Hemophilia Research Articles

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.

Arthroscopic ankle fusion in haemophilic ankle arthropathy: A report of four cases and narrative literature review

Arthroscopic ankle fusion in haemophilic ankle arthropathy: A report of four cases and narrative literature review

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.

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

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

Combined adductor canal (ACB) and sacral erector spinae plane (S-ESP) blocks for total knee arthroplasty pain in hemophilic arthropathy

We present the case of a successful application of combined adductor canal block (ACB) and sacral erector spinae plane (S-ESP) block for the management of a patient suffering from severe hemophilia A with an end-stage arthropathy who underwent total knee replacement. The implementation of a tailored protocol, not incorporating neuraxial techniques, such as spinal anesthesia, facilitated optimal intra- and postoperative pain management and expedited postoperative recovery and rehab without motor weakness and side effects, highlighting the potential benefit of such strategy in selected cases.

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.

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.

Pathogenesis of osteoarthritis, rheumatoid arthritis, and hemophilic arthropathy: The role of angiogenesis

AbstractIntroductionThe term ‘chronic inflammatory arthritis’ (IA) can be used to define a group of heterogeneous diseases in which inflammation of the synovium is the common feature while having different pathogenesis and clinical outcomes. This condition can be found in osteoarthritis (OA), rheumatoid arthritis (RA), and hemophilic arthropathy (HA).AimThe objective is to try to highlight similarities and differences in the three pathological conditions and understand both molecular and physiological mechanisms.MethodWe have carried out a systematic review of the available literature following the guidelines Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA).ResultsBy comparing the data in the literature on OA, RA, and HA we have shown that the three pathologies differ in initial etiology but they motivate the same molecular pathways.ConclusionIn this review we highlighted the similarities and differences between these diseases, creating ideas for future studies both in vivo and in vitro to develop new therapeutic agents and suggest possible biomarkers to follow the evolution and severity of the disease.

Biomarkers Involved in the Pathogenesis of Hemophilic Arthropathy.

Hemophilia, which is a rare disease, results from congenital deficiencies of coagulation factors VIII and IX, respectively, leading to spontaneous bleeding into joints, resulting in hemophilic arthropathy (HA). HA involves complex processes, including synovial proliferation, angiogenesis, and tissue remodeling. Despite ongoing research, factors contributing to HA progression, especially in adults with severe HA experiencing joint pain, remain unclear. Blood markers, particularly collagen-related ones, have been explored to assess joint health in hemophilia. For example, markers like CTX-I and CTX-II reflect bone and cartilage turnover, respectively. Studies indicate elevated levels of certain markers post-bleeding episodes, suggesting joint health changes. However, longitudinal studies on collagen turnover and basement membrane or endothelial cell markers in relation to joint outcomes, particularly during painful episodes, are scarce. Given the role of the CX3CL1/CX3XR1 axis in arthritis, other studies investigate its involvement in HA. The importance of different inflammatory and bone damage biomarkers should be assessed, alongside articular cartilage and synovial membrane morphology, aiming to enhance understanding of hemophilic arthropathy progression.

Early Detection and Evaluation of Pediatric Knee Joint Hemophilic Arthropathy; Added Value of 3d Fast Field Echo to Conventional MRI Sequences in symptomatic and asymptomatic joints

Early Detection and Evaluation of Pediatric Knee Joint Hemophilic Arthropathy; Added Value of 3d Fast Field Echo to Conventional MRI Sequences in symptomatic and asymptomatic joints

MR Imaging of Hemosiderin Deposition in the Ankle Joints of Patients with Haemophilia: The Contribution of a Multi-Echo Gradient-Echo Sequence-Correlation with Osteochondral Changes and the Number and Chronicity of Joint Bleeds.

