Search

For several decades, therapeutic options for inherited deficiencies of factor VIII or IX (hemophilia A or B, respectively) have largely been the replacement of the missing clotting factor with plasma-derived or recombinant products. Hemostasis laboratories use standard activated partial thromboplastin time (aPTT)-based clotting or chromogenic assays to monitor plasma factor levels to guide therapy. The emergence in the past 10 years of extended half-life replacement products and other novel therapies for hemophilia has led to a reappraisal of assay suitability, with studies of product measurement showing some existing assay types or reagents to be unsuitable for some products. The hemostasis laboratory must adapt to the changing landscape by adding new assays or modifying existing assays to ensure accurate results for product measurement. These strategies include switching from a chromogenic assay to a clotting assay, or vice versa, changing an aPTT reagent brand, or introducing product specific calibrators. This article evaluates the effects of some of the newer treatment options on the laboratory testing of factor levels and related assays. [ABSTRACT FROM AUTHOR]

Patients with hemophilia frequently require supplementary interventions, either invasive (suturing, gel foam, or cauterization) or non-invasive (fibrin sealant/glue), to attain hemostasis post dental procedures. This study aimed to compare the efficacy of fibrin sealant against traditional methods for achieving hemostasis post dental surgery. The medical records of patients with factor VIII or IX deficiency, or von Willebrand disease, who underwent dental procedures in the Department of Dentistry, Seth GSMC and KEM Hospital, were evaluated for inclusion in this retrospective matched cohort study. Cohort-1 included those treated with a fibrin sealant (Tisseel Lyo) with/without traditional hemostatic measures post-procedure, while cohort-2 (controls) included those in whom no fibrin sealant was used. A total of 128 patients, 64 in each group, were evaluated. There was no statistically significant difference in demographics, disease-related variables, dental complaints, or preoperative treatment given between the groups. However, there was a significant reduction (P < 0.001) in the requirement for secondary procedures for hemostasis (suturing, gel foam application, and/or cauterization) and postoperative requirement for factor replacement (P = 0.003) in the fibrin glue group as compared to the controls. In this study, fibrin sealant demonstrated superior efficacy in mitigating the necessity for active hemostasis control. [ABSTRACT FROM AUTHOR]

Introduction Aim Methods Results Conclusion 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. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions The 24‐month, prospective, non‐interventional, European multicenter A‐SURE study evaluated the real‐world effectiveness of prophylaxis using an extended half‐life recombinant factor VIII (FVIII) Fc fusion protein, efmoroctocog alfa (hereinafter rFVIIIFc), compared with prophylaxis using standard half‐life (SHL) FVIII products in patients with hemophilia A.Primary endpoints were annualized bleeding rate (ABR), annualized injection frequency, and annualized factor consumption. A comparative study design unique for an observational hemophilia study was implemented to reduce potential confounding in effectiveness estimates, wherein each patient prescribed rFVIIIFc was matched with one receiving SHL FVIII. Propensity scores were used for adjustment in statistical analyses.Outcomes for all primary endpoints were significantly better in the rFVIIIFc group (n = 184) compared with the SHL FVIII group (n = 170): mean ABR 1.5 versus 2.3 (difference of −0.8; p = 0.0147); mean annualized injection frequency 114.4 versus 169.2 (difference of −54.8; p < 0.0001); and mean annualized factor consumption 243 024.2 versus 288 718.6 International Units (difference of 45 694.5; p = 0.0003). rFVIIIFc was well tolerated, with no inhibitor development.rFVIIIFc has superior prophylactic effectiveness versus SHL FVIII, providing higher bleed protection with fewer injections and lower factor consumption. [ABSTRACT FROM AUTHOR]

Background: Hemophilia is a rare X-linked bleeding disorder. Prophylaxis has improved outcomes, but there are still unmet needs to be addressed. The aim of this study was to develop a patient journey in pediatric patients with hemophilia, a visual tool that illustrates patients' relationship with the healthcare provider through time useful for identifying patient needs, potential concerns ("pain points"), and gaps in care. Methods: qualitative study in a pediatric hemophilia unit using a human-centered design methodology. First stage: discover and empathize: (a) semi-structured interviews to patients/families and stakeholders; (b) observation techniques ("shadowing") to patients/families and professionals. Second stage: analyzing the collected information to create the patient journey. Results: A preliminary "clinical journey" was built using information from eight interviews with professionals from the interdisciplinary hemophilia team. Interviews with patient association representatives, 13 patients/families, and six "shadowing" techniques with patients and professionals were used to compare the "clinical journey" with the patient's reported experience. Main "pain points" were detected before diagnosis, at diagnosis, during assimilation, at treatment initiation, during training, and when patients start asking about their condition. The empowerment process was detected as a potential moment to improve patient/family experiences. Conclusions: The patient journey helps to better understand patient/family experiences related to the disease in different scenarios. Caregivers and patient learning and empowerment processes are significant moments where the interdisciplinary team should focus to offer valuable solutions to improve outcomes. Further research is required in this area, particularly empirical research to amend or confirm the suggested patient journey. [ABSTRACT FROM AUTHOR]

Key Points women and girls were infrequently represented in haemophilia clinical trials intentional recruitment strategies are needed for haemophilia trials to be more inclusive of women and girls [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Patients with severe and sometimes moderate hemophilia B are prophylactically treated with factor IX concentrates to prevent bleeding. For some time now, various extended terminal half‐life (EHL) recombinant factor IX concentrates are available allowing less frequent administration during prophylaxis in comparison to standard half‐life recombinant FIX (rFIX). Especially, recombinant FIX‐Fc fusion protein (rFIXFc; Alprolix®) exhibits a rapid distribution phase, potentially due to binding to type IV collagen (Col4) in the extravascular space. Studies suggest that the presence of extravascular rFIXFc is protective against bleeding as without measurable FIX activity in plasma, and no extra bleeding seems to occur. The physiologically based pharmacokinetic (PBPK) model for rFIXFc which we describe in this study, is able to accurately predict the observed concentration‐time profiles of rFIXFc in plasma and is able to quantify the binding of rFIXFc to Col4 in the extravascular space after an intravenous dose of 50 IU/kg rFIXFc in a male population. Our model predicts that the total AUC of rFIXFc bound to Col4 in the extravascular space is approximately 19 times higher compared to the AUC of rFIXFc in plasma. This suggests that rFIXFc present in the extravascular compartment may play an important role in achieving hemostasis after rFIXFc administration. Further studies on extravascular distribution of rFIXFc and the distribution profile of other EHL‐FIX concentrates are needed to evaluate the predictions of our PBPK model and to investigate its clinical relevance. [ABSTRACT FROM AUTHOR]

