Hemophilia Patients Research Articles

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.

Moderate haemophilia A: Recommendations from a Spanish panel of experts.

Diagnosing moderate haemophilia A (MHA) solely based on deficient FVIII protein levels limits its optimal management and delays the initiation of prophylaxis. Updating protocols and incorporating new variables into its diagnosis could prevent underestimating disease severity, avoiding early arthropathies and impairing patients' quality of life. To propose recommendations to improve the comprehensive management of people with MHA. Recommendations from a Spanish panel of eight experts from public comprehensive care centres (CCCs) for people with haemophilia and over 140 people with MHA in follow-up. In a previous analysis, the panel identified the unmet needs of people with MHA and the necessity to develop new specific recommendations for their management. The panel proposed recommendations in four areas: diagnosis, treatment, follow-up and referrals. They detailed the necessary steps and procedures for the diagnosis, adding other variables to the FVIII levels like bleeding phenotype, genetic profile and joint status to specify the severity and risk classification of people with MHA. Experts proposed an algorithm with unique independent criteria to facilitate the decision to initiate prophylaxis, where the recommended FVIII levels and variables coexist for treatment decision-making. Follow-up proposals addressed periodicity, recommended tests and required visits to CCCs. For referrals, experts proposed criteria and situations considered urgent for a transfer to a CCC for haemophilia patients. The proposals agreed upon by this expert panel can contribute to update and optimize the management of people with MHA, delaying joint deterioration, pain and disabilities, and improving their quality of life.

Clots and bleeds: the outcomes of percutaneous coronary intervention in hemophilia patients with acute coronary syndrome.

Hemophilia is a disease characterized by a high risk of bleeding. With advances in treatment, life expectancy and aging-associated diseases such as coronary artery disease have increased. Our primary objective is to assess for major adverse outcomes, mortality, and length of hospital stay in individuals with hemophilia presenting for acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). Our retrospective cohort study analyzed data from the Nationwide Inpatient Sample Database (NIS) for 2018 to investigate the outcomes of ACS management with PCI in adults with and without hemophilia. We used ICD-10 codes to exclude patients with significant comorbidities and identify those with ACS undergoing PCI. Propensity score matching and multivariable logistic regression were employed to account for over 20 baseline characteristics, mitigating confounding factors. The incidence of gastrointestinal bleeding (11.0% vs. 2.8%, p < 0.001), hemorrhagic stroke (10.0% vs. 1.4%, p < 0.001), and retroperitoneal hemorrhage (5.6% vs. 1.4%, p < 0.001) was significantly higher in individuals with hemophilia undergoing PCI compared to those without hemophilia. Additionally, venous thromboembolism (VTE) incidence was notably higher in the hemophilia cohort (6.6% vs. 2.4%, p = 0.027). The hemophilia cohort also experienced a higher mortality rate (7.1% vs. 3.3%, p = 0.037) and longer hospital stays. Patients with hemophilia undergoing PCI are at a significantly greater risk of adverse events, increased mortality, and longer hospital stays than the general population. To mitigate the risk of unfavorable outcomes, it is crucial to ensure adequate replenishment of coagulation factors and establish close collaboration between cardiologists and hematologists.

Real-world insights into the management of hemophilia A in Italy: treatment patterns and healthcare resource utilization

PurposeThis real-world analysis described the Hemophilia A (HA) population in Italy, evaluating drug utilization and consumption of factor VIII (FVIII) products of patients under prophylaxis and on-demand therapy.MethodsFrom Jan-2017 to Jun-2022, male patients with HA were identified through prescriptions of FVIII products [extended half-life FVIII, standard half-life recombinant FVIII, and plasma-derived FVIII (EHL FVIII, SHL rFVIII, and pdFVIII, respectively)], or emicizumab or FVIII plus von Willebrand factor or HA-related hospitalization using administrative flows of Italian healthcare entities. Patients on treatment with FVIII products during 2021–2022 were stratified by treatment regimen (prophylaxis/on-demand). The mean annual consumption expressed in International Units (IU) of EHL FVIII and SHL FVIII in patients treated during 2021–2022 having at least 12-month follow-up were assessed.ResultsAmong included HA patients, 145 (39.5%) received EHL FVIII and 222 (60.5%) SHL FVIII. Of 165 patients on prophylaxis, 105 (64%) received an EHL FVIII and 60 (36%) an SHL FVIII. The mean annual consumption of FVIII was 336,700 IU (median 319,000 IU) for EHL FVIII and 440,267 IU (median 360,500 IU) for SHL FVIII. Specifically, for patients on EHL FVIII, the most common drugs were efmoroctocog alfa (N = 51) and damoctocog alfa pegol (N = 50), followed by turoctocog alfa pegol (N = 25) and rurioctocog alfa pegol (N = 19). Of 702 HA patients initially treated with FVIII products, 74 (10.5%) switched to emicizumab during follow-up.ConclusionThese findings revealed an extensive use of EHL FVIII products, suggesting growing efforts from clinicians to optimize prophylactic strategies and achieve better bleeding protection.