We aim (a) to introduce an easy-to-perform multi-echo gradient-echo sequence (mGRE) for the detection of hemosiderin deposition in the ankle joints of boys with haemophilia (b) to explore the associations between the presence and severity of hemosiderin deposition and the other components of haemophilic arthropathy, the clinical score, and the number and chronicity of joint bleeds. An MRI of 41 ankle joints of 21 haemophilic boys was performed on a 3 T MRI system using an mGRE sequence in addition to the conventional protocol. Conventional MRI and mGRE were separately and independently assessed by three readers, namely, two musculoskeletal radiologists and a general radiologist for joint hemosiderin. We set as a reference the consensus reading of the two musculoskeletal radiologists, who also evaluated the presence of synovial thickening, effusion, and osteochondral changes. Excellent inter-reader agreement was obtained using the mGRE sequence compared to the conventional protocol (ICC: 0.95-0.97 versus 0.48-0.89), with superior sensitivity (90-95% versus 50-85%), specificity (95.2-100% versus 76.2-95.2%), and positive (95-100% versus 71-94.4%) and negative predictive value (91.3-95.5% versus 87-63%). Hemosiderin deposition was associated with osteochondral changes, synovial thickening, clinical score, and the total number of ankle bleeds, while it was inversely related with the time elapsed between the last joint bleed and MRI. (p < 0.05). The application of an mGRE sequence significantly improved hemosiderin detection, even when performed by the less experienced reader. Joint hemosiderin deposition was associated with the other components of haemophilic arthropathy and was mostly apparent in recent joint bleeds.

Proteomic exploration of potential blood biomarkers in haemophilic arthropathy.

The pathophysiology of haemophilic arthropathy (HA) is complex and largely undefined. Proteomic analyses provide insights into the intricate mechanisms of the HA.Our study aimed to identify differentially expressed proteins in relation to the severity of HA, explore their pathophysiological roles, and evaluate their potential as HA biomarkers. Our cross-sectional observational study encompassed 30 HA patients and 15 healthy subjects. Plasma samples were pooled into three groups of 15 samples from those with severe haemophilic arthropathy (sHA), mild haemophilic arthropathy (mHA) and healthy controls. Proteomic analysis was performed using liquid chromatography-mass spectrometry. The severity of HA was assessed using the World Federation of Haemophilia Physical Examination Score and ultrasonography following the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) guidelines. A total of 788 proteins were identified, with 97% of the uniquely identified proteins being expressed in all analysed groups. We identified several up and downregulated proteins across the groups that were mainly related to inflammatory and immunity-modulating processes, as well as joint degeneration. We highlighted ten proteins relevant for the development of HA: cathepsin G, endoplasmic reticulum aminopeptidase 2, S100-A9, insulin-like growth factor I, apolipoprotein (a), osteopontin, pregnancy zone protein, cartilage oligomeric matrix protein, CD44, and cadherin-related family member 2. Our analysis identified several proteins that shed further light on the distinctive pathogenesis of HA and could serve for biomarker research. However, these results need to be validated on a larger patient group.

Therapeutic Potential of FXI Inhibitors: Hype or Hope?

Significant advancements have shaped the landscape of anticoagulant therapy in the past two decades, including the introduction of direct oral anticoagulants (DOACs), characterized by favorable safety and efficacy profiles and reduced drug-to-drug or food interaction resulting in excellent patient compliance. However, residual concerns still exist with standard-of-care anticoagulant therapy, including the inability to use DOACs in several clinical settings and the need to further reduce the risk of bleeding. Recent improvements in the understanding of the mechanisms behind thrombus formation have led to the awareness that the intrinsic pathway of the coagulation cascade may play an important role in pathological thrombosis, but not in hemostasis. This has represented the rationale for targeting this pathway with factor XI (FXI) inhibitors, with the aim of uncoupling hemostasis and thrombosis. Clinical evidence from patients with FXI deficiency further supports this concept. A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). To date, the majority of available trials have not gone beyond completion of phase 2 and results are conflictive making it difficult to appraise the clinical benefit of these compounds in the different clinical settings where they have been tested (i.e., atrial fibrillation, acute ischemic stroke, acute myocardial infarction, end-stage renal disease, total knee arthroplasty). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs.

Association Between Physical Activity and Fear of Movement in Patients with Hemophilic Arthropathy

Association Between Physical Activity and Fear of Movement in Patients with Hemophilic Arthropathy

Clinical, Laboratory Aspects and Management of Factor X Deficiency.