Severe protein C deficiency (SPCD) is a rare inherited thrombotic disease associated with high morbidity and mortality. In the current study, we established a viable murine model of SPCD, enabling preclinical gene therapy studies. By creating SPCD mice with severe hemophilia A (PROC−/−/F8−), the multi-month survival of SPCD mice enabled the exploration of recombinant adeno-associated viral vector-PC (rAAV8-PC) gene therapy (GT). rAAV8- PC (1012 vg/kg of AAV8-PC) was injected via the tail vein into 6–8-week-old PROC−/−/F8- mice. Their plasma PC antigen levels (median of 714 ng/mL, range 166–2488 ng/mL) and activity (303.5 ± 59%) significantly increased to the normal range after GT compared to untreated control animals. PC's presence in the liver after GT was also confirmed by immunofluorescence staining. Our translational research results provide the first proof of concept that an infusion of rAAV8-PC increases PC antigen and activity in mice and may contribute to future GT in SPCD. Further basic research of SPCD mice with prolonged survival due to the rebalancing of this disorder using severe hemophilia A may provide essential data regarding PC's contribution to specific tissues' development, local PC generation, and its regulation in inflammatory conditions. [ABSTRACT FROM AUTHOR]

Objectives: Haemophilia B (HB), characterised by deficient factor IX (FIX), leads to spontaneous bleeds. Severe cases require prophylactic FIX replacement. This post hoc analysis assessed the first spontaneous bleeds among previously untreated patients (PUPs) with HB treated with recombinant FIX Fc fusion protein (rFIXFc) (NCT02234310) to identify factors influencing bleeds. Methods: Subjects included paediatric PUPs with HB (≤2 IU/dL endogenous FIX). Analyses described treatment patterns (on demand [OD] vs. prophylaxis) and prophylaxis type (started on vs. switched to prophylaxis). Kaplan–Meier analyses assessed the time to first spontaneous bleed, including median time to event and fitting models with predictors for treatment regimen and/or baseline age. Results: PUPs B‐LONG enrolled 33 subjects. Baseline age did not influence the time to first spontaneous bleed for any rFIXFc regimen. Those who started on prophylaxis with rFIXFc (n = 11), compared with those treated OD (n = 22), had an extended time to first spontaneous bleed. Starting prophylaxis afforded a 93% reduced risk of first spontaneous bleed versus starting OD (hazard ratio [95% confidence interval]: 0.071 [0.009–0.592]) (p =.015). Conclusion: rFIXFc prophylaxis, particularly starting early, reduced the risk of bleeding and delayed time to first spontaneous bleed compared with rFIXFc OD. Hence, initial treatment regimens impact bleed patterns in paediatric PUPs. [ABSTRACT FROM AUTHOR]

Since June 2021 in France, patients with haemophilia A with anti-factor VIII inhibitors and patients with severe haemophilia A without anti-factor VIII inhibitors have the choice between the community and the hospital pharmacy for dispensing emicizumab (Hemlibra®). This study aims to investigate patient-centred access to treatment by evaluating and comparing the dimensions of the Penchansky and Thomas model, between community and hospital pharmacies. The evaluation of access to treatment was based on the dimensions of the Penchansky and Thomas model: accessibility, availability, acceptability, accommodation and affordability. These were assessed using appropriate and specific indicators in the study context and calculated for patients choosing community pharmacy or hospital pharmacy for emicizumab dispensing. Geographical data collected as part of the national 'PASO DOBLE DEMI' study were used for this analysis. The findings reveal that dispensing emicizumab in community pharmacies improves accessibility by significantly reducing travel time. The availability of healthcare services is also improved due to the territorial coverage of community pharmacies. The extended opening hours and low waiting time also contribute to better access to emicizumab in community pharmacies. The dimension of acceptability must be improved, and further investigations are needed to address the affordability dimension. Several months after emicizumab became available in French community pharmacies, access to treatment has significantly improved, reducing the burden of this rare chronic disease for patients and their careers. These results suggest that this innovative model could be extended to other medicines and even other therapeutic areas. [ABSTRACT FROM AUTHOR]

Hemophilia B is an inherited hemorrhagic disorder characterized by a deficiency of blood coagulation factor IX (FIX) that results in abnormal blood coagulation. The blood coagulation is already evident in hemophiliacs at the fetal stage, and thus intracranial hemorrhage and other bleeding complications can occur at birth, leading to sequelae. Therefore, it is important to develop effective treatments for hemophiliacs in utero. In this study, in order to transplacentally deliver FIX from pregnant mice to their fetuses, an improved adenovirus (Ad) vector expressing human FIX fused with the IgG Fc domain (FIX Fc fusion protein), which plays a crucial role in neonatal Fc receptor (FcRn)-mediated transcytosis across the placenta, was intravenously administered to E13.5 pregnant mice. Significant levels of FIX Fc fusion protein were detected in 0-day-old newborn mice whose mothers were administered an Ad vector expressing FIX Fc fusion protein. Wild-type FIX overexpressed in the pregnant mice was not delivered to the fetuses. Plasma FIX levels in the newborn mice were relatively well correlated with those in their mothers, although transplacental delivery efficiencies of FIX Fc fusion protein were slightly reduced when the FIX Fc fusion protein was highly expressed in the mother mice. Plasma FIX levels in the newborn mice were about 3.6–6.4% of those in their mothers, Transplacental delivery of FIX Fc fusion protein to their fetuses successfully improved the blood clotting ability in the newborn mice. [Display omitted] • An improved adenovirus vector mediated efficient expression of FIX Fc fusion protein. • FIX Fc fusion protein, not wild-type FIX, was delivered from pregnant mice to fetuses. • Transplacental delivery of FIX to fetuses improved blood clotting ability in neonates. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Hemophilia A (HA) is an X-linked recessive bleeding disorder characterized by reduced or absent coagulation factor (F) VIII activity. The empirical evidence on the prevalence of HA in Africa has reported inconsistent findings and seems to present such a wide range of prevalence that it is hard to swiftly ascertain its average extent. Hence, this review aimed to pool the results of primary studies reporting the prevalence of HA into a single estimate in the region. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published in EMBASE, PubMed, Web of Science, SCOPUS, Science Direct, and Cochrane Library databases were searched. Observational studies revealing the prevalence of HA in Africa between 2010 and 2023 were incorporated. We assessed the quality of each study using the Newcastle-Ottawa quality assessment tool. The prevalence of HA was estimated as the cases (the sample size) per 100,000 population multiplied by 1000. To produce the pooled estimate, Der Simonian random-effects models were computed with Metaprop on the STATA command. The studies' heterogeneity was assessed using the I-squared (I2) value test and the Galbraith plot. A funnel plot was conducted to evaluate publication bias. Results: Of the 337 studies accessed, we included 15 that fulfilled the eligibility criteria. The random-effect model meta-analysis demonstrated the overall pooled prevalence of HA was 6.82 cases per 100,000 persons (95% confidence interval: 5.16, 8.48) with heterogeneity (I2 = 0.00%, p < 0.001). Conclusions: This systematic review and meta-analysis revealed that HA is an alarming problem that may pose a future threat to public health in Africa. Given the detrimental effects of the disease on health and the complications involved, we recommended that African regions increase patient access to factor VIII medication, improve carrier detection rates, and take the initiative toward the development and access to gene therapy. [ABSTRACT FROM AUTHOR]

