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The novel mixed-matrix membrane (MMMs) by incorporating covalently amino groups grafted nano-silica (Amino-NP) into an eco-friendly, organic solvent-free waterborne polyurethane (OSF-WPU) matrix for the separation application of CO2/N2. This investigation focused on the gas permeance and separation performance of the MMMs. The optimized CO2/N2 separation factor reached 8. 2 1 ± 0. 4 7 , with a CO2 permeance of 1 6. 7 2 ± 1. 0 2 GPU under conditions of 1.0 bar and 25∘C in a wet mixed-gas state. Incorporating even a tiny amount of Amino-NP efficiently enhanced CO2 permeability and CO2/N2 selectivity. OSF-WPU/Amino-NP MMMs demonstrated superior performance, emphasize their potential for stable long-term operation in practical CO2 separation applications. [ABSTRACT FROM AUTHOR]

Background: Patients with hemophilia A can develop joint hemarthroses, degenerative changes, and eventually undergo total shoulder arthroplasty (TSA). Few data exist concerning complications and prosthesis survival after TSA in this population. Questions/purposes: (1) Is hemophilia A associated with more bleeding and thromboembolic adverse events after TSA relative to matched controls? (2) Is 5-year TSA prosthesis survival reduced in patients with hemophilia A compared with matched controls? Methods: The 2010 to 2022 PearlDiver M161 database was used to identify patients who underwent primary anatomic or reverse TSA. Given that the X-linked recessive condition hemophilia A presents nearly exclusively in males, male patients with hemophilia A who underwent TSA were matched 1:10 with male patients without hemophilia who underwent TSA based on age and Elixhauser comorbidity index (ECI). This yielded 73 patients with hemophilia A who underwent TSA who were matched 1:10 with 729 patients without hemophilia. Ninety-day adverse events were compared with multivariable analysis. Revision within 5 years was assessed using Kaplan-Meier analysis. Results: Compared with the control cohort, patients with hemophilia had greater odds of bleeding issues (hematoma, OR 6.8 [95% CI 3.0 to 15.3]; p < 0.001; anemia, OR 2.5 [95% CI 1.5 to 4.2]; p < 0.001, transfusion, OR 5.0 [95% CI 2.4 to 10.3]; p < 0.001), venous thromboembolic events (VTE) (OR 1.9 [95% CI 1.1 to 3.1]; p = 0.01), and prosthetic loosening (OR 3.5 [95% CI 1.4 to 8.0]; p = 0.004). Based on available data, 5-year implant survival was not different in patients with hemophilia (97.3% [95% CI 93.6% to 100.0%]) relative to matched controls (95.2% [95% CI 93.4% to 97.2%]; p = 0.60). Conclusion: The elevated risks of both 90-day bleeding complications (hematoma, anemia, and transfusion) and VTE (DVT and PE) in patients with hemophilia emphasize the special challenges of carefully balancing factor replacement and VTE prophylaxis pre-, intra-, and postoperatively on an individual patient basis with careful hematologist coordination. Further study on Factor VIII levels and targets as well as tranexamic acid and VTE prophylaxis in this population is necessary to provide further guidance. Furthermore, 5-year implant survival was not different between patients with hemophilia and matched controls (patients without hemophilia) based on available data, suggesting that TSA survivorship remains durable and may be offered to patients in this population as indicated. Level of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

The mainstay of treatment for persons with hemophilia A (PwHA) with severe bleeding phenotype is prophylaxis. The pharmacokinetic (PK) profile of native factor VIII (FVIII) imposes the need for rather frequent intravenous injections to ensure effective prophylaxis, but this represents a relevant treatment burden and is associated with suboptimal adherence to treatment. In this light, the advent of extended half-life (EHL) FVIII molecules has improved prophylaxis feasibility and outcomes by favoring treatment individualization and tailoring protection according to specific clinical and nonclinical needs. Different technologies have been used to enhance FVIII PK properties including Fc-fusion and conjugation with polyethylene glycol. Data from clinical development programs for such molecules, together with growing real-world experience, have shown numerous benefits related to the use of EHL FVIII in PwHA. Recently a new class of ultra-long-acting EHL FVIII has been developed to further improve protection against bleeding episodes and achieve the ambitious goal of providing PwHA with hemostatic protection in the nonhemophilia range over longer time periods, hence ensuring very low bleeding rates and improving joint health and quality of life. In this review, the achievements and perspectives of replacement therapies for PwHA are summarized and discussed. [ABSTRACT FROM AUTHOR]

Non-factor replacement therapies (NFTs) have been developed to address the limitations of conventional replacement therapies, aiming to improve hemostasis and provide enhanced protection against bleeding episodes and long-term joint damage for patients both with and without inhibitors. Factor VIII (FVIII)-mimetic agents, such as emicizumab, have transformed the management of hemophilia A with inhibitors, offering a lower treatment burden and an effective alternative for those without inhibitors as well. Rebalancing agents, including anti-tissular factor pathway inhibitor agents (concizumab and marstacimab) and serpin inhibitors like fitusiran, have shown promising efficacy for patients with hemophilia B with inhibitors and other hemophilia subtypes. Administered subcutaneously, NFTs generate stable thrombin levels and feature a long half-life, which can shift severe hemophilia toward a milder phenotype. These therapies are effective regardless of inhibitor status and hold potential for application in other bleeding disorders. Evaluating the potential thrombotic risk after implementing mitigation measures, along with the development of anti-drug antibodies (ADAs), remain critical areas for further analysis. NFTs pose additional challenges due to their complex mechanism of action and the absence of a standardized laboratory assessment method. Unresolved issues include optimal management strategies for major surgeries and tailored approaches for safe use in older populations. This review highlights the progress and future potential of NFTs in treating persons with hemophilia. [ABSTRACT FROM AUTHOR]

Strides in advancements of care of persons with hemophilia include development of long-acting factor replacement therapies, novel substitution and hemostatic rebalancing agents, and most recently approved gene therapy. Several decades of preclinical and clinical trials have led to development of adeno-associated viral (AAV) vector-mediated gene transfer for endogenous production of factor VIII (FVIII) in hemophilia A (HA). Only one gene therapy product for HA (valoctocogene roxaparvovec) has been approved by regulatory authorities. Results of valoctocogene roxaparvovec trial show significant improvement in bleeding rates and use of factor replacement therapy; however, sustainability and duration of response show variability with overall decline in FVIII expression over time. Further challenges include untoward adverse effects involving liver toxicity requiring immunosuppression and development of neutralizing antibodies to AAV vector rendering future doses ineffective. Real-life applicability of gene therapy for HA will require appropriate patient screening, infrastructure setup, long-term monitoring including data collection of patient-reported outcomes and innovative payment schemes. This review article highlights the success and development of HA gene therapy trials, challenges including adverse outcomes and variability of response, and perspectives on approach to gene therapy including shared decision-making and need for future strategies to overcome the several unmet needs. [ABSTRACT FROM AUTHOR]

People with nonsevere hemophilia (PWNSH) are phenotypically more diverse than those with severe hemophilia. Perceptions relating to a "nonsevere" phenotype have contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance and clinical assessment for affected individuals. In many cases, episodes of abnormal bleeding could, if investigated, have led to earlier diagnosis. Furthermore, the major recent developments in therapy for hemophilia have largely focused on severe disease and, as a group, PWNSH have not been included in many key clinical trials. Benefiting people with severe disease, innovative replacement therapies have generally targeted factor levels that are above those present in a large proportion of PWNSH. Therapeutic advances can lead to improvement in phenotype for people with severe hemophilia over that currently experienced by many PWNSH. As a result, we are approaching a point where PWNSH may, in many countries, have a higher risk of bleeding and restriction in lifestyle than those with severe disease but with more limited therapeutic options. Given the multiple major advances in treatment for people with hemophilia, it is timely to review the aspects of nonsevere disease, to ensure equity in care and management for all individuals with this condition. [ABSTRACT FROM AUTHOR]

