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Over recent decades, management of people with hemophilia (PwH) has been greatly improved by scientific advances that have resulted in a rich and varied therapeutic landscape. Nevertheless, treatment limitations continue to drive innovation, and emerging options have the potential to realize further improvement. We advocate four general principles to optimize benefits from innovation: individualizing the treatment approach, targeting 'normal,' making the most of available resources, and considering treatment affordability. Ultimately, all PwH-men and women, of all ages and severities, and worldwide-should have access to treatment that fully prevents bleeding, while allowing personal, social, family, and professional lives of choice. Clearly, we are not there yet, but developing goals/milestones based on the principles we describe may help to achieve this., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JB has received consultation and/or speaker’s fees from NovoNordisk, Roche, Sobi, Takeda, and CSL Behring. JA has received research grants from Sobi, CSL Behring, Takeda/Shire, and Bayer, and speaker’s fees and consultancy for Octapharma, Novo Nordisk, Pfizer, Bayer, Sobi, CSL Behring, Takeda/Shire, BioMarin, Uniqure, and Spark Therapeutics. CC has received payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events, and support for attending meetings and/or travel from Sobi, Bayer, Roche, and Novo Nordisk, and has also participated in data safety monitoring boards or advisory boards for Sobi, Bayer, Roche, and Novo Nordisk. GD has received consulting fees from Pfizer, Biomarin, CSL, Roche, and Sobi, and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Pfizer, Spark Therapeutics, CSL, Bayer, Takeda, Roche, Chugai, and Sobi. KF has received unrestricted research grants from CSL Behring, Sobi, and Novo Nordisk, as well as consultancy fees from Hoffman-La Roche, Sanofi, Sobi, and Novo Nordisk, with all fees paid to her institution. CH has received research funding from Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Shire/Takeda, and Sobi, as well as honoraria/speaker’s bureau fees from Bayer, CAF-DCF, CSL Behring, Hoffmann-La Roche, LFB, Novo Nordisk, Octapharma, Pfizer, Shire/Takeda, Sobi, and UniQure. KH has received grants for research or clinical studies (paid to her institution) from Bayer, CSL Behring, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Sobi, as well honoraria or consultancy fees from Bayer, Biomarin, Biotest, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda. VJ-Y has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, BioMarin, CSL Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma, and Pfizer. RK has received consultancy fees and honoraria for lectures and advisory boards from Bayer, Biomarin, CSL Behring, Novo Nordisk, Grifols, Octapharma, Pfizer, Roche/Chugai, Sanofi, Sobi, and Takeda. ML has served on an advisory board for CSL Behring, as a consultant for Sobi, CSL Behring, Takeda, and Band Therapeutics, and has received research funding from Takeda and speaker fees from Sobi and Takeda. PJL has received research support to his institute from Sobi, Sanofi, BioMarin, and Roche. SL has acted as a paid consultant to Faust Pharmaceuticals Inc. MEM has acted as a paid speaker/consultant/advisor for Bayer, Biomarin, CSL Behring, Kedrion, LFB, Octapharma, Novo Nordisk, Pfizer, Roche, Sanofi, Sobi, and Takeda. JM has received honoraria and/or educational support from Sobi, Roche, Bayer, and CSL. JSO’D declares no conflicts of interest beyond the support for this manuscript from Sobi. CK has received funding from BFSH, Bayer, CSL Behring, Florio, MSD, Novo Nordisk, Roche/Chugai, Sobi/Sanofi, and Takeda for presentations and/or scientific advice, and his institution has received research funding from Bayer, Biotest, CSL Behring, Intersero, Novo Nordisk, Pfizer, Roche/Chugai, Sobi/Sanofi, and Takeda., (© The Author(s), 2024.)

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.