Objective: To observe the joint lesions in patients with hemophilia A using conventional ultrasound, power Doppler imaging (PDI), and super-micro flow imaging (SMI) techniques, and evaluate the preventive treatment efficacy of different treatment regimens in hemophilia patients. Methods: Severe hemophilia A patients who were admitted to North China University of Science and Technology Affiliated Hospital were collected and divided into four groups according to different treatment regimens: Pharmacokinetics (PK) guided individualized preventive treatment group (group A), standard dose preventive treatment group (group B), low dose preventive treatment group (group C), and on-demand replacement treatment group (group D). Haemophilic Early Arthropathy Detection Results: As the treatment time increased, the HEAD-US-C scores in group A, B, and C decreased, with a more significant decrease in group A than group B and C, while there was an increase in group D. The AJBR in all four groups increased, with a more significant change in group D than the other three groups, and the change in group A was the lowest. There was a correlation between HEAD-US-C score and AJBR. Conclusion: Preventive treatment can slow down the progression of joint lesions in hemophilia patients, effectively alleviate joint inflammation and reduce bleeding times. PK guided individualized preventive treatment is superior to other preventive treatments and on-demand replacement treatment. The HEAD-US-C can be used to assess joints, which has certain application value for evaluating the therapeutic effect of hemophilia, providing imaging evidence for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and methodsResultsConclusionsTo evaluate the efficacy of an immersive movement visualization intervention in patients with hemophilia and hemophilic knee arthropathy.Randomized, single-blind clinical study. Twenty-eight patients with hemophilia were recruited. Patients were randomized to an experimental group (four weeks of immersive movement visualization) and a control group (no intervention). The intensity of pain, pressure pain threshold in the knee, tibialis anterior muscle, lower back level, conditioned pain modulation, range of knee motion, and lower limb functionality were evaluated.There were statistically significant differences in the intergroup effect on knee pain intensity (F = 23.71; p < 0.001) and lower limb functionality (F = 7.11; p = 0.003). 42.86% of the patients in the experimental group exhibited changes greater than the minimum detectable change (MDC) in functionality. 39.29% of the patients subject to the intervention experienced changes greater than the MDC in the knee pressure pain threshold.Immersive motion visualization can improve the intensity of joint pain and functionality in patients with hemophilic knee arthropathy. Functionality, pressure pain threshold, and pain intensity improved in those patients who conducted immersive movement visualization.Implications for rehabilitationImmersive visualization of movement significantly improves intensity of joint pain, functionality, pressure pain threshold, joint health, and conditioned pain modulation in patients with hemophilic knee arthropathy.The fact that it is a therapy without potential aversive stimuli makes it a possible access pathway for patients with high levels of kinesiophobia and/or catastrophism.This low-cost, home-based technology allows its use in patients far from hemophilia reference centers or with difficult access to physiotherapy treatments.The immersive visualization of movement influences the democratization of treatment, in accordance with the WHO's Sustainable Development Goal 3 (health and well-being for all).Immersive visualization of movement significantly improves intensity of joint pain, functionality, pressure pain threshold, joint health, and conditioned pain modulation in patients with hemophilic knee arthropathy.The fact that it is a therapy without potential aversive stimuli makes it a possible access pathway for patients with high levels of kinesiophobia and/or catastrophism.This low-cost, home-based technology allows its use in patients far from hemophilia reference centers or with difficult access to physiotherapy treatments.The immersive visualization of movement influences the democratization of treatment, in accordance with the WHO's Sustainable Development Goal 3 (health and well-being for all). [ABSTRACT FROM AUTHOR]

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product's optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences. [ABSTRACT FROM AUTHOR]

Introduction: Acquired haemophilia A (AHA) is a bleeding disorder caused by autoantibody development against factor VIII (FVIII). Studies on AHA have mainly focused on patients treated at specialist centres. Aim: To determine the incidence, clinical characteristics and outcomes of AHA in an unselected population‐based patient cohort from Finland. Methods: This retrospective observational cohort comprised all cases diagnosed with AHA in Finland between 2006 and 2019. Patients were identified by the two central laboratories performing FVIII antibody testing in Finland, the Finnish Red Cross Blood Service and HUSLAB. Clinical details were collected from all hospitals and healthcare units where patients were treated. This study was performed in conjunction with the AHA in the Nordics study. Results: The median incidence of AHA was 0.65 per million per year (range 0.19‐1.27). Fifty‐five patients were identified, with a median age of 76 years and an even sex ratio (51% women). When diagnosed, all had bleeding symptoms with severe bleeds in 92%. First‐line immunosuppressive treatment regimens included steroid monotherapy in 31% of cases, steroids and a cytotoxic agent in 51% and a rituximab‐based regimen in 16%. Clinical remission was achieved in 71% of cases, and 15% had relapses. Mortality was 13% for bleeds and 9% for treatment‐related infections. Overall survival was 64% for 1 year and 56% for 2 years after diagnosis. Conclusions: In a nationwide population‐based cohort study, we discovered a lower incidence of AHA than previously reported. Mortality among patients with AHA was high, calling for the consideration of updated treatment strategies. [ABSTRACT FROM AUTHOR]

Damoctocog alfa pegol (BAY 94-9027, Jivi®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate®/Adynovi®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences. [ABSTRACT FROM AUTHOR]

Improving bone health and preventing osteoporosis is an essential approach for hemophilia patients. Regarding precautions, the treatment model may affect bone health. To detect the effect of a treatment model (prophylaxis/on-demand treatment) on bone metabolism in patients with severe hemophilia A was the primary aim of this study. The biochemical markers of bone metabolism and bone mineral density were obtained from the patients enrolled in the study. No statistically significant differences were found between the groups due to the limitations of the prophylaxis group, such as adaptation problems, personal differences, and type of prophylaxis. [ABSTRACT FROM AUTHOR]