The American Society of Hematology–International Society on Thrombosis and Haemostasis–National Hemophilia Foundation–World Federation of Hemophilia 2021 International Guidelines (IGL) on von Willebrand disease (VWD) have pointed out many challenges, mainly in the diagnostic approach of VWD patients. To determine the impact of these IGL on the current clinical and laboratory diagnosis of Italian VWD patients, we have recently conducted a survey among 43 centers affiliated with the Italian Association of Hemophilia Centers (AICE). Directors and colleagues responsible for the management of VWD patients were invited to report in a detailed questionnaire how IGL recommendations about the assessment of the specific activities of von Willebrand Factor (VWF) could be applied at their local sites. Results from such a survey showed that bleeding assessment tools, VWF antigen, and factor VIII procoagulant are currently in use in all centers. The automated assays for platelet-dependent VWF activity with or without ristocetin described in IGL have been used since 2021 in 37/43 (86%) centers. Among other laboratory tests, VWF collagen binding, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF:FVIII binding assay were available in 49, 63, 26, 7, and 28% of AICE, respectively. Analyses of VWF gene defects are available only at 3/43 (7%) centers. Desmopressin (DDAVP) infusion trials at diagnosis, with measurements of VWF activities at 1 and 4 hours post-DDAVP, is currently performed at 38/43 (88%) centers. Based on this information, a simplified clinical diagnosis using a few automated tests before and after DDAVP has been proposed. Such a diagnostic approach will be validated prospectively in a large cohort of Italian VWD patients. [ABSTRACT FROM AUTHOR]

Nonregular fractional factorial designs are a preferable alternative to regular resolution IV designs because they avoid confounding 2‐factor interactions. As a result, nonregular designs can estimate and identify a few active 2‐factor interactions. However, due to the sometimes complex alias structure of nonregular designs, standard factor screening strategies can fail to identify all active effects. We report on a screening technique that takes advantage of the alias structure of these nonregular designs. This alias‐informed‐model‐selection (AIMS) technique has been used previously for a specific 6‐factor nonregular design. We show how the AIMS technique can be applied to 7‐ and 8‐factor nonregular designs, completing the exposition of this method for all 16‐run 2‐level designs that are viable alternatives to standard Resolution IV fractional factorial designs. We compare AIMS to three other standard analysis methods for nonregular designs, stepwise regression, the lasso, and the Dantzig selector. AIMS consistently outperforms these methods in identifying the set of active factors. [ABSTRACT FROM AUTHOR]

Background Severe hemophilia A is managed with factor VIII replacement or hemostatic products that stop or prevent bleeding. Data on gene therapy with hematopoietic stem-cell (HSC)–based expression of factor VIII for the treatment of severe hemophilia A are lacking. Methods We conducted a single-center study involving five participants 22 to 41 years of age with severe hemophilia A without factor VIII inhibitors. Autologous HSCs were transduced with CD68-ET3-LV — a lentiviral vector including a new F8 transgene (ET3) with a myeloid-directed CD68 promoter — either without transduction enhancer (group 1) or with transduction enhancer (group 2). Transduced HSCs were transplanted into recipients after myeloablative conditioning. The treatment was assessed for safety (engraftment and regimen-related toxic effects) and efficacy (factor VIII activity and annualized bleeding rate). Results Participants received CD68-ET3-LV–transduced autologous CD34+ HSCs at doses of 5.0×106 to 6.1×106 per kilogram of body weight. The vector copy numbers in the final drug product were 1.0 and 0.6 copies per cell for the two participants in group 1 and 1.5, 0.6, and 2.2 copies per cell for the three participants in group 2. The duration of severe neutropenia was 7 to 11 days and of severe thrombocytopenia was 1 to 7 days. The median factor VIII activity level, measured with the use of a one-stage assay, after day 28 until the last follow-up visit was 5.2 IU per deciliter (range, 3.0 to 8.7) and 1.7 IU per deciliter (range, 1.0 to 4.0) with a peripheral-blood vector copy number of 0.2 and 0.1 copies per cell, respectively, in the two group 1 participants, and 37.1 IU per deciliter (range, 18.3 to 73.6), 19.3 IU per deciliter (range, 6.6 to 34.5), and 39.9 IU per deciliter (range, 20.6 to 55.1) with a peripheral-blood vector copy number of 4.4, 3.2, and 4.8 copies per cell, respectively, in the three group 2 participants. The annualized bleeding rate was zero for all five participants over a cumulative follow-up of 81 months (median follow-up, 14 months; range, 9 to 27). Conclusions Gene therapy for hemophilia A with the use of lentiviral vector–transduced autologous HSCs resulted in stable factor VIII expression, with factor VIII activity correlating to vector copy number in the peripheral blood. [ABSTRACT FROM AUTHOR]

Retinal vein occlusion (RVO) is the leading cause of vision loss due to an obstruction in the retinal venous system. While RVO is often linked to thrombotic tendencies and coagulation abnormalities, the exact role of coagulation traits in its development is not fully understood. This study aims to investigate the potential causal relationship between coagulation traits and the risk of RVO by analyzing publicly available genome-wide association study (GWAS) summary statistics. A two-sample Mendelian randomization (MR) analysis framework was employed to investigate the causal relationship between coagulation traits and the risk of RVO. Stringent quality control measures were applied to select appropriate instrumental variables strongly linked to exposure, such as coagulation factor III (FIII), coagulation factor V (FV), coagulation factor VIII (FVIII), coagulation factor XI (FXI), coagulation factor VII (FVII) and coagulation factor X (FX), as well as plasmin, platelet count, platelet crit (PCT), mean platelet volume (MPV), and platelet distribution width (PDW). The study utilized the FinnGen project RVO GWAS summary statistics cohort, consisting of 372 RVO cases and 182,573 controls. The analysis focused on 11 coagulation traits. The research suggests that genetically predicted plasma levels of FIII, FVII, MPV, and PCT may be potentially causative for reducing the risk of RVO, and that levels of FVIII may be potentially causative for increasing the risk of RVO. Our MR analysis, utilizing GWAS data from a comprehensive population-based study, revealed a causal association between plasma levels of FIII, FVII, FVIII, MPV, and PCT with the risk of RVO. [ABSTRACT FROM AUTHOR]

Amniote skulls are diverse in shape and skeletal composition, which is the basis of much adaptive diversification within this clade. Major differences in skull shape are established early in development, at a critical developmental interval spanning the initial outgrowth and fusion of the facial processes. In birds, this is orchestrated by domains of Shh and Fgf8 expression, known as the frontonasal ectodermal zone (FEZ). It is unclear whether this model of facial development applies to species with diverse facial skeletons, especially species possessing a skull morphology representative of early amniotes. By investigating facial morphogenesis in the lizard, Anolis sagrei, we show that reptilian skull development is driven by the same genes as mammals and birds, but the manner in which those genes regulate facial development is clade-specific. These genes are not expressed in the frontal-nasal prominence, the region of the avian FEZ. Downregulating Shh and Fgf8 signaling disrupts normal facial development, but in pathway-specific ways. Our results demonstrate that early facial morphogenesis in lizards does not conform to the FEZ model. Lizard skull development may be more representative of the ancestral amniote than other model species with highly derived facial skeletons suggesting that the FEZ may be an avian-specific novelty. The function of two genes, Sonic hedgehog and Fibroblast growth factor 8, have changed greatly during amniote facial evolution. The expression of these genes can explain variation in the proportion of the facial skeletal elements among species. [ABSTRACT FROM AUTHOR]