Management of patients with hemophilia A (HA) requires the knowledge and experience of specialized health care professionals. However, these patients may need to be attended in emergencies, outside the referral hospital, where health care professionals do not know about hemophilia and/or new innovative treatments. This study aimed to develop a simple and practical algorithm that could be used in emergency situations by nonspecialized treaters in HA and bleeding with or without factor VIII (FVIII) inhibitors under emicizumab prophylaxis. A group of experts agreed on a simple algorithm, easy to operate, adapted from previous international guidelines, and based on their clinical experience. The proposed algorithm starts with identifying the patient, confirming the diagnosis of HA, prophylaxis with emicizumab, and/or use of other treatments. After stabilizing the patient and stratifying the bleeding risk, the patient is managed according to the presence/absence of FVIII inhibitors. Patients without FVIII inhibitors should receive FVIII concentrate. Dose and follow-up depend on bleeding localization and severity. Patients with FVIII inhibitors should preferably receive recombinant activated factor VII as bypass agent. A basic coagulation assay, FVIII assessment, and FVIII inhibitors detection assays are necessary in an emergency. However, these tests should be interpreted with caution and appropriately chosen, as emicizumab may alter the results. The management of patients with HA is challenging in emergency situations, especially if they are treated with new agents. Nonspecialized in coagulopathies health care professionals have limited understanding of the disease, highlighting the need for an algorithm to assist them in making informed decisions., Competing Interests: Conflict of Interest V.J-Y. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, BioMarin, CSL-Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma, and Pfizer. M.T.Á-R. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, CSL-Behring, Novo Nordisk, Sobi, Roche, Grifols, Novartis, Amgen, and Pfizer. R.B.M. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, CSL-Behring, Novo Nordisk, Sobi, Roche, Boehringer Ingelheim, and Pfizer. S.B. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, CSL-Behring, Novo Nordisk, SOBI, Roche, Biomarin, and Pfizer. J.M.C.V. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, CSL-Behring, Novo Nordisk, Sobi, Roche, and Pfizer. R.G.G. has received personal fees from Novo Nordisk. J.R.G.P. has received reimbursement for attending symposia/congresses from Roche, Amgem, Novo Nordisk, and Pfizer, and funds for consulting from Roche. R.J.N.V. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Octapharma, Bayer, CSL-Behring, Novo Nordisk, Grifols, Sobi, Roche, and Pfizer. M.R.L. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Octapharma, CSL-Behring, Novo Nordisk, Sobi, Roche, and Pfizer., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: The treatment of older people with hemophilia A (HA) can be complicated by comorbidities., Objectives: This post hoc analysis evaluates the efficacy and safety of emicizumab in people with HA aged ≥50 years with cardiovascular (CV) risk factors or HIV and/or hepatitis C virus (HCV) infection., Methods: The HAVEN 1 (NCT02622321), HAVEN 3 (NCT02847637), HAVEN 4 (NCT03020160), and STASEY (NCT03191799) studies enrolled adults/adolescents with severe HA. Participants were categorized as having a comorbidity if they had any CV risk factors (including history of CV disease, hypertension, diabetes, hyperlipidemia, prior stroke, or obesity), HIV, and/or HCV infection. Efficacy and safety outcomes were compared by age (<50 vs ≥50 years)., Results: Of 504 participants at data cutoff, 408 were aged <50 years and 96 were aged ≥50 years. In people with HA aged <50 years, 26.7% had ≥1 CV risk factor and 29.4% had HIV and/or HCV infection. In people with HA aged ≥50 years, 72.9% had ≥1 CV risk factor and 74.0% had HIV and/or HCV infection. The mean (95% CI) annualized bleed rate for treated bleeds was 1.29 (0.07-6.06) for people with HA aged <50 years and 1.82 (0.19-6.93) for people with HA aged ≥50 years. No significant differences in annualized bleed rates were observed for those with comorbidities compared with those without. Safety outcomes were similar regardless of age., Conclusion: This pooled analysis suggests that emicizumab efficacy and safety in people with HA aged ≥50 years with CV and HIV/HCV comorbidities were consistent with those in people with HA aged <50 years enrolled in the HAVEN 1, 3, and 4 and STASEY studies., (© 2024 The Authors.)

Abstract: Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, mimicking the function of missing or deficient activated FVIII in people with hemophilia A (HA)., Objectives: To evaluate the long-term efficacy and safety of emicizumab prophylaxis in people with HA without FVIII inhibitors in the HAVEN 3 and 4 studies., Methods: HAVEN 3 and 4 were phase 3 open-label studies. Participants received emicizumab maintenance doses of 1.5 mg/kg every week or 3 mg/kg every 2 weeks (HAVEN 3), or 6 mg/kg every 4 weeks (HAVEN 4). Long-term efficacy and safety were assessed., Results: A total of 151 and 40 individuals without FVIII inhibitors received emicizumab in HAVEN 3 and 4, respectively. At the last patient, last visit dates (May 12, 2022 [HAVEN 3] and June 29, 2022 [HAVEN 4]), the median (range) duration of emicizumab exposure across the 2 studies was 248.1 (6.1-287.1 ) weeks. The mean (95% CI) annualized bleed rate for treated bleeds was 2.0 (0.23-7.15) for weeks 1 to 24, decreasing to 0.9 (0.01-5.28) by weeks 217 to 240. Overall, 188 (98.4%) participants experienced ≥1 adverse event (AE), with 185 treatment-related AEs in 71 (37.2%) participants. Forty-four (23.0%) participants reported a serious AE. Two thromboembolic events were reported, which were deemed unrelated to emicizumab by the investigator. No thrombotic microangiopathies were reported., Conclusion: With nearly 5 years of emicizumab exposure across the HAVEN 3 and 4 studies in people with HA without inhibitors, these data indicate continued bleed control with no new safety signals observed during long-term follow-up., (© 2024 The Author(s).)

Aim: Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed., Methods: The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators., Results: Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2 ± 11.8 and 32.7 ± 14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p < .01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients., Conclusion: This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted., (© 2024 John Wiley & Sons Ltd.)