Despite the controversies regarding the appropriateness and justification of simultaneous bi- and multi-concomitant surgical procedures, this operative technique is increasingly undertaken for economic reasons. This paper discusses three cases of simultaneous interventions: two involving osteoarticular procedures and one involving a complex approach encompassing general and plastic surgery. The indications in emergency-driven cases are mandatory, life-saving, and limb-saving, and not subject to debate. [ABSTRACT FROM AUTHOR]

Background: This study aimed to conduct molecular diagnostics among individuals with hemophilia B (HB) and carriers of hemophilia in Mongolia. Methods: Eight patients (six severe, two mild) with HB and their 12 female relatives were enrolled from eight families. Sanger sequence was performed for mutation identification. The questionnaire survey was conducted to evaluate carrier symptoms in female relatives. Results: Two families had a history of HB. A total of five different variants (c.223C > T; c.344A > G; c.464G > C; c.187_188del; and c.1314_1314delA) were identified in six patients with severe HB. Of these, two (c.187_188del and c.1314_1314delA) were novel. No variant in the entire F9 was found in two patients with mild HB. Nonsense c.223C > T (p.Arg75*) mutation was detected in two unrelated patients. Carrier testing identified five mothers as carriers, while one younger sister was a non‐carrier. The carrier status of six female relatives of the two mild patients remained undetermined. By questionnaire survey, only one of the five genetically identified carriers displayed noticeable symptoms of being a carrier. Conclusion: The novel variants c.187_188del and c.1314_1314delA can cause severe hemophilia B. This study did not observe a significant association between symptoms and carrier status in the five carriers. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Acquired hemophilia A can upshot in a life‐threatening hemorrhage and airway obstruction. Airway bleeding is a weighty emergency in hemophilia care, necessitating the immediate start of effective hemostatic therapy (porcine factor VIII, the factor eight inhibitor bypassing activity and recombinant factor VIIa) and the decision to undertake proper airway control, such as tracheal intubation and tracheostomy. However, due to the dearth deficiency of effective hemostatic measures we relied upon the use of fresh frozen plasma and cryoprecipitate to gain control of the bleeding despite the precarious threat of infectious disease transmission associated with their use. [ABSTRACT FROM AUTHOR]

Intra-articular blood, iron and hemosiderin, hydroxyl radical cytokines, and neo-angiogenesis cause synovial inflammation, which leads to cartilage and joint damage. Platelet-rich plasma (PRP) inhibits most of the mediators that produce and maintain synovitis. We compile here our work showing the clinical effectiveness of intra-articular PRP injections and their potential role in stopping articular cartilage damage due to bleeding and its possible repair. A total of 116 joints, including knees (63%), elbows (19.8%), and ankles (17.2%), were treated with intra-articular injections of PRP. Moreover, we also show here the number of extracellular DNA traps (ETs) and the PRP effect in the synovial fluid of patients at the time of treatment and six months after. Clinically, it is demonstrated that PRP is effective in reducing bleeding episodes (p < 0.001) and pain (p < 0.0001) and improving the hemophilia joint health score (HJHS) (p < 0.001) at one year of follow-up. Furthermore, our results demonstrate that PRP inhibits ET formation in vitro and reconstitutes the immune system's cellular components in the synovial fluid of patients after treatment. We conclude that PRP can be considered an effective, safe, and easy treatment for hemophilic synovitis. [ABSTRACT FROM AUTHOR]

Adolescents with hemophilia are a patient population with special requirements, having to manage their condition alongside the typical challenges of adolescence. Given the psychosocial impact of hemophilia and a desire to fit in with non-hemophilic peers, they may perceive treatment as more of a burden than a benefit. This can result in low adherence and a high risk of hemophilia-related complications. Hemophilia management has changed over time. To best inform shared decision-making with adolescent patients and their families, healthcare professionals must consider all the currently available evidence, highlighting treatment benefits as appropriate. They should also appreciate the requirements of all adolescents affected by hemophilia, including individuals with non-severe disease and girls/women. We discuss specific issues relating to the management of adolescents with hemophilia: prevention and management of bleeds, treatment adherence, joint health and physical activity, and other health-related issues. A multidisciplinary approach is advocated, and the potential role of digital technology in helping to equip patients with self-management skills to fully engage with treatment is considered. Currently, available hemophilia management generally enables adolescents with hemophilia to lead normal lives, participating in physical activities while maintaining good joint health. However, more work is required to help address both actual and perceived limitations. [ABSTRACT FROM AUTHOR]

To explore how plyometric-based hydro-kinesiotherapy (Plyo-HKT) would affect pain, muscle strength, postural stability, and functional performance in a convenience sample of children with hemophilic knee arthropathy (HKA). Forty-eight children with HKA (age: 8–16 years) were randomly allocated to the Plyo-HKT group (n = 24; underwent the Plyo-HKT for 45 min, twice/week over 12 wk in succession) or the comparison group (n = 24; performed the standard exercise rehabilitation at an equivalent frequency and duration). Pain, peak concentric torque of quadriceps and hamstring (produced at two angular velocities: 120 and 180 o/sec), dynamic limits of postural stability (DLPS), and functional performance [Functional Independence Score in Hemophilia (FISH) and 6-Minute Walk Test (6-MWT)] were assessed pre- and post-intervention. In contrast with the comparison group, the Plyo-HKT group achieved more favorable pre-to-post changes in pain (p =.028, η2p = 0.10), peak torque of quadriceps [120°/sec (p =.007, η2P = 0.15); 180°/sec (p =.011, η2P = 0.13)] and hamstring [120°/sec (p =.024, η2P = 0.11); 180°/sec (p =.036, η2P = 0.09)], DLPSdirectional [forward (p =.007, η2P = 0.15); backward (p =.013, η2P = 0.12); affected side (p =.008, η2P = 0.14); non-affected side (p =.002, η2P = 0.20)], DLPSoverall (p <.001, η2P = 0.32), and functional performance [FISH (p <.001, η2p = 0.26); 6-MWT (p =.002, η2p = 0.19)]. Plyo-HKT is likely helpful for reducing pain, improving strength, enhancing postural stability, and boosting functional capabilities in children with HKA. Physical rehabilitation practitioners should, therefore, consider this intervention strategy. [ABSTRACT FROM AUTHOR]

This article discusses the detection of blood-borne pathogens in clotting factor concentrates from the 1970s and 1980s. The study found that concentrated coagulation factors derived from human blood donations during this time period were contaminated with viruses such as HIV-1 and hepatitis C. The authors used qPCR assays to test the clotting factor samples for various viruses and found that HCV, B19V, and HPgV-1 were the most frequently detected viruses. The study highlights the need for continued screening of blood products and the development of safer clotting products. [Extracted from the article]