Hemophilia A (HA) is associated with FVIII coagulation insufficiency or inactivity leading to excessive bleeding. Elevated FVIII, on the contrary, is associated with thrombophilia, thrombosis, myocardial infarctions, and stroke. Active FVIII (aFVIII) uses its C2 domain to bind to blood cells' membranes, consequently carrying out its coagulative function. We developed a reliable flow cytometry (FC) method for FVIII detection that can be utilized for assessing surface-bound FVIII on leukocytes in different coagulation/clinical states; we analyzed 49 pediatric subjects, encompassing patients with HA, other coagulopathies, venous thrombosis, and normal coagulation. Interestingly, the total leukocyte surface FVIII showed a declining trend across thrombosis, normal, and hypo-coagulation states. As expected, the leukocytes of HA patients displayed significantly lower levels of cellular-surface FVIII in comparison to patients with thrombosis. However, no significant correlation was observed between circulating levels of FVIII in plasma and the levels of FVIII bound to leukocytes, indicating that the differences in FVIII surface binding are not directly proportional to the availability of FVIII in the circulation and suggesting a specific binding mechanism governing the interaction between FVIII and leukocytes. Intriguingly, when analyzing the distinct blood subpopulations, we observed that surface FVIII levels were significantly elevated in classical monocytes of thrombosis patients compared to HA patients, healthy controls, and patients with other coagulopathies. Our study highlights the reliability of our FC platform in assessing FVIII abundance on leukocytes' membranes across coagulation states. Monocytes, particularly in cases of thrombosis, exhibit active binding of FVIII on their surface, suggesting a potential role in the pathophysiology of thrombosis that requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Clinical research has offered many definitions and fragmented perspectives of joint morbidity in haemophilia. As joint damage, pain and mobility impairment can be present without clinical record of persistent bleeding, a person-centric joint morbidity characterisation remained a priority for the haemophilia community, giving rise to the 'problem joint' concept. As diagnosing and managing joint morbidity is critical, the aim of this study was to analyse the holistic burden of problem joints in people with moderate or severe haemophilia A (HA). Data from the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS) cross-sectional studies were used. CHESS-Paediatrics included male paediatric patients (≤ 17 years) with congenital moderate or severe haemophilia, while CHESS II included adult males (≥ 18 years) of any severity. Both studies sought to collect detailed information on the clinical, economic and humanistic burden of haemophilia. Demographics, clinical outcomes, treatment regimen, adherence, physical activity, healthcare resource use and number of problem joints were evaluated and described by HA severity and number of problem joints (none, 1, ≥ 2). Results: In total, 1171 people with non-inhibitor moderate or severe HA from CHESS-Paediatrics (n = 703) and CHESS II (n = 468) were included in this analysis. Presence of problem joints was more prevalent among CHESS II participants (44%) than in CHESS-Paediatrics (14%). Around two-thirds (67%) of CHESS-Paediatrics and 39% of CHESS II participants received prophylactic factor VIII replacement therapy. The presence of chronic pain was greater in severe HA with ' ≥ 2' problem joints in both cohorts. Clinical symptoms and bleed-related hospitalizations were more prevalent in the presence of problem joints regardless of HA severity in both cohorts. Conclusions: This analysis of the CHESS population studies has expanded on previous work by examining the relevance of the problem joint measure of haemophilic morbidity and its associated burden. Adverse clinical symptoms and increased bleed-related hospitalizations were observed in the presence of problem joints in both children/adolescents and adults across HA severities. Use of person-centric characterizations of joint morbidity may improve analysis of long-term outcomes and lead to improvements in future haemophilia care. [ABSTRACT FROM AUTHOR]

This perspective discusses the critical role of laboratory assessments in assessing factor VIII (FVIII) inhibitors. These are auto- and alloantibodies that can develop against both endogenous and exogenous FVIII, respectively. Assessment for inhibitors represents a key part of the management of both congenital hemophilia A (CHA), an inherited deficiency, and acquired hemophilia A (AHA), an autoimmune condition. Both conditions pose significant bleeding risks, necessitating careful monitoring of FVIII levels and inhibitor presence and level. Laboratory assays, particularly the Bethesda assay, are essential for detecting these inhibitors and assessing their levels. The complexities of FVIII inhibitor kinetics may pose challenges to interpretation of assay results, such that even normal FVIII levels do not always exclude inhibitor presence. Clinical practice guidelines recommend ongoing monitoring of AHA/CHA patients until inhibitors are no longer detectable. Overall, timely laboratory evaluations are essential to optimizing treatment strategies for patients with hemophilia, aiming to improve patient outcomes and quality of life. We summarize our approach to the laboratory assessment of FVIII inhibitors, as reflecting our perspective and as informed by local practice. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies. [ABSTRACT FROM AUTHOR]

Context Studies describing the coagulation profile in adrenal adenomas still need to be added. Objective We explored how sex and mild autonomous cortisol secretion (MACS) affect coagulation parameters in patients with adrenal adenomas. Design Cross-sectional study. Methods From January 2019 until April 2023, participants in the Impact of Adrenal IncidenTalomas and Possible Autonomous Cortisol Secretion on Cardiovascular and Metabolic Alterations trial (NCT04127552) diagnosed with adrenal adenoma were categorised according to the 1 mg overnight dexamethasone-suppression test (1 mg-DST). Coagulation parameters were evaluated, and two-way ANOVA was used to elucidate the cortisol-by-sex interaction. Results Of 153 patients screened, 90 were enrolled (62.2% female, mean age 62 ± 10 years): 41 with non-functioning adrenal tumour (1 mg-DST ≤ 1.8 µg/dL), and 49 with a MACS (1 mg-DST > 1.8 µg/dL). Platelet counts were higher in the MACS group (P =.01). Regression analysis identified female sex (B = 36.603, P =.011), 1mg-DST (B = 0.238, P =.042), and younger age (B = −1.452, P =.038) as independent predictors for elevated platelet count. In patients with MACS, women exhibited higher levels of procoagulant factors fibrinogen (P =.004) and factor VIII (P <.001), and coagulation inhibitors protein C (P =.003) and antithrombin III (P =.005) than males. No differences were observed in the non-functioning adrenal tumour group, providing a cortisol-by-sex interaction regarding fibrinogen (P =.047), factor VIII (P =.046), and protein C (P =.028). Conclusion Our findings revealed a worse coagulation profile in women with MACS, underscoring the need for a sex-specific approach in clinical practice to manage thrombotic risks effectively. Dedicated prospective studies are needed to validate and integrate these findings into clinical strategies for thromboprophylaxis. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Trial Registration Subcutaneous emicizumab, a factor VIII (FVIII)‐mimicking bispecific monoclonal antibody, can effectively prevent bleeds in haemophilia A (HA) patients with/without inhibitors; however, its standard‐dose regimens are financially burdensome. Low‐dose emicizumab prophylaxis may alternatively be applied to noninhibitor HA patients in resource‐limited settings.During 2023, Thai patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype (historical annualized bleeding rate [ABR] >5 bleeds/year before regular FVIII prophylaxis) who received low‐/intermediate‐dose FVIII secondary prophylaxis ≥8 months were enrolled. After the 4‐day washout period, low‐dose emicizumab prophylaxis (2.0–2.5 mg/kg every fortnight for two loading doses, then every 4 weeks) was implemented for 8 months. Pre‐/post‐emicizumab ABR, annualized joint bleeding rates (AJBR), haemophilia joint health scores (HJHS) and haemophilia‐specific quality‐of‐life (QoL) scores were analysed. Emicizumab plasma levels on modified one‐stage FVIII assays were also monitored.In 15 subjects, ABR (median of differences, −2 bleeds/year; interquartile range, −3 to 0; p = 0.002), but not AJBR (p = 0.07), were reduced after switching to low‐dose emicizumab prophylaxis, although the pre‐dose emicizumab plasma levels at the steady state, achieved since week 12, were modest (median monthly level, 8.4 µg/mL; interquartile range, 4.3–10.4). Concurrently, HJHS (p = 0.008) and QoL score (p < 0.001) were decreased, and 46.7% had zero bleeds while receiving low‐dose emicizumab.Low‐dose emicizumab, compared to low‐/intermediate‐dose FVIII secondary prophylaxis, meaningfully improves bleeding prevention, joint health and QoL in patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype. This regimen potentially helps address previously unmet needs in HA care among low‐to‐middle‐income countries.ClinicalTrials.gov identifier NCT06155955. [ABSTRACT FROM AUTHOR]