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.

Evaluating the benefits of emicizumab prophylaxis for haemophilia A with inhibitors: A cost-effectiveness and budget impact analysis in Thailand's upper-middle income setting.

In Thailand, an upper-middle-income country, managing haemophilia A (HA) with inhibitors poses significant challenges, often necessitating bypassing agents (BPAs) for bleeding control. This study evaluates the cost-effectiveness and budget impact of emicizumab, a novel prophylactic agent, as an alternative to both episodic and prophylactic BPA treatments from a societal perspective. A Markov model was employed to estimate the lifetime societal costs and outcomes of emicizumab prophylaxis for HA patients with inhibitors. Treatment efficacy, cost, and epidemiological data were obtained through a comprehensive literature review and incorporated into the model. A 5-year budget impact analysis complemented the cost-utility analysis, with a 3% annual discount rate applied to future costs and outcomes. In the base-case scenario, emicizumab prophylaxis in HA patients aged 2 years and above demonstrated superior cost-effectiveness, yielding 18.1 quality-adjusted life years (QALYs) per patient over a lifetime and resulting in cost savings of 138 million Thai Baht (THB) compared to BPA prophylaxis. Compared to episodic BPA treatment, emicizumab yielded 30.5 QALYs and saved 25 million THB per patient. The 5-year budget impact was projected at 1775 million THB. Emicizumab offers a cost-saving approach for HA treatment with inhibitors in Thailand, promising significant health benefits and budgetary savings. This supports its potential inclusion in Thailand's National List of Essential Medicines to enhance haemophilia care access. Managing haemophilia A (HA) with inhibitors in Thailand, an upper-middle-income country, faces challenges due to limited access to effective treatments or newer drugs for bleeding management. Emicizumab prophylaxis found to as a cost-effective and viable alternative to traditional treatments, effectively preventing bleeding in Thai HA patients over 2 years old with inhibitors. Demonstrating improved clinical outcomes and reduced costs, emicizumab prophylaxis outperforms episodic BPA treatments, positioning it as a superior treatment option for HA patients with inhibitors in Thailand.

Hemophilia: is arevolution in treatment options taking place?

Prophylactic replacement therapy for hemophiliaA (hereditary factor VIII deficiency) is asuccess story of the production of coagulation factor concentrates from donor plasma. Recombinant factor concentrates, which are also produced with modified gene constructs for coagulation factor VIII in order to improve pharmacological properties, have since proven their worth. This successful development over many years of factor concentrates for the successful treatment of hemophilia patients has now been followed by the innovation of afactor VIII mimetic in the form of amonoclonal antibody, which was developed in Japan already some years back. Emicizumab is ahumanized, bispecific monoclonal antibody for therapeutic use in hemophiliaA. With this therapeutic agent, the treatment of the hereditary coagulation defect is based, for the first time, on acompletely new active principle. The specific antibody simulates the properties of coagulation factor VIII as acofactor for the formation of the tenase complex with the coagulation factors IX and X. As a result under steady state conditions almost normal thrombin and thus fibrin formation can be achieved.

Haemophilia care in Iraq; a multi-centre study.