Copyright of Ege Journal of Medicine is the property of Ege University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This study presents a detailed case analysis of a 40-year-old male patient with hemophilia A and severe chronic elbow arthropathy, exploring the surgical challenges and outcomes within the context of the current literature. The patient, with a history of multiple comorbidities including Hodgkin's lymphoma and cardiomyopathy, exhibited significant joint damage and functional impairment. A comprehensive approach was employed, collecting all relevant clinical data, including radiographic and MRI findings, to inform treatment decisions. Clinical findings and treatment decisions are presented as they occurred in real time, simulating the clinical reasoning process. Subsequent references to the clinical and instrumental findings as well therapeutic interventions are discussed in light of the current literature to reinforce the decision-making framework. This report underscores the importance of multidisciplinary care in optimizing patient outcomes and contributes to the ongoing discourse on the management of advanced musculoskeletal conditions in hemophilic patients. The findings emphasize the necessity for early intervention and specialized care to mitigate complications and improve long-term prognosis. [ABSTRACT FROM AUTHOR]

Improving bone health and preventing osteoporosis is an essential approach for hemophilia patients. Regarding precautions, the treatment model may affect bone health. To detect the effect of a treatment model (prophylaxis/on-demand treatment) on bone metabolism in patients with severe hemophilia A was the primary aim of this study. The biochemical markers of bone metabolism and bone mineral density were obtained from the patients enrolled in the study. No statistically significant differences were found between the groups due to the limitations of the prophylaxis group, such as adaptation problems, personal differences, and type of prophylaxis.

Abstract Background Hemophilia A (HA) is an X-linked recessive bleeding disorder characterized by reduced or absent coagulation factor (F) VIII activity. The empirical evidence on the prevalence of HA in Africa has reported inconsistent findings and seems to present such a wide range of prevalence that it is hard to swiftly ascertain its average extent. Hence, this review aimed to pool the results of primary studies reporting the prevalence of HA into a single estimate in the region. Methods We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published in EMBASE, PubMed, Web of Science, SCOPUS, Science Direct, and Cochrane Library databases were searched. Observational studies revealing the prevalence of HA in Africa between 2010 and 2023 were incorporated. We assessed the quality of each study using the Newcastle-Ottawa quality assessment tool. The prevalence of HA was estimated as the cases (the sample size) per 100,000 population multiplied by 1000. To produce the pooled estimate, Der Simonian random-effects models were computed with Metaprop on the STATA command. The studies’ heterogeneity was assessed using the I-squared (I2) value test and the Galbraith plot. A funnel plot was conducted to evaluate publication bias. Results Of the 337 studies accessed, we included 15 that fulfilled the eligibility criteria. The random-effect model meta-analysis demonstrated the overall pooled prevalence of HA was 6.82 cases per 100,000 persons (95% confidence interval: 5.16, 8.48) with heterogeneity (I2 = 0.00%, p

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

Katharine Batt,1,&ast; Robert Klamroth,2,&ast; Maria Elisa Mancuso,3,4,&ast; Andreas Tiede,5,&ast; Lorenzo G Mantovani6,7,&ast; 1Department of Internal Medicine, Section of Hematology/Medical Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA; 2Department for Internal Medicine, Vascular Medicine and Coagulation Disorders, Vivantes Hospital, Friedrichshain, Berlin, Germany; 3Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Italy; 4Humanitas University, Pieve Emanuele, Milan, Italy; 5Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 6Center for Public Health Research, University of Milano-Bicocca, Monza, Italy; 7Value-Based Healthcare Unit, IRCCS MultiMedica Research Hospital, Sesto San Giovanni, Italy&ast;These authors contributed equally to this workCorrespondence: Katharine Batt, Wake Forest University Baptist Medical Center, 1 Medical Center Blvd, Winston-Salem, NC, 27157, USA, Tel +1 919-593-6188, Email katharine.batt@aya.yale.eduAbstract: Hemophilia A is rare, which makes large, randomized, controlled, statistically driven, head-to-head comparison trials difficult. Matching-adjusted indirect comparisons (MAICs) are validated statistical tools designed to help make the results of non-comparative trials more comparable. The purpose of this commentary is to provide an insight into the MAIC method, in order to assist the hemophilia community with interpretation of MAIC data. It includes a comparison of the findings from previously published MAICs comparing recombinant factor replacement options and their methodologies. As MAICs are being used more often to compare treatment options for patients with hemophilia A, it is paramount that robust and consistent methodologies for cross-trial comparisons are used and that all efficacy analysis findings are linked to factor utilization.Keywords: hemophilia, MAIC, methodology

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

In the fields of medicine and bioscience, gene editing is increasingly recognized as a promising therapeutic approach for treating pathogenic variants in humans and other living organisms. With advancements in technology and knowledge, it is now understood that most genetic defects are caused by single-base pair variants. The ability to substitute genes using genome editing tools enables scientists and doctors to cure genetic diseases and disorders. Starting with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas, the technology has evolved to become more efficient and safer, leading to the development of base and prime editors. Furthermore, various approaches are used to treat genetic disorders such as hemophilia, cystic fibrosis, and Duchenne muscular dystrophy. As previously mentioned, most genetic defects leading to specific diseases are caused by single-base pair variants, which can occur at many locations in corresponding gene, potentially causing the same disease. This means that, even when using the same genome editing tool, results in terms of editing efficiency or treatment effectiveness may differ. Therefore, different approaches may need to be applied to different types of diseases. Prevalently, due to the safety of adeno-associated virus (AAV) vectors in gene therapy, most clinical trials of gene therapy are based on AAV delivery methods. However, despite their safety and nonintegration into the host genome, their limitations, such as confined capacity, dosage-dependent viral toxicity, and immunogenicity, necessitate the development of new approaches to enhance treatment effects. This review provides the structure and function of each CRISPR-based gene editing tool and focuses on introducing new approaches in gene therapy associated with improving treatment efficiency.