Background  Guidelines surrounding emicizumab prophylaxis and perioperative treatment for people with hemophilia A (PwHA) with factor (F)VIII inhibitors undergoing surgeries are limited. The phase IIIb multicenter, single-arm STASEY study evaluated safety and tolerability of emicizumab prophylaxis in PwHA aged ≥12 years with FVIII inhibitors. This analysis assesses surgeries during study conduct, associated hemophilia medications, and postoperative bleeds (treated and untreated). Methods  PwHA with FVIII inhibitors received emicizumab 3.0 mg/kg/week for 4 weeks, then 1.5 mg/kg/week until 2 years. Surgeries were managed and documented by treating physicians. Bleeds and treatments were recorded by physicians and participants. Results  Forty-six participants had ≥1 on-study surgery, 37 underwent 56 minor surgeries, and 13 underwent 22 major surgeries. Four participants underwent both minor and major surgeries. Of 18 (81.8%) and 4 (18.2%) major surgeries managed with/without additional hemostatic medication, 33.3 and 25.0% were associated with a treated postoperative bleed, respectively. Of 24 (42.9%) and 32 (57.1%) minor surgeries managed with/without additional hemostatic medication, 15.6 and 25.0% were associated with a treated postoperative bleed, respectively. Recombinant activated FVII was the most common medication for prophylaxis and bleed treatment. There were no thrombotic microangiopathies (TMAs). One hypertrophic clot, considered unrelated to emicizumab, occurred following tooth extraction. Conclusion  In this challenging population with a high bleeding risk, major surgeries were performed in PwHA receiving emicizumab with/without additional hemostatic medication. Postoperative bleeds occurred following 59.1% of major surgeries; 53.8% were treated. No arterial/venous thrombotic events or TMAs occurred due to concomitant emicizumab and bypassing agents. Trial registration  This trial is registered at ClinicalTrials.gov (NCT03191799)., Competing Interests: Conflict of Interest G.C. has received consulting fees from CSL Behring and F. Hoffmann-La Roche Ltd; has received payment or honoraria for speaking at company satellite symposia/webinar from BioMarin, Grifols, LFB, Kedrion, Takeda, F. Hoffmann-La Roche Ltd, Novo Nordisk, CSL Behring, Sanofi, SOBI, and Werfen; and has participated on advisory boards for Bayer, BioMarin, CSL Behring, LFB, SOBI, Pfizer, F. Hoffmann-La Roche Ltd, and Takeda. F.P. has received speaker fees for participating in educational meetings for Grifols, F. Hoffmann-La Roche Ltd; and has participated on advisory boards for Sanofi, SOBI, Takeda, F. Hoffmann-La Roche Ltd, and BioMarin. J.A.K.H. has acted in a consultation or advisory role for Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, Sanofi, SOBI, and Takeda; has received speakers' bureau from CSL Behring, F. Hoffmann-La Roche Ltd, Sanofi, SOBI, and Takeda; has received research funding for the Interprofessional Hemophilia Care EHCCC Inselspital from Bayer, CSL Behring, Novo Nordisk, F. Hoffmann-La Roche Ltd, and SOBI, and for the hereditary TTP registry: Baxter, now part of Takeda; has given expert testimony for Federal Office of Public Health, Switzerland, and has received fees for travel, accommodation, and expenses from Bayer and SOBI. R.E.G.S. has acted in a consultation or advisory role for Bayer and Novartis and received research funding from Bayer, CSL Behring, Hemab, Novo Nordisk, Octapharma, and SOBI. S.R. and K.M. are employees of and shareholders in F. Hoffmann-La Roche Ltd. V.J-Y. has received grants or contracts from F. Hoffmann-La Roche Ltd, Novo Nordisk, SOBI, Takeda, Grifols, Bayer, Pfizer, Octapharma, and CSL Behring, and consulting fees and payment or honoraria for lectures, presentations, speakers' bureau, manuscript writing or educational events from F. Hoffmann-La Roche Ltd, Novo Nordisk, Sanofi, SOBI, Takeda, Grifols, Bayer, Pfizer, Spark Therapeutics, BioMarin, Octapharma, and CSL Behring., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Introduction: Patient-reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under-reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen., Aim: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA., Methods: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses., Results: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended-half-life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m 2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health-related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores., Conclusion: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real-world practice with ≤1 year's follow-up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well-being., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Despite the efficacy of splenectomy for chronic immune thrombocytopenia (ITP), its considerable failure rate and its possible related complications prove the need for further research into potential predictors of response. The platelet sequestration site determined by 111 In-labelled autologous platelet scintigraphy has been proposed to predict splenectomy outcome, but without standardisation in clinical practice. Here, we conducted a single-centre study by analysing a cohort of splenectomised patients with ITP in whom 111 In-scintigraphy was performed at La Paz University Hospital in Madrid to evaluate the predictive value of the platelet kinetic studies. We also studied other factors that could impact the splenectomy outcome, such as patient and platelet characteristics. A total of 51 patients were splenectomised, and 82.3% responded. The splenic sequestration pattern predicted a higher rate of complete response up to 12 months after splenectomy (p = 0.005), with 90% sensitivity and 77% specificity. Neither age, comorbidities, therapy lines nor previous response to them showed any association with response. Results from the platelet characteristics analysis revealed a significant loss of sialic acid in platelets from the non-responding patients compared with those who maintained a response (p = 0.0017). Our findings highlight the value of splenic sequestration as an independent predictor of splenectomy response., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4)., Objectives: Here, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4., Methods: Participants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials., Results: Emicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen)., Conclusion: In HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers., (© 2024 The Authors.)