To evaluate the level of care available for haemophilia patients. The descriptive, retrospective analytical study was conducted from December 15, 2020, to March 1, 2021, after approval from the Mustansiriyah University, Baghdad, Iraq, and comprised data from 3 haemophilia treating centres in Iraq participating in the World Bleeding Disorders Registry. The data collected related to patients with haemophilia A and B enrolled in the registry since March 2018, and included age at diagnosis, type of haemophilia, disease severity, age at first bleed and at first joint bleed, type of replacement therapy and outcome. Data was analysed using statistical package of social sciences (SPSS) version 20. Of the 638 patients with mean age 16.2±4.3 (range: 9-29 years), 581(91%) had haemophilia A, 57(8.9%) had haemophilia B, 385(60.5%) had severe haemophilia, 126(19.8%) moderate and 125(19.7%) mild. Further, 259(41%) patients had been diagnosed for <1 year. There were 1354 bleeding events, and haemarthrosis accounted for 959(70.8%) of them. The mean annualised bleeding rate for severe patients was 2 ± 0.6(range 0-4), while the mean annualised joint bleeding rate was 4 ± 1.3(range :2-8). There were 256(32.3%) patients who were tested for inhibitors, and 62(24.3%) were positive. Among 426(73.3%) haemophilia A patients with a treatment history, 248(58%) were on prophylactic therapy, and the corresponding value among 37(65%) haemophilia B patients was 17(46%). Access to treatment was found to be limited, and patients were found to be suffering from high bleeding rates and joint damage.

Functional evaluation of joint in moderate to severe hemophilia patients treated with on-demand factor replacement: insights from a single hemophilia treatment center in Bangladesh

BackgroundHemophilia patients are prone to spontaneous or post-traumatic bleeding, particularly in joints and various other body sites. The high incidence of joint hemorrhages in hemophilia patients underscores the importance of routine joint assessments in clinical care to monitor the condition and evaluate the efficacy of hemophilia treatments.AimThis study aimed to assess the joint health of hemophilia patients receiving FVIII or FIX on-demand replacement therapy treatment at a tertiary care hospital in Bangladesh.MethodsThis single-center study involved 93 patients diagnosed with moderate (n = 72;77.4%) and severe (n = 21;22.6%) hemophilia. The assessment of joint health was carried out on six key joints—both elbows, knees, and ankles—using the Hemophilia Joint Health Score (HJHS) version 2.1. Clinical and laboratory data were meticulously documented in a structured questionnaire.ResultsAmong the 93 hemophilic patients, the majority had hemophilia A (96.8%). The median HJHS of the patients was 15 (IQR:9.5–20) with the knee joint being mostly affected (88.2%). A significant positive correlation was observed between HJHS and age (r = 0.385, p < 0.001) and total number of joints involved (r = 0.405, p < 0.001). No significant association was found between factor level, education status, and socio-economic status with HJHS score.ConclusionEarly assessment and monitoring of joint health are essential in clinical practice to prevent severe complications in hemophilia patients.

Real‐world effectiveness of eptacog beta in patients with haemophilia and inhibitors: A multi‐institutional case series

AbstractIntroductionThe management of bleeding events (BEs) in haemophilia A (HA) and B (HB) patients with inhibitors necessitates the use of bypassing agents. The recombinant factor VIIa bypassing agent eptacog beta has demonstrated efficacy at treating BEs and managing perioperative bleeding in adults in phase three clinical studies.AimTo provide real‐world descriptions of eptacog beta use for BE treatment in patients on emicizumab or eptacog beta prophylaxis.MethodsThis is a retrospective case series of 14 patients who received eptacog beta at seven haemophilia treatment centres, with HA (n = 11) or HB (n = 3) and inhibitors or anaphylaxis to factor replacement.ResultsTwenty‐four spontaneous and traumatic BEs are described (muscle hematomas, joint hemarthroses, port site, and epistaxis) involving 11 subjects. Eptacog beta was effective for acute bleed treatment as both first‐line therapy and for treatment of BEs refractory to eptacog alfa in 23/24 events. When eptacog beta was used for prophylaxis, 2/3 patients reported a decreased frequency of breakthrough BEs compared with prophylactic eptacog alfa and one patient experienced a similar frequency of breakthrough BEs compared with prophylactic activated prothrombin complex concentrate. Eptacog beta provided effective bleed control for three subjects who underwent minor surgical procedures. Treatment with eptacog beta was estimated to be 46%–72% more cost‐effective than eptacog alfa. No safety concerns or adverse events were reported.ConclusionsIn this case series, eptacog beta was safe, effective, and economical as first‐line therapy, treatment of refractory BEs, management of perioperative bleeding, or prophylaxis in haemophilia patients with inhibitors.