Long-term medication leads some people with HIV (PWH) to limited treatment options (LTO) due to multiple factors. The present study investigated the prevalence of PWH with LTO in Japan and their clinical characteristics, persistence, and adherence. PWH who received antiretroviral therapy (ART) between 2017 and 2022 were identified in the Medical Data Vision (MDV) Japanese claims database. PWH with LTO were defined as: 1) receiving regimens indicative for LTO or 2) having a complex treatment history (≥4 different core agents, ≥11 ART agents). Prevalence by calendar year, clinical characteristics, persistence, and adherence measured by the proportion of days covered (PDC) of ART were investigated. A total of 5740 PWH were included, and 207 (3.6 %) were identified as LTO. Mean (SD) age was 50.3 (11.8) years, 148 (71.5 %) had evidence of AIDS-defining condition, and 25 (12.1 %) had hemophilia. The prevalence of PWH with LTO increased from 2.58 % in 2017 to 3.55 % in 2022. Persistence at 1 year was estimated as 70.3 % and mean PDC through 1 year was 96.7 %. Between the years 2017–2022, 3.6 % (approximately 200) Japanese PWH were identified as having LTO. The results of this analysis found clinical characteristics of PWH with LTO as older age and higher percentages with an AIDS-defining condition and hemophilia than the general HIV population. Low persistence indicates that treatment optimization is required in this population. These results will help health care providers to understand the clinical characteristics of PWH with LTO and may contribute to the establishment of appropriate treatment strategies. [ABSTRACT FROM AUTHOR]

Objective Total hip arthroplasty (THA) effectively treats end‐stage hemophilic hip arthropathy. Given hemophilia's unique characteristics, perioperative bleeding remains a significant risk for patients undergoing THA. Tranexamic acid (TXA), an efficient antifibrinolytic agent, may benefit the outcomes of THA for patients with hemophilia (PWH). This study aims to explore the clinical efficacy of intra‐articular injection of TXA in treating perioperative bleeding in PWH and assess its additional clinical benefits. Methods The retrospective study comprised data of PWH who received THA from January 2015 to December 2021 in the research center. A total of 59 individuals were included in the study, divided into a TXA group (n = 31) and a non‐TXA group (n = 28). We compared various parameters, including total blood loss (TBL), visible blood loss (VBL), occult blood loss (OBL), intraoperative coagulation factor VIII (FVIII) consumption, perioperative total FVIII consumption, hemoglobin (HB), erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), length of hospital stay, hospitalization costs, length of surgery, total protein, activated partial thromboplastin time (APTT), D‐dimer, rate of joint swelling, hip joint range of motion (ROM), visual analogue scale (VAS), and Harris hip joint function scale (HHS) between the two groups. Follow‐up assessments were conducted for up to 24 months. A Student's t test was utilized for the statistical analysis. Results This study demonstrated that intra‐articular TXA effectively reduced TBL (1248.19 ± 439.88 mL, p

الملخص: أهداف البحث: يصاب حوالي شخص واحد من كل مليون شخص بالهيموفيليا المكتسبة. يعد التشخيص في الوقت المناسب أمرا بالغ الأهمية لإدارة المرض بطريقة مناسبة والوقاية من المضاعفات التي تهدد الحياة. قد يلجأ هؤلاء المرضى في البداية إلى أطباء غير متخصصين وقد يبقون غير مشخصين لسنوات عدة. يهدف هذا الإجماع إلى توفير إرشادات لجميع الممارسين في المملكة العربية السعودية لتشخيص وإدارة الهيموفيليا المكتسبة. طرق البحث: تعكس هذه البيانات الإجماعية الآراء التي تم صياغتها بواسطة مجموعة من أخصائيي أمراض الدم باستخدام عملية منهجية صريحة لتحديد مجالات الاتفاق والاختلاف. النتائج: يمكن استخدام هذا البيان الإجماعي كدليل لجميع الممارسين في المملكة العربية السعودية فيما يتعلق بتشخيص المظاهر السريرية، والعلاقة، وخصائص أعراض النزيف، وإدارة هذه الحالات، مع توجيه خاص للأخصائيين غير المتخصصين. سوف يناقش الإجماع جميع جوانب الإدارة، من التشخيص إلى أساليب العلاج. الاستنتاجات: قد يلجأ مرضى الهيموفيليا المكتسبة في البداية إلى أطباء يفتقرون إلى الخبرة المناسبة في تشخيص وإدارة هؤلاء المرضى. يوفر هذا البيان الإجماعي وثيقة مفصلة لتشخيص وإدارة الهيموفيليا المكتسبة، بتوجيه من أفضل الخبراء في المرض في المملكة العربية السعودية. Abstract: Objectives: Acquired hemophilia affects approximately one in 1 million people. Timely diagnosis is key to appropriate disease management and the prevention of life-threatening complications. Patients with this condition may initially be seen by inexperienced physicians and remain underdiagnosed for several years. This consensus statement is aimed at providing guidelines for all practitioners in the Kingdom of Saudi Arabia (KSA) to diagnose and manage acquired hemophilia A. Methods: This consensus statement reflects the opinions drafted by a group of hematology specialists, who used an explicit systematic process to identify areas of agreement and disagreement. Results: This consensus statement provides a guide for all practitioners in the KSA regarding the diagnosis of clinical presentation, relevance, characteristics of bleeding symptoms, and case management; it additionally provides guidance for non-specialists. All management aspects, including diagnosis and treatment modalities, are discussed. Conclusions: Patients with acquired hemophilia may initially be seen by physicians who lack appropriate expertise in diagnosing and managing this condition. This consensus statement from the premier experts on the disease in the KSA provides details for diagnosing and managing acquired hemophilia.