Hemophilia A (HA) patients under emicizumab prophylaxis may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction (ITI). The aim of this study is to evaluate the ex vivo procoagulant effect of plasma-derived FVIII concentrates containing von Willebrand factor (pdFVIII/VWF) in samples from patients with severe HA without inhibitors on emicizumab prophylaxis. Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10–400 IU/dL) (Fanhdi®/Alphanate®, Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Global coagulation was measured by rotational thromboelastometry (ROTEM) (clotting time [CT] and time to maximum clot formation velocity [MAXV-t]) and thrombin generation (TG) assay (thrombin peak [TP] and endogenous thrombin potential [ETP]). Samples from HA patients under emicizumab prophylaxis showed CT and MAXV-t values above HC levels, while TP and ETP were below HC levels. Ex vivo pdFVIII/VWF supplementation increased TP and ETP and shortened CT and MAXV-t dose-dependently. At 50 IU/dL (≈25 IU/kg), pdFVIII/VWF normalized clot formation and restored TG within HC normal range. The highest pdFVIII/VWF concentration (400 IU/dL) and rFVIIa did not result in an excessive procoagulant profile. However, aPCC induced ex vivo an excessive TG and markedly decreased ROTEM parameters (CT and MAXV-t). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Aim Methods Results Conclusion Acquired haemophilia A (AHA) is characterized by the development of autoantibodies against factor VIII, reducing its activity and potentially resulting in bleeding.To assess the characteristics of people with AHA undergoing rehabilitation and/or with low activities of daily living (ADL) scores, thereby characterizing unmet needs in the management of AHA and informing treatment optimization.ORIHIME II, the largest epidemiological and treatment survey of AHA in Japan, is a descriptive, retrospective, observational study conducted using health claims data from April 2008 to October 2021. The primary outcome measures were rehabilitation practice and ADL scores on hospital admission and discharge; use of haemostatic agents and immunosuppressive therapy were also assessed.Overall, 427 patients in Japan were eligible for the study. Median (Q1–Q3) age was 78.0 (70.0–84.0) years; 264 patients (61.8%) were male. Median (Q1–Q3) time to start rehabilitation was 9 (4–21) and 14 (6–31) days for those with an admission ADL score of <85 and ≥85, respectively. Of the 427 patients, 249 underwent rehabilitation. The most common rehabilitation type was for disuse syndrome; haemostatic agents were more commonly used in patients undergoing earlier rehabilitation.The physical condition of the patient at hospitalization was associated with rehabilitation practice and the ability of the patient to perform day‐to‐day activities independently. Treatment strategies should be optimized to allow initiation of rehabilitation as early as possible in the course of AHA. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusion To report the long‐term safety and efficacy of BAY 81‐8973 in the LEOPOLD Kids extension phase.Patients received BAY 81‐8973 (25–50 IU/kg) at least twice weekly. The primary endpoint was safety, assessed in all patients who entered the extension phase (n = 82). Efficacy endpoints were assessed in patients without high‐titre inhibitors/immune tolerance induction (n = 67).Children (n = 82) received BAY 81‐8973 for a median of 3.1 years per patient and a median of 405 exposure days per patient. Long‐term BAY 81‐8973 treatment was well tolerated, with no cases of de novo inhibitor development in the extension phase. Annualised bleeding rates (ABRs) within 48 h of prophylaxis were low for all bleeds (median [IQR], 0.7 [0–1.9]; mean, 1.4 [SD, 2.1]) and for joint bleeds (median [IQR], 0 [0–0.7]; mean, 0.5 [SD, 1.1]) (n = 67). Twenty‐one of 67 patients (31.3%) had zero bleeds within 48 h of prophylaxis; the treatment response was ‘good’/‘excellent’ in 87.9% of bleeds, and most bleeds resolved with ≤ 2 BAY 81‐8973 infusions (83.5%).Long‐term BAY 81‐8973 treatment is well tolerated and maintains low ABRs for all bleeds and joint bleeds in children with severe haemophilia A.Trial Registration: ClinicalTrials.gov identifier: NCT01311648 [ABSTRACT FROM AUTHOR]

ABSTRACT Hematology laboratories have traditionally monitored hemophilia replacement therapy by measuring coagulation factors before and after infusion. However, new drugs that do not rely on the replacement of the deficient factor require new approaches to laboratory monitoring, as factor VIII (FVIII) or factor IX (FIX) assays are no longer adequate. Non‐factor therapies come in many different forms, that have one thing in common: they all increase thrombin generation. Their main adverse effect is thrombosis which may occur when too much thrombin is formed. This is the perfect mirror image of anticoagulant treatment, which always diminishes the amount of thrombin formed and has bleeding as its main adverse effect. Thrombin‐forming capacity is decreased in congenital bleeding disorders and increased in prothrombotic conditions, indicating it governs bleeding and thrombosis. Therefore, the thrombin generation assay (TGA) is a logical tool for monitoring non‐factor therapies, offering a comprehensive assessment of hemostatic balance. TGA identifies patients with severe bleeding, helps to optimize bypassing therapy, and detects hypercoagulability, making it ideal for guiding and monitoring hemophilia treatment with non‐factor therapies. It also assesses the efficacy and safety of combined therapies, including non‐factor therapies with bypassing agents or FVIII/FIX concentrates. The purpose of this paper is to review the current state of knowledge regarding the use of TGA to monitor novel hemophilia therapies. It will address controversies, limitations, and knowledge gaps related to the integration of TGA into personalized medicine in routine clinical practice. [ABSTRACT FROM AUTHOR]

Hemophilia is a recessively inherited genetic disorder that causes abnormalities in the blood clotting process, which can lead to bleeding that is difficult to stop. One of the rare but significant complications of hemophilia is hemophilia pseudotumor, which occurs in 1-2% of hemophilia A and B patients. This study aims to analyze and evaluate the management of pseudotumor hemophilia. This study aims to analyze and evaluate the management of hemophilia pseudotumor in pediatric patients, focusing on the case of an 8-year-old boy who developed a pseudotumor in the left hand area due to hemophilia A. This case involves a boy with a history of hemophilia A who developed swelling of the left hand after experiencing trauma. Diagnosis was done through clinical examination, radiology (Xray and MRI), and hematology evaluation. Treatment was factor VIII therapy, tranexamate, and amputation, as well as rFVIIa for bleeding prevention. The patient showed improved function after left hand amputation. Although conservative management can be considered for newly formed pseudotumors, in this case, a surgical approach was necessary due to the significant size and complications. Hemophilic pseudotumors can cause damage to surrounding tissues and require a multidisciplinary approach for management. Hemophilic pseudotumor is a rare but serious complication in people with hemophilia. Appropriate management, including surgical intervention, can improve the functional outcome of patients, despite the significant risks involved. Further research is needed to develop more effective treatment protocols. [ABSTRACT FROM AUTHOR]