Higher Prevalence of Hepatitis B and C Infections among Indian Patients with Von Willebrand Disease

Background: The use of recombinant coagulation factors has reduced the incidence of hepatitis B and C infections in hemophilia patients. As recombinant von Willebrand factor is not easily available, patients with von Willebrand disease (VWD) may be at higher risk for acquiring hepatitis B and C infections. The prevalence of hepatitis B and C infections in the Indian population is ~0.95% and ~0.3%, respectively. Aims: This single tertiary center study aimed to assess the prevalence of hepatitis B and C infections and the profile of liver disease caused by these viruses among patients with VWD. Methodology: We retrospectively enrolled VWD patients treated in our center from January 2012 to December 2022 and analyzed the prevalence of hepatitis B and C infection and stage of liver disease. Results: Among 189 patients with VWD during the study period, 5 of 61 (8.1%) VWD patients screened were hepatitis B surface antigen positive (age: 34 [24–42] years; median (range); plasma VWF antigen: 10.1, [0–40] IU/dL). One patient had cholangiohepatoma at presentation, whereas none had chronic liver disease. Four of five patients received multiple bloodproduct transfusions before coming to our institution, with 10 (7–18) years interval between 1st transfusion and to detection of hepatitis B infection. Four of the 47 VWD patients (8.5%) screened were positive for hepatitis C virus antibody (48 [43–59] years, plasma VWF antigen: 20 [0–21.5] IU/dL). One patient had chronic liver disease. All four patients received multiple blood product transfusions before coming to our institution, with 15.5 (2–39) years interval between 1st transfusion and to the detection of hepatitis C infection. Conclusions: The prevalence of hepatitis B infection (8.1%) and hepatitis C infection (8.5%) was 8-fold and 28-fold higher, respectively, in VWD patients than the general population in India. VWD patients remain at high risk for acquiring transfusion-transmitted viral infections and appropriate interventions are needed to address this.

Impacts of the COVID-19 pandemic on pediatric and adult patients with hemophilia.

The coronavirus disease 2019 (COVID-19)-associated mortality rate of hemophilia patients is similar to that of the general population, but the risk of hospitalization and bleeding is higher. However, the specific impact of this infection on hemophilia patients remains unknown. We aimed to investigate the impact of the pandemic on the infection susceptibility, symptoms, drug use, and social intercourse of patients with hemophilia. A survey was distributed to 265 patients with hemophilia (185 adults and 80 children) in the Fujian hemophilia therapeutic center (Fuzhou City, China) during the COVID-19 pandemic, and data were collected between January 2022 and January 2023. The impacts of SARS-CoV-2 infection on hemophilia symptoms, drug use, and social intercourse of these patients were investigated, and the association between the recovery time and disease conditions was explored in infected patients. During the pandemic, compared with adult patients, pediatric patients had significantly reduced social intercourse and outdoor activities because of the fear of contracting COVID-19 (85.0% vs. 66.5%). Bleeding events were also significantly fewer in children than in adults (61.2% vs. 81.1%). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in those living in rural areas (74.3% vs. 53.6%). The duration of symptomatic recovery from COVID-19 was not significantly associated with hemorrhage, type and classification of hemophilia, presence of inhibitors, complications, and vaccination status. Having COVID-19 infection did not significantly influence the symptoms and treatments in patients with hemophilia. Pediatric patients had significantly fewer bleeding events than adults.

Perioperative Management for Port Catheter Procedures in Pediatric Patients with Severe Hemophilia and Inhibitors.