Introduction Aim Methods Results Conclusions Both men and women can be diagnosed with haemophilia and the experience with haemophilia may be different between men and women.This study aimed to compare patient‐reported outcomes in men versus women with haemophilia.This cross‐sectional study is a post‐hoc analysis of data collected as part of the Haemophilia‐related Distress Questionnaire validation study. Adults aged ≥18 years with haemophilia A or B were recruited from one of two haemophilia treatment centres between July 2017 and December 2019. Outcomes included quality of life, measures of mental and physical health, and overall health. Unadjusted and multivariable linear regression models were used to examine potential mediators of sex‐based differences in outcomes.Of the 139 study participants included (21 women, 118 men), the mean age was 36.9 years and most (89.2%) had haemophilia A. Approximately 85.7% and 26.3% of women and men had mild haemophilia, respectively.  PHQ‐9 depression and PROMIS‐29 Profile anxiety and fatigue scores were significantly higher in women than men in unadjusted and adjusted analyses. There were no statistically significant differences in other outcomes.Women with haemophilia are more likely to experience depression, anxiety, and fatigue than men with haemophilia. This study highlights the need for mental health services to be integrated into the care of women with haemophilia. Future research is needed to understand whether women with haemophilia are more or less likely to experience depression, anxiety, and fatigue than women without haemophilia as well as determine the impact of reduced mental health on clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Coagulopathies can manifest on a spectrum, from minor mucosal bleeding to life-threatening hemorrhage. Minor cases can be discovered in the setting of known risk factors, such as malignancy, old age, immunosuppression. However, acquired hemophilia A diagnosed after a snake bite is of lesser-known incidence and can present in a more acute, potentially life- or limb-threatening fashion. To properly diagnose this coagulopathy, one must be familiar with the related signs, symptoms, and laboratory findings so that swift diagnosis can follow. Diagnosis is key for early proper management, as displayed in the following case. Case Report: Our case report details a male patient presenting with diffuse bruising after a snake bite. Initially, on presentation to outside facilities, the diagnosis of acquired hemophilia A was not found. However, upon worsening of bruising in the setting of previous treatments initiated for the patient, he presented to our facility, where he subsequently received a diagnosis with acquired hemophilia A. He developed compartment syndrome due to excessive bleeding, requiring surgical intervention. With proper diagnosis, his bleeding diathesis was corrected with multiple rounds of repletion of factors and immunosuppression. His follow-up laboratory test results and examinations have shown continued resolution of his symptoms. Conclusions: As acquired hemophilia A is less often linked with snake bites, this case highlights the importance of considering this disease process as a differential in patients with bleeding diathesis after a snake bite. The coagulation dysfunction can be severe, and, as such, early identification of this diagnosis leads to more targeted and effective therapy [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Classical hemophilia A, an X-linked recessive disorder, is characterized by an inability to produce factor VIII in normal quantities. This condition, also leading to factor IX deficiency, underpins the bleeding disorder known as hemophilia A. Among the complications of this illness, spontaneous retroperitoneal hematoma is rare but can be associated with congenital coagulopathies such as von Willebrand disease or hemophilia A. This type of spontaneous internal bleeding has been the subject of a limited number of studies. Case Report: A 38-year-old man with a known diagnosis of hemophilia A presented to the Emergency Department exhibiting acute pain in the right lower abdomen. A computed tomography scan of the abdomen identified a rightsided retroperitoneal mass, suspected to be a hematoma. Within 7 h after admission, the patient experienced significant drops in the hemoglobin level and platelet count. He was administered packed red blood cells, fresh frozen plasma, and platelet transfusions prior to transfer to the Intensive Care Unit. There, he was treated with factor VIII and recombinant factor VIIa, coupled with stringent monitoring. Following clinical and laboratory findings and stabilization, he was discharged with specific medications, and a follow-up appointment was scheduled. Conclusions: Spontaneous retroperitoneal hematoma in patients with hemophilia A is a rare and grave emergency. This case underscores the need for precise diagnostic approaches, tailored management strategies, and vigilant surveillance to prevent and mitigate the potentially life-threatening complications associated with spontaneous hemorrhage in this population. [ABSTRACT FROM AUTHOR]

Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the second quarter of 2024 through the first quarter of 2025 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 52 novel drugs awaiting US Food and Drug Administration approval. New cellular and gene therapies for cancers continued to strengthen the pipeline, in addition to new drugs targeting previously untreatable conditions. Several novel drugs are being developed for rare and ultra-rare diseases such as hemophilia, Niemann-Pick disease type C, hereditary angioedema, and aromatic l -amino acid decarboxylase deficiency. Conclusion The current drug pipeline includes new drugs with various indications for cancers and rare diseases as well as diabetes, acute coronary syndrome, chronic skin disorder, and chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

Background: Patients with Hemophilia are continually monitored at treatment centers to avoid and control bleeding episodes. This study estimated the direct and indirect costs per patient with hemophilia A in Brazil and evaluated the cost variability across different age groups. Methods: A prospective observational research was conducted with retrospective data collection of patients assisted at three referral blood centers in Brazil. Time-driven Activity-based Costing method was used to analyze direct costs, while indirect costs were estimated based on interviews with family and caregivers. Cost per patient was analyzed according to age categories, stratified into 3 groups (0–11;12–18 or older than 19 years old). The non-parametric Mann-Whitney test was used to confirm the differences in costs across groups. Results: Data from 140 hemophilia A patients were analyzed; 53 were 0–11 years, 29 were 12–18 years, and the remaining were older than 19 years. The median cost per patient per year was R$450,831 (IQR R$219,842; R$785,149; $174,566), being possible to confirm age as a cost driver: older patients had higher costs than younger's (p = 0.001; median cost: 0–11 yrs R$299,320; 12–18 yrs R$521,936; ≥19 yrs R$718,969). Conclusion: This study is innovative in providing cost information for hemophilia A using a microcosting technique. The variation in costs across patient age groups can sustain more accurate health policies driven to increase access to cutting-edge technologies and reduce the burden of the disease. Highlights: This study provides cost data, measured with microcosting methodology, for Hemophilia A patients in an LMIC, demonstrating how costs are sensible to the patient's age. The results showed the importance of considering patients' clinical and demographic characteristics to establish adequate reimbursement policies driven to reduce the health impact of the disease, due to the cost variability observed. Brazil has one of the biggest hemophilia A populations, and based on the cost measured, the financial burden associated with this condition is estimated to be R$ 5,19 billion yearly. [ABSTRACT FROM AUTHOR]

Multiple Coagulation Factor Deficiency (MCFD) is an uncommon haematological disorder characterised by simultaneous deficiency of multiple clotting factors, which leads to an increased risk of bleeding and compromised haemostasis. The present series aimed to provide a comprehensive analysis of MCFD, shedding light on its aetiology, clinical manifestations, and potential therapeutic interventions in a case-by-case manner, highlighting the individualised treatment options that are needed for many of these cases. A prospective combined clinical and laboratory study was performed on all patients who presented with bleeding tendencies and were subsequently diagnosed with MCFD. Clinical records and laboratory data of all these patients were reviewed to identify commonalities and variations among affected individuals. Haematological assays were performed to quantify the extent of coagulation factor deficiencies. The present series identified a diverse cohort of eight individuals (2 females and 6 males) with MCFD, showcasing variability in age of onset, severity of symptoms, and potential underlying genetic mutations. Clotting factor assays revealed deficiencies of Factor V and Factor VIII (F5F8D), Vitamin K-dependent clotting factor deficiency, and failure of synthesis of clotting factors of hepatic origin. Clinically, patients presented with a spectrum of bleeding phenotypes, ranging from mild to severe, requiring tailored therapeutic strategies. The present series provides an overview of some of the presentations of MCFD, emphasising the need for a multidisciplinary approach in its diagnosis and management. Clinicians should be vigilant in recognising the varied clinical presentations of MCFD and consider genetic testing for precise diagnosis and management. [ABSTRACT FROM AUTHOR]

(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. [ABSTRACT FROM AUTHOR]