Cardiac surgery poses a significant risk of perioperative bleeding and allogeneic blood transfusions, particularly in patients with bleeding disorders. Increasingly frequent use of coagulation factor concentrates could impact haemorrhagic risks, thromboembolic events, and costs. We describe the use of coagulation factor concentrates and allogeneic blood products in cardiac surgical patients with hereditary and acquired bleeding disorders to assess pertinent outcomes, including perioperative haemorrhage, thromboembolism, and hospital costs. We conducted a retrospective cohort study using the Premier Health Database, including adult cardiac surgical patients diagnosed with hereditary or acquired bleeding disorders compared with those without bleeding disorders. Patients with acquired bleeding disorders required more extensive use of coagulation factor concentrates and blood products compared with those with hereditary bleeding disorders or without bleeding disorders. The highest exposures to coagulation factor concentrates were found in the acquired bleeding disorders group, with 24% receiving factor VIIa and 11.7% receiving prothrombin complex concentrate. This group also experienced significantly higher rates of complications, including a 15.8% rate of haemorrhage and a 19.2% rate of thromboembolic events. The acquired bleeding disorders group had longer intensive care and hospital stays, and the highest mortality rate (19.2%). The increased use of perioperative replacement of factor VIII and factor IX in the hereditary bleeding disorders group led to increased pharmacy costs but did not significantly impact blood bank charges. Acquired bleeding disorders in cardiac surgery patients are associated with increased use of haemostatic interventions, postoperative complications, and increased healthcare costs. Improved management of perioperative haemostasis and thromboprophylaxis strategies are essential for optimising patient outcomes and reducing expenses. [ABSTRACT FROM AUTHOR]

Background: Variants within factor VIII (F8) are associated with sex-linked hemophilia A and thrombosis, with gene therapy approaches being available for pathogenic variants. Many variants within F8 remain variants of uncertain significance (VUS) or are under-explored as to their connections to phenotypic outcomes. Methods: We assessed data on F8 expression while screening the UniProt, ClinVar, Geno2MP, and gnomAD databases for F8 missense variants; these collectively represent the sequencing of more than a million individuals. Results: For the two F8 isoforms coding for different protein lengths (2351 and 216 amino acids), we observed noncoding variants influencing expression which are also associated with thrombosis risk, with uncertainty as to differences in females and males. Variant analysis identified a severe stratification of potential annotation issues for missense variants in subjects of non-European ancestry, suggesting a need for further defining the genetics of diverse populations. Additionally, few heterozygous female carriers of known pathogenic variants have sufficiently confident phenotyping data, leaving researchers unable to determine subtle, less defined phenotypes. Using structure movement correlations to known pathogenic variants for the VUS, we determined seven clusters of likely pathogenic variants based on screening work. Conclusions: This work highlights the need to define missense variants, especially those for VUS and from subjects of non-European ancestry, as well as the roles of these variants in women's physiology. [ABSTRACT FROM AUTHOR]

The present study is aimed to explore the therapeutic attributes of diosgenin against atherosclerosis and associated health disorder. Side effects associated with synthetic drugs for the treatment and management of diseases worldwide have necessitated scientists to investigate and evaluate the therapeutic potential of phytochemicals and their pharmacological activities. Plants including Smilax China, Dioscorea alata, and the Trigonella foenum graecum are rich sources of diosgenin. In addition to being a crucial component in the creation of several steroidal medications, this bioactive phytochemical has shown great promise in the treatment of a wide range of diseases, including cancer, hypercholesterolemia, inflammation, and multiple infections. Diosgenin can reduce hyperlipidemia by lowering the amount of low-density lipoproteins, interfering with the absorption of cholesterol and increasing its excretion. Diosgenin inhibits the expression of NPCIL1 receptor, LXR-alpha, HMG CoA and SRB1, increases expression of ABC G5/G8 transporters to prevent dietary cholesterol accumulation in the body. Diosgenin exhibits antithrombotic activity by inhibiting platelet activation, and modulating anti coagulation by significantly decreasing factor Viii activity. Diosgenin inhibits the oxidation of LDLs, hence preventing atherosclerosis. It also possesses antithrombotic activity by inhibiting pancreatic lipase activity. Diosgenin provides anti-inflammatory benefits to the human body. It inhibits inflammatory markers including Interlukin-1 beta (IL-1β), Tumor necrosis factor – alpha (TNF-α), Nitric Oxide and cytokines. Moreover, it promotes the synthesis of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase. By modifying the IKKβ pathway, it reduces endothelial damage linked to insulin resistance. This review discusses the recent advancements to explore diosgenin potential in reducing atherosclerotic cardiovascular diseases, diabetes, cancer, inflammation, clinical application, pharmacokinetics underlying mechanism with existing scientific evidences. [ABSTRACT FROM AUTHOR]

Objectives: Acquired hemophilia A (AHA) is a rare autoimmune disorder that presents with spontaneous bleeding due to the development of autoantibodies against coagulation factor VIII. This study aims to highlight the challenges in diagnosing and treating AHA, particularly through presenting two cases managed with rituximab, an anti-CD20 antibody, to demonstrate its safety and efficacy as a treatment option. Methods: Two male patients, aged 38 and 68, with significant bleeding episodes and prolonged activated partial thromboplastin time (aPTT), were evaluated. Both patients received standard care, including factor VIII replacement and corticosteroids. Due to persistent symptoms, rituximab was administered weekly for four weeks, and follow-up assessments were performed to monitor factor VIII levels, aPTT, and clinical symptoms. Results: Both cases showed improvement with rituximab. In Case 1, a 38-year-old male with idiopathic AHA achieved normal factor VIII levels and aPTT, with complete resolution of symptoms and no recurrence. In Case 2, a 68-year-old male with congenital hemophilia A and superimposed AHA responded positively to rituximab, showing stabilized factor VIII levels and no further bleeding episodes at a six-month follow-up. Discussion: The management of AHA is complex due to its rarity and severe bleeding risks. Although corticosteroids and bypassing agents are primary treatments, rituximab is emerging as a promising therapeutic option. Current literature supports rituximab for patients with contraindications to first-line agents or poor prognosis, yet further studies are required to assess its potential as a first-line treatment. Conclusion: These cases emphasize the efficacy and safety of rituximab in managing AHA. Given its potential benefits, further randomized controlled trials are warranted to evaluate rituximab's role as a first-line treatment. A structured monitoring protocol is recommended to ensure safe administration and manage potential side effects associated with immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Objectives: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. Methods: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. Results: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69–10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. Discussion: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. Conclusion: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan. [ABSTRACT FROM AUTHOR]

Objective: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia. Methods: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t1/2), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used. Result: Compared with standard-collected blood samples, prolonged APTT results (P-values < 0.01) and decreased FVIII activity (P-values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P < 0.0001) and FVIII-S level(r = 0.68, P < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = −0.24, P < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t1/2, lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group. Conclusion: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance. [ABSTRACT FROM AUTHOR]

Objectives: To describe clinical characteristics, factor consumption, and events of interest in patients with haemophilia A without inhibitors receiving prophylaxis in France, and the clinical impact of switching to Elocta® in this population. Methods: This retrospective, observational study using the Système National des Données de Santé database, analysed data from patients with haemophilia A without inhibitors using prophylactic factor VIII (FVIII) replacement therapy during 2016–2019. Clinical characteristics, treatment patterns and switches, factor consumption, and rate of events of interest were determined. In a sub-cohort of patients treated with Elocta®, clinical characteristics, factor consumption, and rate of events of interest before and after switching to Elocta® were compared. Results: For 545 patients, with mean age (standard deviation [SD]) 25.4 (17.8) years, Elocta® was the most used treatment. Bleeding events and articular non-bleeding events leading to hospitalization occurred in 15.4% and 13.9% of patients, respectively, and 9.9% of patients had surgeries or procedures related to haemophilic arthropathy. The mean (SD) FVIII product consumption was 344 (93) IU/kg/month for extended half-life treatment, and 331 (98) IU/kg/month for standard half-life products. For the sub-cohort of 146 patients, bleeding events (SD) decreased from 0.32 (2.2) to 0.09 (0.42) events/patient/year (p = 0.227) after switching to Elocta®. There was no statistically significant difference in rates of factor consumption or articular non-bleeding events before and after initiation of Elocta®. Conclusion: This study provides real-world insights that advance the understanding of treatment patterns and events of interest in patients with haemophilia A on prophylactic regimens in France. [ABSTRACT FROM AUTHOR]