The objective of this systematic study was to assess the perioperative management and outcome of surgery in pediatric patients with hemophilia A/B and inhibitors compared to nonhemophilic pediatric patients. The surgical outcome of 69 port catheter operations in patients with hemophilia who developed inhibitory antibodies against the administered factor was compared to 51 procedures in the control group. In the patients with hemophilia and inhibitors, a standardized protocol for recombinant activated factor VII was used to prevent perioperative bleeding. Hemophilic pediatric patients with inhibitors showed no significant differences in perioperative management (blood transfusion: p = 0.067, duration of surgery: p = 0.69; p = 0.824) in comparison to patients without hemophilia. The length of hospital stay was significantly longer in pediatric patients with hemophilia and inhibitors (20 days vs. 4 days for insertion; 12 days vs. 1 day for explantation). Moreover, no statistically significant difference was found for secondary bleeding (three patients with hemophilia vs. none in the control group; p = 0.11) or surgical complications (five hemophilia patients vs. none with grade I complication; one hemophilia patient vs. none with grade II complications; p = 0.067). This study has demonstrated that port catheter insertion and removal is safe in these patients. Moreover, it shows the importance of a coordinated approach with a multidisciplinary team.

Activated factor X delivered by adeno-associated virus significantly inhibited bleeding and alleviated hemophilic synovitis in hemophilic mice.

In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and restore coagulation in hemophilia patients. In this study, the cassettes that expressed FXa, FXaop and FXa-FVII were packaged into an engineered AAV capsid, AAV843, and were delivered into hemophilia A and B mice by intravenous injection. AAV-FXaop could be stably expressed in vivo and showed the best immediate and prolonged hemostatic effects, similar to those of commercial drugs (Xyntha and Benefix). AAV-FXaop also significantly inhibited bleeding in hemophilia A mice with inhibitors. In addition, FXa expression in joints significantly alleviated the occurrence of hemophilic synovitis. AAV-delivered FXa may be a novel target for treating hemophilic and hemophilic synovitis.

Clot waveform analysis to differentiate mild, moderate, and severe hemophilia A

Background Clot waveform analysis can be used to evaluate clot formation profiles. This waveform can be obtained from activated partial thromboplastin time (APTT) assays without additional reagents and shows different patterns in hemophilia patients with coagulation factor VIII (F VIII) deficiency or abnormality. Objective To determine the clot wave pattern and its process in clot formation phases (pre-coagulation, coagulation, and post-coagulation) in normal and hemophilia A subjects, analyze for possible correlations between clot wave parameters and F VIII activity, and obtain the pattern of coagulation curves in hemophilia subjects as a step to assess clot waveform analysis as a possible screening tool for hemophilia. Methods In this cross-sectional study, we performed clot wave analysis in 145 adult and pediatric subjects with hemophilia to obtain the clot wave pattern in this condition. Clot wave analysis was also done in 160 subjects with normal hemostasis to obtain reference clot wave parameters. Results In this study, the starting point of coagulation phase in normal subjects was between 30-40 seconds, with a shorter pre-coagulation phase and steeper slope. Hemophilia patients had a longer pre-coagulation phase and flatter slope, especially in severe hemophilia A patients, who had longer and more variable coagulation starting points (P&lt;0.001). The absolute values of maximum coagulation velocity (Min1), maximum coagulation acceleration (Min2), and maximum coagulation deceleration (Max2) of hemophilia A patients were also lower than those of normal hemostasis patients, with lower absolute value seen in severe than in mild-moderate hemophilia A patients. A moderate correlation was found between Min1, Min2, and Max2 with F VIII activity (P&lt;0.001). Conclusion Clot wave analysis may be considered as a method for screening hemophilia patients to distinguish mild-moderate and severe hemophilia A patients in health facilities that lack the ability to perform F VIII assays.

Clinical, Demographic, And Haematological Profile of Haemophilia Patients at Sir Sunder Lal Hospital Varanasi With CoE Haemoglobinopathies And Day Care Centre