Hemophilia A is an X-linked disorder characterized by quantitative deficiency of coagulation factor VIII (FVIII) caused by pathogenic variants in the factor 8 (F8) gene. Our study's primary objective was to identify genetic variants within the exonic region of F8 in 50 Colombian male participants with severe hemophilia A (HA). Whole-exome sequencing and bioinformatics analyses were performed, and bivariate analysis was used to evaluate the relationship between identified variants, disease severity, and inhibitor risk formation. Out of the 50 participants, 21 were found to have 17 different pathogenic F8 variants (var). It was found that 70% (var = 12) of them were premature truncation variants (nonsense, frameshift), 17.6% (var = 3) were missense mutations, and 11.7% (var = 2) were splice-site variants. Interestingly, 35% (var = 6) of the identified variants have not been previously reported in the literature. All patients with a history of positive inhibitors (n = 4) were found to have high-impact genetic variants (nonsense and frameshift). When investigating the relationship between variant location (heavy versus light chain) and specific inhibitor risk, 75% (n = 3) of the inhibitor participants were found to have variants located in the F8 light chain (p = 0.075), suggesting that conserved domains are associated with higher inhibitor risk. In summary, we identified genetic variants within the F8 that can possibly influence inhibitor development in Colombian patients with severe HA. Our results provide a basis for future studies and the development of further personalized treatment strategies in this population. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Recommendations advise factor IX desensitization before immune tolerance induction in severe hemophilia B, supported by immunosuppression. A child with inhibitor and anaphylaxis to factor IX showed successful immunosuppression‐free immune tolerance induction using very low and slowly increasing doses of a factor IX extended‐half‐life product. Immune tolerance to factor IX based on this protocol merits further study. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathies frequently associate with hemostatic alterations. Thrombotic events occur with high incidence particularly upon treatment, while in rarer cases hemorrhagic diathesis can be observed. The pathology of these tendencies could be caused by thrombocytopenia or hyperviscosity burden of circulating monoclonal antibodies. Studies also suggest interference of monoclonal antibodies with primary hemostasis. We isolated monoclonal whole IgG paraproteins from two myeloma patients to observe their effect on thrombin formation and fibrin polymerization. Monoclonal whole IgG was prepared from sera of two newly diagnosed untreated multiple myeloma patients and control normal plasma samples. Fibrin formation was measured using thrombin time and dilute prothrombin time tests and thrombin formation was detected with a fluorimetric thrombin generation assay. In addition, molecular interactions were investigated by surface plasmon resonance (SPR). Thrombin time was prolonged upon addition of monoclonal IgG even at 30 g/L by 12 %, increasing up to 36 % at 60 g/L concentration. Dilute prothrombin time was prolonged by 20 % even at 30 g/L. Thrombin generation assay indicated an impairment in thrombin formation at the presence of monoclonal IgG compared to polyclonal at equivalent concentration. By an SPR assay we determined that both clonality IgG preparations interacted with fibrinogen, however interaction with human thrombin was only detected with monoclonal immunoglobulins (KD=1.03 × 10-7 M). Here we provide evidence that isolated monoclonal whole IgG from myeloma patients can impair both fibrin and thrombin formation and we demonstrate by SPR assay that it interacts with components of the final phase of the coagulation system. [ABSTRACT FROM AUTHOR]

Objective: To review efficacy and safety data of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparavovec (Hemgenix), novel gene therapies for the treatment of the life-threatening bleeding disorders hemophilia A and B, respectively. Data Sources: A PubMed/Google Scholar search from inception through August 11, 2023 was conducted using the following keywords: gene therapy, hemophilia A, hemophilia B, etranacogene dezaparavovec, valoctocogene roxaparvovec, and bleeding. Study Selection and Data Extraction: Data, including phase 1 to 3 clinical trials (non-comparator), were obtained from primary literature and package inserts. These reports evaluated clinical pharmacology, efficacy, safety, adverse events, warnings, and precautions. Data Synthesis: Valoctocogene phase 3 study in males (n = 134): 87% had factor VIII (FVIII) levels that at least met criteria for mild hemophilia. Etranacogene phase 3 study in males (n = 54): within 3 weeks of infusion, mean factor IX (FIX) levels had reached 26.8 IU/dL. Both therapies provided clinically and statistically significant decreases in bleeding events and prophylactic factor infusions. Most common adverse event was elevations in liver function tests that were treated with glucocorticoids. Relevance to Patient Care and Clinical Practice in Comparison with Existing Drugs: The endogenous production of clotting factors mimics physiological production while decreasing morbidity and mortality related to bleeding events similar to the effects of existing replacement strategies. Gene therapy was also shown to increase patient quality of life. Conclusion: Valoctocogene and etranacogene provide another treatment for selected patients with hemophilia. Treatment for the patient with hemophilia (gene therapy vs replacement strategy) must be personalized as new clinical data are published being cognizant of drug affordability. [ABSTRACT FROM AUTHOR]

Background: Haemophilia A (HA; Factor VIII deficiency) is a congenital X-linked bleeding disorder characterized by trauma-related or spontaneous bleeding events, most notably arising within the intraarticular space and resulting in chronic inflammation and degeneration of affected joints. Endogenous clotting factor activity relative to normal levels determines the severity of HA symptoms, as mild (> 5–40%), moderate (1–5%), or severe (< 1%). Within the current environment of rapid evolution in HA management, we seek to understand the interplay of condition severity and health-related quality of life (HRQoL) to characterise and differentiate unmet needs among people with HA (PwHA). Methods: A generalised linear regression model (GLM) was developed to explore the relationship between HA severity and EQ-5D-5 L index score from adult HA patients sampled in the "Cost of Haemophilia across Europe – a Socioeconomic Survey II" (CHESS II) cross-sectional, retrospective burden of illness study among adults with hereditary haemophilia A or B from eight European countries. HA patients of any severity with no active inhibitors during the 12 months prior to data capture and a completeEQ-5D-5 L response were included. A base GLM model was specified with covariates for demographic and clinical characteristics (age, body mass index, country, employment, HA severity, annual bleeding rate, problem joints, and chronic pain). Results: Of 381 evaluable patients, 221 (58.0%) had severe HA, 96 (25.2%) had moderate HA, and 64 (16.8%) had mild HA. Among the covariates included in the GLM model and after controlling for haemophilia-related outcomes, a significant association was observed between mild HA and higher EQ-5D-5 L index score (average marginal effects, 0.084; p = 0.016) relative to severe HA. Patient country of residence and magnitude of HA-related chronic pain were also associated with significant differences in index scores, with the latter showing a negative relationship with HRQoL outcomes. Conclusions: Condition severity and chronic pain are significant predictors of HRQoL in PwHA. Durable bleeding protection and effective management of chronic pain have the potential to address unmet treatment needs in this population. [ABSTRACT FROM AUTHOR]