Objectives: We aimed to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) versus three extended half-life (EHL) recombinant FVIII (rFVIII) concentrates., Methods: Treatment effects were compared using matching-adjusted indirect comparisons after matching individual patient-level baseline characteristics for simoctocog alfa (pharmacokinetic [PK]-guided personalized prophylaxis) against published aggregate personalized prophylaxis data for efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol., Results: A higher percentage (p < .001) of patients with zero bleeds was found with simoctocog alfa compared with efmoroctocog alfa (75% vs. 45%), damoctocog alfa pegol (77% vs. 38%), and rurioctocog alfa pegol (target trough level 1%-3%; 78% vs. 42%). Similar efficacy was found comparing simoctocog alfa against rurioctocog alfa pegol 8%-12% (77% vs. 62%). The mean total annualized bleeding rate was lower (p < .001) with simoctocog alfa than damoctocog alfa pegol (1.5 vs. 4.9). Consistent with approved dosing, the mean FVIII weekly dose was higher (p < .001) for simoctocog alfa than efmoroctocog alfa, damoctocog alfa pegol, or rurioctocog alfa pegol 1%-3%, but lower (p < .001) than rurioctocog alfa pegol 8%-12%., Conclusions: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to higher zero bleed rates compared with personalized EHL rFVIII concentrate regimens, albeit with higher weekly doses, and a lower percentage of patients treated twice weekly or less., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors., Aim: To report the efficacy and safety results from the NuProtect study., Methods: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study., Results: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events., Conclusion: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose of Review: We present a case of a boy diagnosed in 2007 with severe haemophilia B [factor IX (FIX) concentration < 1%] at age of 9 months. He was initially treated with recombinant FIX concentrates, but changes in regimens were frequent due to spontaneous hemarthros. In 2013, he entered a phase III trial (NCT01662531) and received rIX-FP, IDELVION at 50 IU/kg once a week. Although the boy was safely maintained with this regimen (2015-2017), the number of hemarthros increased after he started to play football. Thus, rIX-FP regimen was modified (40 IU/kg twice/week) to optimize therapy. This modification was efficient on maintaining patient's thought levels (33%), helped during his fully incorporation at school and social life, and significantly improved synovial hypertrophy. In the last year, the boy has not suffered any bleeding episode and his joint situation improved significantly, which allowed reducing doses to weekly recommended doses., Recent Findings: FIX replacement therapies with intravenous plasma-derived FIX (pdFIX) or standard half-life recombinant FIX (rFIX) concentrates are hampered by the relatively short terminal elimination half-life (t1/2) of these substances (around 17-34 h), resulting in the need for frequent infusions (e.g. once every 3 or 4 days) to maintain protective FIX levels. In the past years, the first genetically recombinant fusion of rFIX with another protein - a recombinant human albumin - was developed (albutrepenonacog-alfa or rIX-FP; IDELVION) as a strategy to extend the t1/2 of rFIX-FP (around 95 h)., Summary: We provide information about the difficult management of a patient with a major bleeding haemorrhagic phenotype, which caused serious limitations in the patient's daily life, impacting his quality of life at his young age, and how the switch to IDELVION allowed the situation to improve considerably., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors., Methods: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed., Results: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time., Conclusions: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.)., (Copyright © 2023 Massachusetts Medical Society.)

Recently, there have been reports of what could be a new lymphoproliferative entity: breast implant-associated Epstein-Barr virus positive (EBV+) diffuse large B-cell lymphoma (EBV+ BIA-DLBCL). The new World Health Organization classification has categorized it as fibrin-associated large B-cell lymphomas (FA-LBCLs); therefore, it could be referred to as breast implant-associated fibrin-associated large B-cell lymphomas (BIA-FA-LBCLs). Although the association between breast implants and lymphomas has been known since the mid-1990s, it has been almost exclusively breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Here, we describe the first case of BIA-FA-LBCL at our center, with a literature review of the clinical features, diagnosis and treatment approach of this lymphoma. We also explore the differential diagnosis of BIA-FA-LBCL, highlighting the diagnostic challenges and the reasons that have led these lymphomas to being labeled as a new face of FA-LBCL.

Competing Interests: VJ-Y has received honoraria for consulting from Takeda, Bayer, BioMarin Pharmaceutical, CSL Behring, Grifols, NovoNordisk, Sobi, Sanofi, Spark Therapeutics, Roche, Octapharma, and Pfizer, and funds for research from Takeda, Bayer, Grifols, NovoNordisk and Roche. MTÁ-R has received honoraria for consulting from Takeda, Bayer, BioMarin Pharmaceutical, CSL Behring, Grifols, NovoNordisk, Sobi, Roche, Octapharma, and Pfizer, and funds for research from Takeda, Bayer, Grifols, Novo Nordisk and Roche.

