Introduction: von Willebrand Disease (VWD) is a heterogeneous disorder resulting from abnormalities of quantity and function of von Willebrand factor (VWF). The primary symptom of bleeding may manifest in different degrees ranging from mild to severe. The diagnosis and management of severe patients presents with challenges and may require a unique approach that is supported by the ASH ISTH NBDF WFH 2021 guidelines on the management of von Willebrand disease in its recommendation which states “In patients with VWD with a history of severe and frequent bleeds, the guideline panel suggests using long-term prophylaxis rather than no prophylaxis.” Definitions and criteria identifying this group of severe patients vary, taking into account bleeding symptoms, functional level, diagnostic VWD classification, and genetic findings, without meeting any specific standard that would be ideal. This project seeks to establish a working definition of severe von Willebrand disease by consensus amongst a group of experts on VWD. Method: A panel of experts were first identified. A total of 23 individuals were invited, with 17 experts agreeing to participate and contribute their opinion. The panel represented a diverse opinion with 14 residing in North America, 2 in Europe, and 1 in Asia, and consisted of 12 physicians, 4 doctoral experts, 4 patients or family members, and 2 with other fields of expertise. A modified Delphi method was selected to establish a consensus. Responses were shared with everyone, although those providing the responses were able to remain anonymous to the rest of the panel. Modification to the methodology included using electronically disseminated surveys to gather opinions in each round and to anonymously share everyone's comments. An initial meeting occurred at the outset to establish the fields and identify the potential criterion within each field that would become the subject for questioning. Questionnaires probed criterion that potentially could be utilized in a definition from each of the fields of genetics, diagnostic classification, functional laboratory results, and clinical bleeding symptoms and a summary of the responses after each round was completed. Each round of question and answers were disseminated sequentially with the subsequent round narrowed and focused by the previous round. Each expert's opinion was summarized to prevent it from interfering with the other expert's opinion. A predefined criteria of 80% concurring opinions established a consensus. Results: The first round established that 1) genetics alone is currently not enough to establish a patient as having severe disease, 2) no diagnostic classification of VWD was sufficient to determine severe disease and 3) any VWD type may be severe or be at risk for severe symptoms, responding most Type 3 VWD are severe (but not all), many Type 2 VWD are severe, and some Type 1 VWD are severe. A preliminary draft definition was created for the summary and a second-round questionnaire was dispersed to further refine it. The second and final round resulted in the following working definition of severe von Willebrand disease: A. Anyone meeting the diagnostic classification for von Willebrand disease AND B. Any VWF antigen or activity: Result <20% regardless of bleeding phenotype Or Result <30% with excessive bleeding symptoms including: a. Bleeding that resulted in hospitalization, required surgical procedure, red blood cell transfusion, Hemoglobin decrease >2g/dL, or b. Intracranial, intraspinal, pericardial, retroperitoneal, intramuscular bleeding with compartment syndrome, or c. Persistent or recurrent bleeding that is disruptive of work or school. Conclusion: von Willebrand disease is a heterogeneous disorder in which management and treatment of the group of patients with severe disease requires a very different approach; however, no specific or uniform standards exist for defining this patient group. This project creates a working consensus definition of severe von Willebrand disease, being vetted by ISTH Scientific and Standardization Committee, which will allow for consistent identification and therefore improved and more effective care of this population.

Gene therapy for severe hemophilia A employs an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in FVIII activity. Thus, hepatocyte health is an essential aspect of safe and successful gene therapy. Many people living with hemophilia A have current or past chronic hepatitis C virus infection, metabolic dysfunction-associated steatosis or steatohepatitis, or other conditions that may compromise the efficacy and safety of AAV-mediated gene therapy. In addition, gene therapy may induce an immune response to transduced hepatocytes, leading to liver inflammation and reduced FVIII activity. The immune response can be treated with immunosuppression, but close monitoring of liver function tests and factor levels is necessary. The long-term risk of hepatocellular carcinoma associated with gene therapy is unknown. Routine screening by imaging for hepatocellular carcinoma, preferable every 6 months, is essential in patients at high risk and recommended in all recipients of hemophilia A gene therapy. This paper describes our current understanding of the biologic underpinnings of how liver health affects hemophilia A gene therapy, and provides practical clinical guidance for assessing, monitoring, and managing liver health both before and after gene therapy.

