement and a control group with no intervention). Twenty-eight consecutive 15-min home sessions, 1 per day, of immersive visualization of ankle flexion-extension movement were carried out. Three evaluations were performed: pretreatment (T0), post-intervention (T1), and at 16 weeks' follow-up (T2). The primary variable was joint-pain intensity (visual analogue scale). The secondary variables were conditioned pain modulation (Conditioned Pain Modulation Index), pressure pain threshold (pressure algometer), range of motion (goniometry) and kinesiophobia (Tampa Scale of Kinesiophophia). There were intergroup differences in pain intensity (F = 37.14; p < 0.001), conditioned pain modulation (F = 5.40; p = 0.006), and dorsal (F = 19.17; p < 0.001) and plantar (F = 9.27; p<0.001) ankle flexion. More than 50% of experimental group patients exhibited changes exceeding the minimum detectable change in pain intensity (MDC = 0.43), and the pressure pain threshold in the extensor carpi radialis longus muscle (MDC = 1.34) and malleolus (MDC = 4.93). 180º immersive video-based visualization of movement can improve the intensity of pain, conditioned pain modulation, and ankle range of motion in patients with haemophilic ankle arthropathy.