Background: Sinusoidal obstructive syndrome (SOS) is a potentially fatal complication secondary to hematopoietic stem cell transplant (HSCT) conditioning. Endothelial damage plasma biomarkers such as plasminogen activator inhibitor-1 (PAI-1), hyaluronic acid (HA), and vascular adhesion molecule-1 (VCAM1) represent potential diagnostic tools for SOS., Methods: We prospectively collected serial citrated blood samples (baseline, day 0, day 7, and day 14) in all adult patients undergoing HSCT at La Paz Hospital, Madrid. Samples were later analyzed by ELISA (enzyme-linked immunosorbent assay) for HA, VCAM1, and PAI-1 concentrations., Results: During sixteen months, we prospectively recruited 47 patients. Seven patients (14%) were diagnosed with SOS according to the EBMT criteria for SOS/VOD diagnosis and received treatment with defibrotide. Our study showed a statistically significant elevation of HA on day 7 in SOS patients, preceding clinical SOS diagnosis, with a sensitivity of 100%. Furthermore, we observed a significant increase of HA and VCAM1 levels on day 14. Regarding risk factors, we observed a statistically significant association between SOS diagnosis and the fact that patients received 3 or more previous lines of treatment before HSCT., Conclusions: The early significant increase in HA levels observed opens the door to a noninvasive peripheral blood test which could have the potential to improve diagnosis and facilitate prophylactic and therapeutic management of SOS before clinical/histological damage is established., Competing Interests: The authors declare that they have no conflicts of interests. Raul Justo Sanz is currently an employee at Takeda Pharmaceutical, Spain, S.A., (Copyright © 2023 Carmen De Ramón Ortiz et al.)

Recent advances in therapeutics are now providing a wide range of options for adults and children living with hemophilia. Although therapeutic choices are also increasing for the youngest individuals with severe disease, challenges remain about early management decisions, as supporting data are currently limited. Parents and healthcare professionals are tasked with helping children achieve an inclusive quality of life and maintain good joint health into adulthood. Primary prophylaxis is the gold standard to optimize outcomes and is recommended to start before 2 years of age. A range of topics need to be discussed with parents to aid their understanding of the decisions they can make and how these will affect the management of their child/children. For those with a family history of hemophilia, prenatal considerations include the possibility of genetic counseling, prenatal investigations, and planning for delivery, together with monitoring of the mother and neonate, as well as diagnosis of the newborn and treatment of any birth-associated bleeding. Subsequent considerations, which are also applicable to families where infant bleeding has resulted in a new diagnosis of sporadic hemophilia, involve explaining bleed recognition and treatment options, practical aspects of initiating/continuing prophylaxis, dealing with bleeds, and ongoing aspects of treatment, including possible inhibitor development. Over time, optimizing treatment efficacy, in which individualizing therapy around activities can play a role, and long-term considerations, including retaining joint health and tolerance maintenance, become increasingly important. The evolving treatment landscape is creating a need for continually updated guidance. Multidisciplinary teams and peers from patient organizations can help provide relevant information. Easily accessible, multidisciplinary comprehensive care remains a foundation to care. Equipping parents early with the knowledge to facilitate truly informed decision-making will help achieve the best possible longer-term health equity and quality of life for the child and family living with hemophilia., Plain Language Summary: Points to be taken into account to help families make decisions to best care for children born with hemophilia Medical advances are providing a range of treatment options for adults and children with hemophilia. There is, however, relatively limited information about managing newborns with the condition. Doctors and nurses can help parents to understand the choices for infants born with hemophilia. We describe the various points doctors and nurses should ideally discuss with families to enable informed decision-making. We focus on infants who require early treatment to prevent spontaneous or traumatic bleeding (prophylaxis), which is recommended to start before 2 years of age. Families with a history of hemophilia may benefit from discussions before pregnancy, including how an affected child would be treated to protect against bleeds. When mothers are pregnant, doctors can explain investigations that can provide information about their unborn child, plan for the birth, and monitor mother and baby to minimize bleed risks at delivery. Testing will confirm whether the baby is affected by hemophilia. Not all infants with hemophilia will be born to families with a history of the condition. Identification of hemophilia for the first time in a family (which is 'sporadic hemophilia') occurs in previously undiagnosed infants who have bleeds requiring medical advice and possibly hospital treatment. Before any mothers and babies with hemophilia are discharged from hospital, doctors and nurses will explain to parents how to recognize bleeding and available treatment options can be discussed. Over time, ongoing discussions will help parents to make informed treatment decisions:• When and how to start, then continue, prophylaxis.• How to deal with bleeds (reinforcing previous discussions about bleed recognition and treatment) and other ongoing aspects of treatment. ○ For instance, children may develop neutralizing antibodies (inhibitors) to treatment they are receiving, requiring a change to the planned approach.• Ensuring treatment remains effective as their child grows, considering the varied needs and activities of their child., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JA has received research grants from Sobi, CSL Behring, Takeda/Shire, and Bayer, and speaker’s fees and consultancy for Octapharma, Novo Nordisk, Pfizer, Bayer, Sobi, CSL Behring, Takeda/Shire, BioMarin, UniQure, and Spark Therapeutics. JB has received speaker’s fees and/or consultancy for Sobi, Roche, Novo Nordisk, and Takeda. CK has received speaker’s fee or advisory honoraria from Bayer, CSL Behring, Novo Nordisk, Roche/Chugai, Sobi/Sanofi, and Takeda, and research funding to the university from Bayer, Biotest, CSL Behring, Intersero, Novo Nordisk, Pfizer, Sobi/Sanofi, and Takeda. CH has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Pfizer, Takeda/Shire, Bayer, Biomarin, Sanofi, CSL Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma, LFB, UniQure, Freeline Therapeutics, and Spark Therapeutics. VJ-Y has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Takeda, Bayer, Biomarin, Sanofi, CSL Behring, Grifols, Novo Nordisk, Sobi, Roche, Octapharma, and Pfizer. DPH has received research grants and/or clinical trial activity and departmental income from Bayer, Biomarin, Sobi, Sigilon, Octapharma, Takeda, and UniQure, as well as speaker’s fees/advisory honoraria from Bayer, Biomarin, Biotest, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark, Sobi, Takeda, and UniQure., (© The Author(s), 2023.)