Coagulation factor X (FX), originally named Stuart-Prower factor, plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in F10 may lead to FX deficiency and to impaired coagulation. FX variants are phenotypically classified as being type I, with the concomitant reduction of FX coagulant activity and FX antigen levels or type II, corresponding to a reduction in activity with normal antigen plasma levels. Patients affected with FX deficiency tend to be one of the most seriously affected among those with rare bleeding disorders. They show a variable bleeding tendency strongly associated with FX coagulant activity levels in plasma and may present, in the severe form of the deficiency, life-threatening symptoms such as gastrointestinal and umbilical stump bleeding and intracranial hemorrhages or central nervous system bleeding. Treatment of FX deficiency was originally based on the replacement of the missing factor using fresh frozen plasma, cryoprecipitate and prothrombin complex concentrates; however, a plasma-derived concentrate, shown to be safe and effective in clinical trials, is now available. In addition, novel nonreplacement therapy such as small interference RNA, gene therapy, drug repurposing, and gene editing may also represent novel therapeutic approaches for FX deficiency, but further, much focused studies are needed before considering this emerging therapy in such patients.

Importance of physical activity in the treatment of hemophilia

Hemophilia is a genetically determined bleeding disorder characterized by a tendency for spontaneous bleeding, mainly into the joints, which can lead to arthropathy and significantly reduce the quality of a patient's life. The objective of this paper is to review the published literature on the impact of physical activity on the course of the disease and its role in current therapeutic protocols. Online databases were used to search for literature. The retrieved articles were analyzed. The review mainly included literature published after 2016. In the past, physical exercise was not recommended for people with hemophilia, primarily due to concerns about joint bleeding and the development of hemophilic arthropathy. Currently, regular, moderate physical activity plays a crucial role in the management of hemophilia, helping to strengthen muscles and improve joint stability, which can reduce the risk of bleeding. This shift in perspective is largely due to the availability of effective therapeutic options, mainly involving the replacement clotting factors. However, entirely new hopes for a permanent cure and the maintenance of physical fitness are brought by modern gene therapy treatments. Physical activity is essential for maintaining the health and fitness of individuals with hemophilia, and most exercises are safe due to effective prophylactic treatment. In addition to the benefits for joint health, regular exercise also helps prevent many lifestyle-related diseases.

Stability, Balance, and Physical Variables in Patients with Bilateral Hemophilic Arthropathy of the Ankle versus Their Healthy Peers: A Case-Control Study.

(1) Background: The recurrence of hemarthrosis in patients with hemophilia triggers a pathophysiological process of degenerative, progressive, and irreversible joint destruction. This hemophilic arthropathy is characterized by chronic pain, muscle atrophy, loss of mobility, and proprioceptive alterations. As the same joint undergoes repeated hemarthrosis, the function of the mechanical receptors deteriorates, causing a pathophysiological modulation and deterioration of the musculoskeletal system. The objective was to analyze the differences in stability and balance, as well as in ankle dorsal flexion, functionality, and muscle strength, between patients with bilateral hemophilic arthropathy and their healthy peers. (2) Methods: A cross-sectional descriptive case-control study was performed. Twenty-two participants were recruited: 10 adult patients with bilateral hemophilic arthropathy of the knee and ankle and 12 healthy subjects. The variables were balance (Rs Scan pressure platform), ankle dorsiflexion range of motion (Leg Motion), functionality (2-Minute Walk Test), and ankle dorsal strength (dynamometry). (3) Results: Statistically significant differences (p < 0.05) were found in the balance without visual support in the Max-Y variable (MD = 2.83; CI95%: 0.33;5.33; Effect size (d) = 0.67), ankle dorsiflexion (MD = 16.00; CI95%: 14.30; 20.0; d = 7.46), and strength of the ankle flexor muscles (MD = 128.50; CI95%: 92.50; 153.60; d = 2.76). (4) Conclusions: Ankle range of motion in dorsal flexion, functionality, and muscle strength in dorsal flexion is poorer in patients with bilateral lower limb hemophilic arthropathy than in their healthy peers. Patients with bilateral hemophilic ankle arthropathy have statistically poorer stability and balance without visual support than their healthy peers.