Introduction: Hemophilia is a recessive coagulation and bleeding disorder that is X-linked and inheritable. The Factor VIII (F8) and Factor IX (F9) genes are involved in hemophilia A and B, two hereditary diseases. The process of hemostasis is hampered by spontaneous or post-traumatic bleeding, which also increases the risk of hemophilia. Aim: The purpose of our study is to evaluate the hematological, clinical, and demographic traits of individuals with hemophilia A and B. Results: A total of 646 hemophilia patients were examined during the study period. the majority of hemophilia A patient 544 (84.21%) and hemophilia B102 (16.01%). Based on severity, severe 342 (52.94%), Moderate 247 (38.24%), and Mild (8.82%) had been diagnosed Most common age group was &lt;1 -58 years. The bulk of the study population had a mean age of (Mean ±SD=18.45±13.00) and a median of 17. Maximum number of patients at the ages of 21 and 30 years (21.05%) and a median of 25. The most common age of spontaneous bleeding across all patients was 17 and there was no discernible difference between those with moderate and severe symptoms of bleeding. Hemarthrosis infection (target joint) was most prevalent (79.10%), then prolonged bleeding after cut/ trauma (62.38%). Hemarthrosis knee joint was the joint that was infected (target joint) the most common (79.10%), followed by joint bleeding (46.75%) Severe disease affected the knee joint more frequently than moderate disease. Conclusion: The present research revealed differences in the incidence and nature of bleeding on its own in hemophilia patients. Gum bleeding and posttraumatic bleeding in a child who is otherwise healthy should alert the doctor to consider hemophilia onset is &lt;1 year. On the other hand, 61.3% of patients had hemophilia when they received their initial diagnosis. The median number of bouts of

Clinical validation and application of targeted long-range polymerase chain reaction and long-read sequencing–based analysis for hemophilia: experience from a hemophilia treatment center in China

BackgroundTargeted long-read sequencing (LRS) is expected to comprehensively analyze diverse complex variants in hemophilia A (HA) and hemophilia B (HB) caused by the F8 and F9 genes, respectively. However, its clinical applicability still requires extensive validation. ObjectivesTo evaluate the clinical applicability of targeted LRS-based analysis compared with routine polymerase chain reaction (PCR)–based methods. MethodsGene variants of retrieved subjects were retrospectively and prospectively analyzed. Whole-genome sequencing was performed to further analyze undiagnosed cases. Breakpoints of novel genomic rearrangements were mapped and validated using long-distance PCR and long-range PCR combined with sequencing. ResultsIn total, 122 subjects were retrieved. In retrospective analysis of the 90 HA cases, HA-LRS assay showed consistent results in 84 cases compared with routine methods and characterized 6 large deletions with their exact breakpoints confirmed by further validation in 6 cases (routine methods only presented failure in amplifying the involved exons). In prospective analysis of the 21 HA subjects, 20 variants of F8 were identified in 20 cases. For the remaining HA patient, no duplication/deletion or single-nucleotide variant (SNV)/insertion and deletion (InDel) was found, but a potential recombination involving exons 14 and 21 of F8 was observed by LRS. Whole-genome sequencing analysis and further verification defined a 30 478 base pairs (bp) tandem repeat involving exons 14 to 21 of F8. Among the 11 HB patients, HB-LRS analysis detected 11 SNVs/InDels in F9, consistent with routine methods. ConclusionTargeted LRS-based analysis was efficient and comprehensive in identifying SNVs/InDels and genomic rearrangements of hemophilia genes, especially when we first expanded the panel to include F9. However, further investigation for complex gross rearrangement is still essential.

Novel injectable adhesive hydrogel loaded with exosomes for holistic repair of hemophilic articular cartilage defect

Hemophilic articular cartilage damage presents a significant challenge for surgeons, characterized by recurrent intraarticular bleeding, a severe inflammatory microenvironment, and limited self-repair capability of cartilage tissue. Currently, there is a lack of tissue engineering-based integrated therapies that address both early hemostasis, anti-inflammation, and long-lasting chondrogenesis for hemophilic articular cartilage defects. Herein, we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin, loaded with exosomes derived from bone marrow stem cells (BMSCs) (Hydrogel-Exos). This hydrogel demonstrated favorable injectability, self-healing, biocompatibility, biodegradability, swelling, frictional and mechanical properties, providing a comprehensive approach to treating hemophilic articular cartilage defects. The adhesive hydrogel, featuring dynamic Schiff base bonds and hydrogen bonds, exhibited excellent wet tissue adhesiveness and hemostatic properties. In a pig model, the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions. Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway. This immunoregulatory effect, coupled with the extracellular matrix components provided by the adhesive hydrogel, enhanced chondrogenesis, promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects. In conclusion, our results highlight the significant application potential of Hydrogel-Exos for early hemostasis, immunoregulation, and long-term chondrogenesis in hemophilic patients with cartilage injuries. This innovative approach is well-suited for application during arthroscopic procedures, offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.