Background: Clinical trial data are scarce for the use of prophylaxis in people with non-severe haemophilia A. The HAVEN 6 study aims to assess safety and efficacy of emicizumab prophylaxis in people with non-severe haemophilia A without factor VIII (FVIII) inhibitors., Methods: HAVEN 6 is a multicentre, open-label, single-arm, phase 3 study taking place in 22 specialty clinics and hospitals in Europe, North America, and South Africa. Eligible participants were people of all ages weighing at least 3 kg with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII >5%-<40%) haemophilia A without FVIII inhibitors requiring prophylaxis as assessed by the treating physician. Participants received subcutaneous emicizumab 3 mg/kg of bodyweight once weekly for 4 weeks, followed by the participant's choice of maintenance dose: 1·5 mg/kg once weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. Safety was the primary objective of the study. Safety endpoints included adverse events, serious adverse events, and adverse events of special interest including thromboembolic events and thrombotic microangiopathies. The primary efficacy endpoint was the annualised bleed rate for treated bleeds. Analyses were done for participants who received at least one dose of emicizumab. This study is registered with ClinicalTrials.gov, number NCT04158648, and is active but not recruiting., Findings: Between Feb 10, 2020, and Aug 31, 2021, we assigned 73 people to treatment. 72 participants received at least one dose of emicizumab (51 moderate [71%]; 21 mild [29%]; 69 male [96%]; three female [4%]; and 61 White [85%]). Median age was 23·5 years (IQR 12·0-36·0); median follow-up was 55·6 weeks (IQR 52·3-61·6) weeks. At baseline, 24 participants (33%) had target joints and 37 (51%) were receiving FVIII prophylaxis. 60 participants (83%) had at least one adverse event; the most common adverse events were headache (in 12 participants [17%]), injection-site reaction (12 [17%]), and arthralgia (11 [15%]). 15 (21%) had at least one emicizumab-related adverse event; no adverse events led to treatment withdrawal, modification, or interruption. Eight participants (11%) reported ten serious adverse events in total, none emicizumab-related. There were no deaths or thrombotic microangiopathies. One participant had grade 1 thrombosed haemorrhoids (classified as a thromboembolic event), unrelated to emicizumab. The annualised bleed rate was 0·9 (95% CI 0·55-1·52) for treated bleeds. 48 participants (67%) had no treated bleeds. All-bleed annualised bleed rates were 10·1 (95% CI 6·93-14·76) from 24 weeks pre-study and 2·3 (1·67-3·12) on-study after a median follow-up of 55·6 weeks., Interpretation: These data show efficacy and a favourable safety profile of emicizumab in people with non-severe haemophilia A without FVIII inhibitors who warrant prophylaxis, confirming emicizumab as a valuable treatment option in this population., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests CN has served as a consultant to BioMarin, Novo Nordisk, F Hoffmann-La Roche/Genentech, Sanofi, Sobi, and Shire/Takeda; received research funding from Novo Nordisk, F Hoffmann-La Roche/Genentech, and Sobi; received honoraria from Bayer, Novo Nordisk, F Hoffmann-La Roche /Genentech, Sanofi, Sobi, Spark Therapeutics, and Shire/Takeda; and has been a member of a board of directors or advisory committee for Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, F Hoffmann-La Roche/Genentech, Sanofi, Sobi, Spark Therapeutics, Shire/Takeda, and UniQure. JM is an employee of University of the Witwatersrand; has received grant or research support from BioMarin, Baxalta, Catalyst Biosciences, CSL, Novartis, Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, and UniQure; consultant fees from BioMarin, Baxalta, CSL Behring, Catalyst Biosciences, Novo Nordisk, F Hoffmann-La Roche, Spark Therapeutics; and speaker bureau fees from Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Takeda, WFH, ISTH, and Springer. ML is an employee and holds stock in F Hoffmann-La Roche. PC has received research funding from Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer, Sobi, and Takeda; honoraria from ApcinteX, Bayer, Boehringer Ingelheim, CSL Behring, Chugai Pharmaceutical, Freeline, Novo Nordisk, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, Sobi, and Takeda. OC is an employee of F Hoffmann-La Roche. RJB is an employee of Genentech, and stockholder in F Hoffmann-La Roche/Genentech. VJ-Y has received grant or research support from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, Sanofi, Sobi, and