Background: While there are multiple studies describing combined coagulation factor deficiencies, their genetic defects and clinical significance remain largely unknown. We present the case of an asymptomatic Black female with deficiencies of both coagulation factor XI and factor XII. To our knowledge, the combination of coagulation factor XI and XII deficiencies has not previously been reported in a Black individual. Case Report: In April 2024, a healthy 29 year old Black female from Honduras without personal or family history of bleeding or bruising, presented with a prolonged activated partial thromboplastin time (aPTT) that was incidentally found during a routine pre-operative evaluation for elective cosmetic surgery. Her prothrombin time (PT) was normal. Her aPTT was prolonged to 43.4 seconds (reference interval 25.4 - 34.9 seconds) and normalized with 1:1 mixing studies of patient and normal plasma. She was therefore evaluated for deficiencies in factors VIII, IX, and XI, as well as for the presence of a lupus anticoagulant. Her factor VIII and IX levels were normal. No lupus anticoagulant was detected. Her factor XI levels were decreased: 47% in April 2024, 56% in June 2024, and 58% in July 2024 (reference range 60 - 150%). Her factor XII levels were also decreased at 39% in April 2024 and borderline normal at 51% in July 2024 (reference range 50 - 150%). She has no past medical history and has never had excessive bleeding. She has been pregnant once and delivered a healthy baby via an uncomplicated spontaneous vaginal delivery at full term. Conclusion: Although detection and identification of combinations of coagulation factor deficiencies is readily available, their underlying genetic defects and clinical significance requires ongoing investigation.

IntroductionIn the past HIV infection was a common complication of haemophilia therapy. Gene therapy trials in Haemophilia patients using rAAV have shown promising results; Unfortunately, the majority of gene therapy trials studies have excluded HIV positive patients. We decided to systematically review the published clinical trials using rAAV for HIV prevention. MethodsA comprehensive literature search was performed to identify studies evaluating clinical trials using rAAV for HIV. The search was conducted using the MEDLINE/PubMed databases. Search keywords included 'gene therapy', 'adeno-associated virus', 'HIV' and 'clinical trial'. ResultsThree studies met our inclusion criteria. Two were phase 1 studies and one was a phase 2 study. One study examined an AAV coding for human monoclonal IgG1 antibody whereas the other two studies delivered a vector coding for viral protease and part of reverse transcriptase. All studies administered the vaccine intramuscularly and showed a response as well a good safety profile. DiscussionThe concept of using a viral vector to prevent a viral infection is revolutionary. Due to the paucity of information regarding application of any gene therapy in HIV patients and the potential use of gene therapy in haemophilia patients with HIV in the future warrants attention.

INTRODUCTION:The experiences of patients with mild-to-moderate haemophilia differ from those of patients with severe haemophilia or those without a bleeding disorder and include a challenging diagnosis and variability in bleeding symptoms and treatment needs. In addition, there is a significant lack of data on mild-to-moderate haemophilia, and many unmet needs remain to be identified and addressed in this group of patients.METHODS:Challenges for these patients, including women with haemophilia, were identified during a roundtable meeting attended by a group of US-based experts including healthcare professionals (e.g., physicians, nurses, and physical therapists) and patients who live with a bleeding disorder.RESULTS:Identified unmet needs included a lack of proper education on the management of their disorder and prompt treatment of bleeds, absenteeism from school and work, and challenges with personal relationships. Initiatives to assist with alleviating these unmet needs were proposed and include suggestions for healthcare professionals, haemophilia treatment centres (HTCs) and national and local organizations within the bleeding disorders community. These included HTC and community engagement programmes for patients with mild-to-moderate haemophilia, revised transition guidelines for these patients as they approach adulthood and revised diagnostic classification of mild and moderate haemophilia. Challenges unique to women with haemophilia and ways to address these issues were also discussed.CONCLUSION:This paper summarizes the challenges, initiatives and suggestions that were identified by the haemophilia experts during the roundtable meeting.

Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 x 10(11); 1.0 x 10(12); or 3.0 x 10(12) vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of similar to 20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization.