Objectives Cryoprecipitated antihemophilic factor (cryo) has been used for fibrinogen replacement in actively bleeding patients, dysfibrinogenemia, and hypofibrinogenemia. Cryo has a shelf life of 4 to 6 hours after thawing and a long turnaround time in issuing the product, posing a major limitation of its use. Recently, the US Food and Drug Administration approved Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex [IFC]) for the treatment of bleeding associated with fibrinogen deficiency, which can be stored at room temperature and has a shelf life of 5 days after thawing. Methods We identified locations and specific end users with high cryoprecipitate utilization and waste. We partnered with our blood supplier to use IFC in these locations. We analyzed waste and turnaround time before and after implementation. Results Operative locations had a waste rate that exceeded nonoperative locations (16.7% vs 3%) and were targeted for IFC implementation. IFC was added to our inventory to replace all cryo orders from adult operating rooms, and waste decreased to 2.2% in these locations. Overall waste of cryoprecipitated products across all locations was reduced from 8.8% to 2.4%. The turnaround time for cryoprecipitated products was reduced by 58% from 30.4 minutes to 14.6 minutes. Conclusions There has been a substantial decrease in waste with improved turnaround time after IFC implementation. This has improved blood bank logistics, improved efficiency of patient care, and reduced costly waste. [ABSTRACT FROM AUTHOR]

Backround: Patients with hemophilia A can develop inhibitors to factor concentrates. Emicizumab, a nonfactorbased therapy, has efficacy despite inhibitors. FVIII activity assessment on emicizumab treatment requires a bovine chromogenic reagent such as TriniCHROM FVIII:C. Methods: FVIII levels were measured in 15 patients with and 35 without hemophilia and 10 patients on emicizumab therapy with a time-to-clot and the TriniCHROM FVIII:C reagents. FVIII inhibitor levels were also determined with both reagents. Results: Acceptable agreement of FVIII and FVIII inhibitor levels were obtained with the 2 reagents (R² = 0.92 and 0.96, respectively) in patients not exposed to emicizumab. The time-to-clot FVIII assay overestimated FVIII levels in patients on emicizumab therapy. The chromogenic FVIII assay delivered accurate endogenous FVIII levels in patients on emicizumab therapy. Conclusions: The TriniCHROM FVIII:C assay is compatible with routine automated coagulation analysers and delivers accurate FVIII and FVIII inhibitor levels. [ABSTRACT FROM AUTHOR]

It is very difficult to identify the genetic variation of haemophilia A. We examined a case report from a sizable, uncommon haemophilia family, analysing the application of DHPLC in the diagnosis of haemophilia A. The comprehensive clinical data and laboratory assessments of the proband within the family were meticulously compiled. Subsequent to this, tests were conducted to evaluate the activated partial prothrombin time (APTT) and the clotting activity of coagulation factor VIII (F VIII: C). Polymerase chain reaction (PCR) techniques were employed to identify any inversions within the F8 gene's introns 22 and 1. Thereafter, direct sequencing methodology was utilised to sequence all exons of the F8 gene. To analyse the copy number variations across all exons of the F8 gene, a multiple PCR combined with denaturing high‐performance liquid chromatography (DHPLC) approach was adopted. In addition, specific pathogenic mutations predisposing to progenitor cell disorders were screened in family members. The APTT of the proband was 60 s. F VIII: C is < 1%. It was found that the progenitor F8 gene exon 14 had a 226 bp insertion sequence, which was of unknown origin and was a pathogenic mutation. The analysis combined with this family situation is consistent with the expectation. The mutation was used as the detection target to complete the prenatal diagnosis. The pathogenic mutation found in this family is a rare large fragment insertion mutation. It is necessary to combine multiple experimental methods to improve the success rate of genetic diagnosis of haemophilia A. [ABSTRACT FROM AUTHOR]

Angiosarcoma of the thyroid gland is a very rare and aggressive mesenchymal tumor with destructive behavior, characterized by high mortality rates. We presented the cyto-histopathological findings of an angiosarcoma case of primarily thyroid origin. A 39-year-old female patient was presented with thyroid tumor appeared as hemorrhagic, non-encapsulated, with focal cystic nodules. Histological appearance of the tumor included vascular-like spaces lined with large epithelioid cells staining positively with factor VIII, CD31. These vascular-like spaces contained erythrocytes. Retrospective cytology showed that malignant endothelial cells were arranged in loosely cohesive clusters. These cells had abundant cytoplasm, distinct nucleoli, irregular contoured and hyperchromatic oval nuclei. This is one of rare cases of primary thyroid angiosarcoma with sufficient cytological material, showing macroscopic and histopathological findings with liquid-based cytology. For the diagnosis of thyroid primary angiosarcoma in aspiration, cytological findings should be evaluated with immunohistochemical methods or, if possible, together with histopathological findings. [ABSTRACT FROM AUTHOR]

Importance: Emicizumab (EMI) is efficacious and safe for hemophilia A (HA) prophylaxis. However, its high cost poses a challenge in China. Objective: To explore the possibility of using reduced‐dosage EMI in Chinese HA children. Methods: We conducted a retrospective study for HA children in our Comprehensive Care Center. Data were collected pre‐ and post‐EMI treatment to evaluate bleeding rates. Laboratory analyses included factor VIII (FVIII)‐like activity and EMI concentration measurements. Results: Thirty‐four HA children receiving EMI prophylaxis for a median (range) 24.5 (2.5–47.9) months by June 2023. Of these, 25 (73.5%) were under 3 years of age, 26 (76.5%) had severe hemophilia and 12 (35.3%) were minimally treated or previously untreated patients. Thirty‐one (91.2%) of the 34 patients received reduced‐dosage EMI for economic reasons. EMI concentration and FVIII‐like activity measured showed a strong correlation. Overall, while on EMI, their annual treated bleeding rate (ATBR) and annual bleeding rate (ABR) decreased significantly (2–0) while their zero‐bleeding rate (ZBR) increased significantly (11.5%–65.4%). After 6 months of EMI, there was no significant difference in ATBR and ABR among various maintenance dosages. However, ZBR was significantly lower in dosages under 4 mg/kg (P = 0.0156). Receiver operator characteristic curves suggested the following cutoff values for zero bleeding: EMI 4‐weekly maintenance dosage 3.8 mg/kg, EMI concentration 48.1 μg/mL, and FVIII‐like activity 15.4 IU/dL. Interpretation: We showed EMI effectively prevented bleeding even at reduced dosages. However, the bleeding risk may be higher with EMI 4‐weekly maintenance dosage <3.8 mg/kg, EMI concentration <48.1 μg/mL, and FVIII‐like activity <15.4 IU/dL for zero bleeding. It is important that dosage reduction be done rationally. Dosage tailoring is possible. [ABSTRACT FROM AUTHOR]

The article discusses the development of a novel bispecific antibody, NXT007, for patients with hemophilia A. The antibody, which mimics activated factor VIII, has shown promise in improving hemostatic function and reducing breakthrough bleeds in patients with hemophilia A. The study demonstrates that NXT007 does not interfere with the anticoagulant effects of tissue factor pathway inhibitor (TFPI), suggesting that it may be a safe and effective treatment option for patients with hemophilia A. The research provides valuable insights into the potential benefits of NXT007 therapy for individuals with hemophilia A. [Extracted from the article]