Octapharma; consultancy fees from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, BioMarin, Sanofi, Sobi, Spark Therapeutics, and Octapharma; honoraria from Grifols, Novo Nordisk, F Hoffmann-La Roche, Takeda, Bayer, CSL Behring, Pfizer, Sanofi, Sobi, Spark Therapeutics, and Octapharma. BMB is an employee and stockholder in F Hoffmann-La Roche. CS is an employee and stockholder in F Hoffmann-La Roche, and is co-inventor of a patent related to an anti-factor IXa/factor X bispecific antibody. GV is employee and stockholder in F Hoffmann-La Roche. JW is an employee at Institute of Hematology and Transfusion Medicine; received research funding from Baxalta, Novo Nordisk, Rigel Pharmaceuticals, F Hoffmann-La Roche, Shire, and Takeda; and received honoraria from Alfasigma, Bayer AG, Baxalta, CSL Behring, Novo Nordisk, Octapharma, Pfizer, F Hoffmann-La Roche, Sanofi-Aventis, Shire, Sobi, Swixx BioPharma, Takeda, and Werfen. Rd'O has received research funding from Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, F Hoffmann-La Roche, BioMarin, Sobi, and Sanofi; and honoraria from Takeda, CSL Behring, LFB, Novo Nordisk, Octapharma, F Hoffmann-La Roche, BioMarin, Sobi, Sanofi, and UniQure. PM is a member of a board of directors or advisory committee for F Hoffmann-La Roche Canada and Bayer. SK is an employee of Genentech. VT is an employee of F Hoffmann-La Roche. ADS is an employee of Indiana Hemophilia and Thrombosis Center,; received consultancy fees from Sangomo Biosciences, Prometic Life Sciences, and Sigilon; research funding from Bioverativ, Sanofi, Genentech, Kedrion Biopharma, Novo Nordisk, Pfizer, Sigilon, Takeda, ProMetic Life Sciences, and Freeline; and honoraria from Genentech, Sigilon, Novo Nordisk, Pfizer, and Catalyst Biosciences; speaker's bureau fees from Genentech and Novo Nordisk; and is a member of a board of directors or advisory committee for Hemophilia Foundation, Genentech, Sigilon, Novo Nordisk, and Sanofi. JO has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda; and consultancy, speaker's bureau, honoraria, scientific advisory board, and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai Pharmaceutical, CSL Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, F Hoffmann-La Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. CH has received research funding from Bayer, Shire/Takeda, Pfizer, Novo Nordisk, CSL Behring, and Sobi; honoraria and speaker's bureau fees from Bayer, Shire/Takeda, Pfizer, Novo Nordisk, CSL Behring, Octapharma, Sobi, LFB, CAF-DCF, F Hoffmann-La Roche, UniQure, and BioMarin., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February-June 2020; n = 769 (66%)) and later (July 2020-February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11-0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01-3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22-0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81-1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes., (©The Author 2022. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Background: Primary prophylaxis with factor VIII concentrates is the therapeutic gold standard for severe hemophilia A. Although this approach will change substantially with the use of nonsubstitutive therapies, the long-term effects of primary prophylaxis remain unclear. We present information on joint health with tailored primary prophylaxis in a consecutive series at a single center., Methods: We retrospectively analyzed 60 patients who did not develop early inhibitors. The annual bleeding rate and annual joint bleeding rate, prophylaxis characteristics, physical activity, adherence, and development of inhibitors were compared between those with and without joint involvement at the end of follow-up. Joint involvement was defined as a Hemophilia Joint Health Score or Hemophilia Early Arthropathy Detection with an ultrasound score ≥1., Results: Among 60 patients with median follow-up of 113 ± 6 months after starting prophylaxis, 76.7% had no joint involvement at the end of the follow-up. Those without joint involvement started prophylaxis at a younger median age (1 [IQR 1-1] year vs 3 [IQR 2-4.3] years). They also had lower annual joint bleeding rate (0.0 [IQR 0-0.2] vs 0.2 [IQR 0.1-0.5]), were more often physically active (70% vs 50%), and had lower trough factor VIII levels. Adherence to treatment was not significantly different between groups., Conclusion: Initiation of primary prophylaxis at a younger age was the main factor associated with long-term preservation of joint status in patients with severe hemophilia A., (© 2022 The Authors.)