Investigation of SEN virus prevalence in hemophilia patients

BackgroundHemophilia and transfusion-dependent patients are at high risk of a wide range of blood-borne agents. Among these, SEN virus (SENV) stands out as a significant concern due to its association with transfusion-induced non-A to non-E hepatitis. This study, therefore, aimed to investigate the prevalence of this virus in hemophilia patients, focusing on potential complications and risk factors. MethodThis was a cross-sectional study conducted in a hemophilia center in the east of Iran. Blood samples were taken from patients and healthy people, and demographic and clinical information was collected. The sera samples were then subjected to DNA extraction. PCR-based methods detected SENV and its genotype, and then phylogenetic analysis was performed. The collected data were analyzed and interpreted by SPSS22 software. ResultsThe mean age of patients and the healthy group was 26.18 ± 14.97 and 41.69 ± 14.05, respectively. Among the patient and healthy groups, 94.5 % and 36.4 % were male, and the rest were female, respectively. Most of the participants in the patient group had hemophilia type A (85.5 %), then type B (7.3 %), VWD type (3.6 %), and F and plt type (1.8 %) were in the next categories. SENV-DNA was detected in 58.2 % of patients and 20 % of healthy groups (P-value: 0.00). Among these, H and D genotypes were found in 35 % and 23.7 % of patients and 12.7 % and 7.3 % of healthy groups, respectively. The prevalence of the virus was significantly related to minor elevation of AST and was higher in hemophilia type A (63.8 %) and severe type of disease (63.2 %). ConclusionThis study underscore the significant prevalence of the SENV virus in hemophilia patients, a particularly noteworthy finding compared to the healthy population. With the limited information available about this virus, our findings highlight the importance of continuous monitoring and follow-up of high-risk groups in relation to blood-borne pathogens, providing reassurance about the ongoing efforts in the field.

Pharmacokinetics of Efmoroctocog alfa by Two-Compartment Model Highlights Hemophilia A Patients with Biphasic Decay, Long Mean Residence Time, and Beta Half-Life.

Background/Objectives: A compartmental pharmacokinetics (PK) analysis of new extended half-life FVIII concentrates has never been performed in a large cohort of hemophilia patients. An improved PK analysis of individual outcomes may help to tailor hemophilia replacement treatment. Methods: PK outcomes after the infusion of a standard single dose of Efmoroctocog alfa were collected from 173 patients with severe/moderately severe hemophilia A in 11 Italian hemophilia centers. Factor VIII clotting activity (FVIII:C) was measured by one-stage clotting assay (OSA) in all patients, and chromogenic substrate assay (CSA) in a subgroup (n = 52). Fifty patients underwent a comparative PK assessment with standard half-life (SHL) recombinant FVIII (rFVIII) products. Non-compartmental analysis (NCA), one compartment model (OCM), and TCM were used to analyze the decay curves of all patients, and one-way paired ANOVA to compare the PK outcomes. Results: All 173 PKs conformed to the NCA and OCM, but only 106 (61%) conformed to the TCM based on the biphasic features of their decay curves. According to the TCM, the Beta HL and MRT of rFVIIIFc were 20.42 ± 7.73 and 25.64 ± 7.61 h, respectively. ANOVA analysis of the outcomes from the three PK models showed significant differences in clearance, half-life (HL), and mean residence time (MRT) (p < 0.001 for all parameters). As anticipated, the HL and MRT of rFVIIIFc were longer than those of SHL rFVIII. Comparing OSA with CSA outcomes, Cmax resulted higher when measured by CSA (p = 0.05) and, according to TCM, Beta HL resulted longer when measured by OSA (p = 0.03). FVIII:C trough levels obtained with SHL concentrates were significantly lower than those obtained with rFVIIIFc at each post-infusion time point. Conclusions: In a large group of hemophilia A (HA) patients, three different PK models confirmed the improved pharmacokinetic (PK) characteristics of rFVIIIFc, compared with standard half-life rFVIII concentrates. The TCM only fits two-thirds of the PKs, highlighting their biphasic decay and a long Beta half-life. In these patients, the TCM would be preferable to properly evaluate individual PK features.