Introduction: Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France. Aim: To describe the real‐world experience of using rVWF in non‐surgical bleeding and surgical procedures in patients with AVWS. Methods: Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres. Results: During bleeding, the median number of infusions was only 1 (range 1–27) with a median loading dose of 58 IU/kg (range 17–116) rVWF and a total median dose of 65 IU/kg (range 35–1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15). During surgeries, the median number of infusions was 3 (range 1–8) with a preoperative loading dose of 60 IU/kg (range 23–118) rVWF and a total median dose of 123 IU/kg (range 31–542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures. There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported. Conclusion: This French 'real‐world' experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Patients with hemophilia A can safely undergo cardiac surgery. Combining continuous infusion and boluses of factor VIII is both safe and cost‐effective. Interdisciplinary approach and meticulous planning are crucial in the prevention of bleeding complications. [ABSTRACT FROM AUTHOR]

Objective is to thoroughly investigate this causal link and delineate the influence of coagulation factors on the risk of ovarian cancer through a rigorous two-sample Mendelian randomization (MR) analysis. Methods: Genetic instrumental variables representing coagulation factors were sourced from four distinct data repositories. Summary statistics pertaining to ovarian cancer were obtained from two extensive Genome-Wide Association Studies (GWAS) for primary and replication analyses, respectively. The primary Mendelian randomization (MR) analysis utilized the inverse-variance weighted (IVW) method. To fortify the reliability of our findings, additional analyses were conducted, including the weighted-median method, MR-Egger regression, MR pleiotropy residual sum and outlier test, Cochran's Q statistic test, MR-Egger intercept analysis, and leave-one-out method, among others. Results: We identified four coagulation factors that were associated with the risk of ovarian cancer in the primary analysis, [odds ratio (OR): 1.365, 95% confidence interval (CI): 1.209– 1.542, P < 0.001 for von Willebrand factor measurement(vWF); OR: 1.060, 95% CI: 1.018– 1.104, P = 0.005 for A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADATMS13); OR: 1.317, 95% CI: 1.002– 1.730, P = 0.048 for activated partial thromboplastin time (aPTT); OR: 1.139, 95% CI: 1.063– 1.221, P < 0.001 for coagulation Factor VIII (FVIII)]. In the meta-analysis, we found that higher levels of coagulation factor VII measurement(FVII) (OR=1.0007, 95% CI: 1.0001– 1.0013, P=1.0007) was associated with increased ovarian cancer risk. The results of sensitivity analyses for these coagulation factors were consistent (P< 0.05). Conclusion: Our systematic analyses have furnished evidence suggesting a plausible causal association between FVII and the susceptibility to ovarian cancer. Further investigations are warranted to delineate the mechanistic pathways through which coagulation factors influence the progression of ovarian cancer. [ABSTRACT FROM AUTHOR]

Axolotl (Ambystoma mexicanum) limb regeneration begins with blastemas of various sizes, in contrast to the limb developmental process. Despite this size variation, normal limb morphology, consistent with a limb stump size, is regenerated. This outcome suggests the existence of underlying scale-invariant mechanisms. To identify such mechanisms, we examined the allometric relationships between blastema size, and Sonic Hedgehog (Shh) and Fibroblast Growth Factor 8 (Fgf8) expression patterns against limb stump size. We found that all factors showed allometric rather than isometric scaling; specifically, their relative sizes decrease with an increase in limb stump size. However, the ratio of Shh/Fgf8 signaling dominant region was nearly constant, independent of blastema/body size. Furthermore, the relative spatial patterns of cell density and proliferation activity, and the relative position of first digit formation were scale invariant in the summed Shh/Fgf8 crosstalk region. This scale-invariant nature may underlie the morphogenesis of normal limbs from different sizes of blastemas. [ABSTRACT FROM AUTHOR]

It has been recognized that shortened activated partial thromboplastin time (aPTT) may be caused by various preanalytical conditions. As coagulation Factor VIII is included in the in vitro intrinsic coagulation cascade measured by aPTT, we hypothesized that the shortened aPTT could be a result of elevated FVIII activity. We aimed to inspect the connection of elevated FVIII with shortened aPTT, and the possible effect inflammation has on routine laboratory parameters. 40 patients from various hospital departments with aPTT measurement below the lower limit of the reference interval (<23.0 s) were included in the study. To compare the obtained results with aPTT measurements in the non-inflammatory state, samples from 25 volunteers (laboratory personnel) were collected. White blood cell count, C-reactive protein, aPTT, and FVIII values were measured in the control group. Only two samples among 40 patients with shortened aPTT (5 %) were clotted. Out of the remaining 38, 26 had FVIII activity above 150 % (upper limit of a reference interval), median value of 194 % (IQR: 143–243 %). Seven samples in the control group had shortened aPTT results (36 %). However, all coagulation samples were clot and hemolysis-free. Multiple regression identified only FVIII activity as an independent variable in predicting aPTT values (p=0.001). Our results support the thesis that shortened aPTT is rarely a consequence of preanalytical problems. Elevated FVIII activity causes shortened aPTT, not only in the inflammatory state but also in individuals with concentration of inflammatory markers within reference intervals. [ABSTRACT FROM AUTHOR]

A mass was removed surgically from the right orbit of a 1-d-old Holstein calf. Grossly, the mass filled the rostral part of an enlarged orbit and compressed the globe toward the caudal pole of the orbit. The brown, 6-cm tumor had central yellow and brown areas, and a smooth, glistening cut surface. Microscopically, the neoplasm was highly cellular and composed of spindle cells arranged in irregular, broad, interlacing streams and bundles, forming a herringbone pattern and supported by a sparse collagenous matrix. Neoplastic cells infiltrated surrounding soft tissues and compressed the globe. The neoplastic cells had positive immunolabeling for α–smooth muscle actin, desmin, and vimentin, and negative immunolabeling for factor VIII, myoglobin, cytokeratin, and skeletal muscle actin. Histopathology and immunohistochemistry results confirmed a diagnosis of leiomyosarcoma. To our knowledge, congenital periocular leiomyosarcoma has not been reported in cattle previously. This rare tumor could be included as a differential diagnosis in newborn calves with periocular masses. [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]

Abstract\nHIGHLIGHTSMilk fat globule-epidermal growth factor 8 (MFG-E8) is a multifunctional glycoprotein regulating intercellular interactions in various biological and pathological processes. This review summarizes the effects and mechanisms of MFG-E8 in neurodegenerative diseases (NDDs), emphasizing its roles in inflammation, apoptosis, and oxidative stress. In this review, will also explore the potential of MFG-E8 as a diagnostic biomarker and its therapeutic applications in neurodegenerative disorders. Recent studies have revealed intriguing characteristics of using MFG-E8 as a potential drug for treating various brain disorders. While the discovery, origin, expression, and physiological functions of MFG-E8 in various organs and tissues are well defined, its role in the brain remains less understood. This is particularly true for NDDs, indicating unmet medical needs. Elucidating its role in the brain could position MFG-E8 as a potential treatment for NDDs.The expression and regulation of MFG-E8 in neurodegenerative diseases.The role of MFG-E8 in the mechanisms of neurodegenerative diseases.Potential application challenges and strategies for MFG-E8 as a therapeutic target.The expression and regulation of MFG-E8 in neurodegenerative diseases.The role of MFG-E8 in the mechanisms of neurodegenerative diseases.Potential application challenges and strategies for MFG-E8 as a therapeutic target. [ABSTRACT FROM AUTHOR]