Background: Several cases of unusual thrombotic events and thrombocytopenia were described after vaccination with recombinant adenoviral vectors encoding the spike protein antigen of SARS-CoV-2., Objectives: The objective of this study was to elucidate the impact of a COVID-19 heterologous vaccination schedule, including priming with adenovirus vaccine, on hemostasis profiles., Methods: The present study is a subanalysis of the CombiVacS clinical trial initiated in April 2021 that included adult participants previously vaccinated with a single dose of ChAdOx1-S. Between 8 and 12 weeks after vaccination, they were randomly assigned (2:1) to receive either BNT162b2 vaccine (intervention group, n  = 99) or continue observation (control group, n  = 50). Samples drawn before and 28 days after a vaccination with BNT162b2 were analyzed for platelet count and markers of hemostasis (D-dimer, anti-PF4 antibodies, cfDNA, PAI-1, thrombin generation, and serum capacity to activate platelets)., Results: Platelet count from all participants after receiving BNT162b2 was within the normal range. Anti-PF4 antibodies were present in 26% and 18% of the subjects from the control and intervention groups, respectively, at day 28. In most cases, the levels of anti-PF4 antibodies were high before receiving BNT162b2. Serum from these participants did not activate platelets from healthy controls. There were no differences between the groups in PAI-1 and cfDNA plasma levels. According to the D-dimer plasma concentration, the thrombin generation test showed that none of the participants had a procoagulant profile., Conclusion: Our data suggest that the heterologous vaccination against COVID-19 with ChAdOx1-S and a second dose with BNT162b2 might be safe in terms of haemostasis., (© 2023 The Authors.)

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The bispecific monoclonal antibody emicizumab bridges activated factor IX and factor X, mimicking the cofactor function of activated factor VIII (FVIII), restoring hemostasis., Objectives: The Phase 3b STASEY study was designed to assess the safety of emicizumab prophylaxis in people with hemophilia A (HA) with FVIII inhibitors., Methods: People with HA received 3 mg/kg emicizumab once weekly (QW) for 4 weeks followed by 1.5 mg/kg QW for 2 years. The primary objective was the safety of emicizumab prophylaxis, including incidence and severity of adverse events (AEs) and AEs of special interest (thrombotic events [TEs] and thrombotic microangiopathies). Secondary objectives included efficacy (annualized bleed rates [ABRs])., Results: Overall, 195 participants were enrolled; 193 received emicizumab. The median (range) duration of exposure was 103.1 (1.1-108.3) weeks. Seven (3.6%) participants discontinued emicizumab. The most common AEs were arthralgia ( n  = 33, 17.1%) and nasopharyngitis ( n  = 30, 15.5%). The most common treatment-related AE was injection-site reaction ( n  = 19, 9.8%). Two fatalities were reported (polytrauma with fatal head injuries and abdominal compartment syndrome); both were deemed unrelated to emicizumab by study investigators. Two TEs occurred (myocardial infarction and localized clot following tooth extraction), also deemed unrelated to emicizumab. The negative binomial regression model-based ABR (95% confidence interval) for treated bleeds was 0.5 (0.27-0.89). Overall, 161 participants (82.6%) had zero treated bleeds., Conclusions: The safety profile of emicizumab prophylaxis was confirmed in a large population of people with HA with FVIII inhibitors and no new safety signals occurred. The majority of participants had zero treated bleeds., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Prophylaxis to prevent bleeding is highly recommended for hemophilia patients. The development of new drugs and tools for modeling personalized prophylaxis provides the means for people with hemophilia to lead active lives with a quality of life comparable to that of nonhemophilic individuals. The choice of regimens must be made on a highly individual basis. Unfortunately, reference guides neither always concur in their recommendations nor provide directions to cover all possible scenarios. In this review, a group of experts identify the significant limitations and unmet needs of prophylaxis, taking advantage of their clinical experience in the disease, and supported by a rigorous literature update. To perform a more systematic and comprehensive search for gaps, the main cornerstones that influence decisions regarding prophylactic patterns were first identified. Bleeding phenotype, joint status, physical activity, pharmacokinetics/medication properties, and adherence to treatment were considered as the primary mainstays that should allow physicians guiding prophylaxis to secure the best outcomes. Several challenges identified within each of these topics require urgent attention and agreement. The scores to assess severity of bleeding are not reliable, and lead to no consensus definition of severe bleeding phenotype. The joint status is to be redefined in light of new, more efficient treatments with an agreement to establish one scale as the unique reference for joint health. Further discussion is needed to establish the appropriateness of high-intensity physical activities according to patient profiles, especially because sustaining trough factor levels within the safe range is not always warranted for long periods. Importantly, many physicians do not benefit from the advantages provided by the programs based on population pharmacokinetic models to guide individualized prophylaxis through more efficient and cost-saving strategies. Finally, ensuring correct adherence to long-term treatments may be time-consuming for practitioners, who often have to encourage patients and review complex questionnaires. In summary, we identify five cornerstones that influence prophylaxis and discuss the main conflicting concerns that challenge the proper long-term management of hemophilia. A consensus exercise is warranted to provide reliable guidelines and maximize benefit from recently developed tools that should notably improve patients' quality of life., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Bleeding in people with hemophilia A can be life threatening, and intra-articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported., Objectives: We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice., Patients/methods: Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial., Results: In the 221 participants enrolled in the NIS (Cohort A, n  = 103; Cohort B, n  = 24; Cohort C, n  = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra-individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis., Conclusion: A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)