Globally, intron 22 inversions (Inv22s) of the factor VIII gene (F8) are the most frequent pathogenic variants and account for 45–50% of severe hemophilia A (SHA) cases, while intron 1 inversion (Inv1) explains 1–5% of SHA cases. The detection of both inversions by an inverse shifting-polymerase chain reaction (IS-PCR) is the first choice worldwide for the diagnosis of patients and carriers of SHA. To improve its sensitivity and reproducibility in the visualization of PCR products, we approached the IS-PCR with fluorescent capillary electrophoresis instead of agarose electrophoresis. Based on the original protocol, we modified two primers by 5'-end labeling with FAM™ fluorescent dye for the detection of the PCR products by capillary electrophoresis. Additionally, the "fast enzymes" BclI and T4-Ligase were incorporated for work saving in the genomic digestion and ligation reactions, respectively. Once we accomplished the standardization and verified the reproducibility of the modified IS-PCR method, we applied it for the diagnosis of a cohort of SHA patients and carriers. The modified IS-PCR by fluorescent capillary electrophoresis for PCR product detection is more sensitive than agarose electrophoresis. The method was also improved by using the new rapid enzymes to save time in the whole process. [ABSTRACT FROM AUTHOR]

Background: A widespread crosstalk between inflammation and coagulation has been shown in numerous studies. This suggests that coagulation can trigger an inflammatory response which ultimately leads to coagulation activation. Previous research has shown that polyphenols can affect blood pressure and endothelial dysfunction, resulting in reduced risk of cardiovascular diseases. This study aimed to investigate whether Silymarin, a flavonolignans, could play a role in the interaction between inflammation and coagulation by influencing endothelial cells. Materials and Methods: In this experimental study, human umbilical vein endothelial cells (HUVECs) were seeded with and without various concentrations of silymarin. In vivo, treatment with silymarin was also carried out. Coagulative and fibrinolytic factors, including Von Willebrand factor (VWF) and Factor VIII (FVIII), tissue plasminogen activator-1 (TPA-1), and inflammatory factors, including interleukin 8 (IL-8) and tumor necrosis rotcaf - ohplo (TNF-α), were evaluated by flow cytometry, Real-Time Polymerase Chain Reaction (qPCR), Enzyme-Linked Immunosorbent Assay (ELISA) and Immunocytochemistry (ICC). Results: Silymarin increased the gene expression, release, and storage of VWF while diminishing the gene expression, release, and storage of TPA-1 (P < 0.05). The activity of FVIII was dramatically increased, and IL-8 and TNF-α levels were augmented. The in vivo study also indicated an elevated plasma level of VWF and IL-8 by silymarin administration. Conclusion: The results showed that, although silymarin reduces inflammatory factors, it can affect coagulation factors by increasing the levels of VWF and FVIII activity and inhibiting TPA-1 production, thereby making thrombosis probable. Consequently, it is advisable to prescribe this medication with caution for individuals who are susceptible to thrombotic events. [ABSTRACT FROM AUTHOR]

It is common practice in laboratories to store biological samples in ultra-low temperature (ULT) freezers. There is growing interest in raising the temperature of ULT freezers in order to save energy and reduce expenses, as energy conservation becomes increasingly important and sustainable laboratory practices gain popularity. In our laboratory, plasma samples are stored for three months for diagnostic purposes. We therefore took the opportunity to investigate the effect of two different storage temperatures (−70 °C vs −80 °C), on activated partial thromboplastin time (APTT), factor VIII (FVIII), international normalized ratio (INR) and factor VII (FVII) measurements on paired plasma samples collected from 26 individuals after three months of storage. Automated coagulation analysers CS-5100 and ACL TOP were used to perform the tests. We found no consistent difference between the two storage temperatures for any of the four coagulation parameters (all p-values > 0.05). We conclude that the temperature of ULT freezers used to store plasma samples for APTT, FVIII, INR, and FVII measurements can be safely increased from −80 to −70 °C without affecting the stability of the samples. [ABSTRACT FROM AUTHOR]

Why has the structural bonus been so small during China's post-reform era? This article explains the puzzle by exploiting the heterogeneity in structural-change patterns across Chinese provinces. Using an original database covering production and factor inputs in 8 sectors and 31 provinces over 1993–2016, I show only those provinces where labour was reallocated from agriculture to manufacturing and services benefited from a structural bonus on labour productivity growth. In the other provinces, this structural-change effect was minimal or negative. Regarding the structural-change effect on total factor productivity (TFP) growth, I find both labour and capital reallocation played a limited role. Labour reallocation has little potential in boosting aggregate TFP growth, as marginal labour returns are similar across sectors. Capital reallocation has a far greater potential but remains restrained, suggesting substantial reallocation frictions. China's TFP growth is mostly explained by within-sector technological progress, which has been dissipating since 2008, leading to declining TFP growth. [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]

Background: Intraoperative hemorrhage in cardiac surgery increases risk of morbidity and mortality. Low pre-operative and perioperative levels of fibrinogen, a key clotting factor, are associated with severity of hemorrhage and increased transfusion of blood components. The ability to supplement fibrinogen during hemorrhagic resuscitation is delayed 45–60 min because cryoprecipitated antihemophilic factor (cryo AHF) is stored frozen, due to a short post-thaw shelf life. Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex, IFC) can be kept thawed, at room temperature, for up to 5 days, making it possible to be immediately available for hemorrhaging patients. This trial will investigate if earlier correction of acquired hypofibrinogenemia with IFC in hemorrhaging cardiac surgery patients reduces the total number of perioperatively transfused allogeneic blood products (red blood cells, plasma, and platelets) as compared to cryo AHF. Methods: This is a single center, prospective, cluster randomized trial with an adaptive design. Acquired hypofibrinogenemia will be assessed by rotational thromboelastometry (ROTEM) and the threshold for cryo AHF/IFC transfusion defined as FIBTEM A10 ≤ 10 mm in bleeding patients. IFC/cryo AHF will be randomized by 1-month blocks. Cardiac surgery patients will be enrolled in the study if they have an eligible procedure and at least one dose of a cryo AHF/IFC product (approximately 2 g fibrinogen) is transfused. Data from the electronic health record, including the blood bank and lab information systems, will be prospectively collected from the health system's data warehouse. Discussion: This trial aims to provide evidence of the clinical efficacy of utilizing readily available thawed IFC during acute bleeding in the cardiac surgery setting compared to traditional cryo AHF. Trial registration: ClinicalTrials.gov NCT05711524. Feb 3, 2023. [ABSTRACT FROM AUTHOR]

Background: To date, there is an ongoing debate regarding the ability to predict PVT development using markers of FVIII or FVIII/PC ratio. This study presents evidence-based medical findings on the influence of FVIII activity levels and FVIII/PC values in the formation of PVT in cirrhosis. Methods: The search for original studies on risk factors for portal vein thrombosis (PVT) associated with cirrhosis was conducted, which primarily focused on comparing circulating FVIII activity levels or FVIII/PC ratio in cirrhotic patients with and without PVT. The quality of evidence from each study was assessed using the Newcastle-Ottawa Scale. Results: The meta-analysis included a total of 10 original studies. In total, 2250 cirrhotic patients were included, with 414 having PVT and 1836 without PVT. The pooled analysis using a random-effects model showed no significant difference in standardized mean difference (SMD) for FVIII activity levels in cirrhotic patients with or without PVT (SMD = 0.12, 95% CI=-0.46 to 0.70, P = 0.68), but there was significant heterogeneity (I2 = 95.52%, P = 0.00). Meta-regression analysis indicated that differences in mean FVIII activity levels in the PVT group, the number of cases in the non-PVT group, and the study design methods partially contributed to the heterogeneity (P < 0.05). However, compared to the non-PVT group, the PVT group had higher FVIII/PC ratio with a statistically significant difference (SMD = 0.39, 95% CI: 0.15 to 0.63, P = 0.00), and there was no significant heterogeneity (I2 = 28.62%). Conclusion: In conclusion, the FVIII/PC ratio not only reflects the severity of liver disease, but also can be used as one of the predictors of PVT development. [ABSTRACT FROM AUTHOR]