Background: Intra-articular bleeding (hemarthrosis) accounts for 80-90% (Roosendaal, et. al. Semin Thromb Hemost . 2003;29:37) of all bleeds and more than 90% of serious bleeding events in patients with severe hemophilia (Valentino. J Thromb Haemost . 2010;8:1895). Recurrent hemarthroses result in progressive joint damage and the development of hemophilic arthropathy (HA) in up to 50% of adults with hemophilia (Forsyth, et al. Haemophilia . 2014;20:44). Acetaminophen is commonly prescribed for pain due to HA yet has limited efficacy at therapeutic doses (Rodriguez-Merchan. Blood Rev. 2018;32:116). Traditional non-steroidal anti-inflammatory drugs (tNSAIDs) inhibit platelet function and cause gastrointestinal (GI) complications including bleeding, both of which can be harmful in patients with hemophilia (Rodriguez-Merchan. Blood Rev. 2018;32:116; Brooks, et al. Rheumatology . 1999;38(8):779). Opioids are prescribed in over 60% of patients with HA(Witkop, et al. Haemophilia. 2012;18:e115) despite dependence, potential for abuse, and an increased risk of falls and other opioid-related injury (Rodriguez-Merchan. Blood Rev. 2018;32:116). Given an unmet need in pain management for HA, alternate approaches are needed. TRM-201 (rofecoxib) is a cyclooxygenase-2 (COX-2) selective NSAID with no impact on platelet function and a lower GI risk than tNSAIDs (Vioxx (rofecoxib) package insert. Merck & Co. I, ed. Whitehouse Station, NJ, 2004). The RESET-HA study is designed to evaluate the efficacy and safety of rofecoxib for HA pain management. Methods/Design: RESET-HA is a multi-national, randomized, double-blind study to evaluate the efficacy and safety of rofecoxib in hemophilia A or B patients with diagnosed HA, aged 12 to 75 years and is based on a previous pilot study (Tsoukas, et al. Blood, 2006;107:1785). Patients must have a history of joint bleeding, and chronic symptomatic pain in one or more joint(s) on 20 of the 30 days prior to screening. Exclusion criteria include use of opioids for greater than 4 days/week, or opioid transdermal patches in the 30 days prior to screening, history of GI perforation, ulcer or bleeding, peptic ulcer disease and major cardiac ischemic symptoms or events. Randomized patients (n=80 per arm) are washed out of analgesics prior to daily administration of TRM-201 (17.5 mg/day) or placebo for 12 weeks (Part I) during which acetaminophen (Stage-1) and acetaminophen plus codeine (Stage-2) are available as rescue medication (where available and acceptable to the patient and study doctor). The patient assessment of hemophilic arthropathy pain, a 0- to 10-point numeric rating scale validated for the assessment of pain across many disease states, is recorded daily. The primary endpoint is the placebo adjusted change from baseline in weekly average of patient assessment of daily HA pain score at Week 12. Key secondary endpoints include patient assessments using the PROMIS physical function instrument and pain interference from the Brief Pain Inventory. Sleep disturbance is also measured using the PROMIS instrument. The study explores the efficacy of rofecoxib on the number of suspected joint bleeds and on the amount of rescue medication used. Following Part I, all study patients (regardless of original randomization arm) receive rofecoxib 17.5 mg once daily for up to 12 additional months (Part II). During Part II of the study, only acetaminophen will be provided as rescue medication. Discussion: The RESET-HA study is intended to evaluate the efficacy and safety of TRM-201 in patients with HA and is the first Phase III trial ever conducted to assess a treatment for HA pain. Pain management in HA requires analgesic anti-inflammatory treatment that does not exacerbate bleeding. Rofecoxib has been shown to have no effect on platelet function, even at supratherapeutic doses(Vioxx (rofecoxib) package insert. Merck & Co. Whitehouse Station, NJ, 2004), a decreased risk of GI side effects, including GI bleeding compared with tNSAIDs, and no greater cardiovascular risk than equipotent doses of COX-2 selective and tNSAIDs (U.S. Food and Drug Administration. J Pain Palliat Care Pharmacother. 2005;19:83). TRM-201 is anticipated to provide analgesic efficacy, with an acceptable tolerability and safety profile, and could become a new treatment option that may possibly facilitate the avoidance of opioid use in patients with HA. (NCT04684511)

Haemophilia is a rare X-linked disorder characterized by a deficiency or dysfunction in circulating coagulation factor VIII or IX. Patients with severe haemophilia are at an increased risk of spontaneous bleeding predominantly into the joints, potentially leading to arthropathy and chronic disability. Haemophilia B is often assumed to be less phenotypically severe than haemophilia A. There has been extensive research and discussion on the value of trough levels in haemophilia A, and many physicians use trough levels as a guide to develop individualized treatment regimens. We read with interest the letter published in Haemophilia from Gill et al, which demonstrated that high trough levels were achievable in patients treated with rIX-FP (IDELVION®; CSL Behring), an extended half-life albumin fusion protein, on an extended dosing regimen.1 This letter intends to build on this data and provoke thought around individualizing treatment, using trough levels as a guide to provide optimized treatment for patients with haemophilia B. It has previously been shown that increased time spent below 1% FIX activity is associated with a higher bleeding rate,2 but a trough level capable of preventing all bleeds has not been determined for patients with haemophilia B. Target trough levels for patients with haemophilia A have been widely discussed; it is important to also consider these conversations for patients with haemophilia B. Recent experience has shown that patients with haemophilia B treated with extended half-life (EHL) FIX products can still experience breakthrough bleeding, despite seemingly adequate trough levels. This phenomenon is also seen in patients with mild haemophilia A and those treated with gene therapy. These data suggest that current trough-guided dosing protocols are inadequate to achieve zero bleeding for all patients. An abstract presented at the 27th annual Congress of the International Society on Thrombosis and Haemostasis, 2019, suggested that extravascular levels of rIX-FP are lower than with other EHL FIX products and this may be a reason for unexpected bleeding.3 However, their analysis was subject to a number of limitations, including a low number of participating Hemophilia Treatment Centers (HTCs) and a lack of data on patients’ baseline data; and, as such, the context of these data is as yet undetermined. This narrative has also been discussed in a recent letter as a potential explanation for uncontrolled bleeding that has been reported in three patients who were switched from twice-weekly rFIX to rIX-FP administered every 14 days.4 Again, a number of issues with this report bring into question the validity of the hypotheses presented. One of the most concerning issues was that the switching protocol was not in line with the rIX-FP product label, which states that patients should be well controlled on a 7-day dosing regimen before switching to an extended dosing regimen. Additionally, their letter reports that all other patients currently treated with rIX-FP at that HTC (n = 22) are doing well on an extended dosing regimen. Stafford et al identified that collagen IV binds extracellular FIX.5 In that study, FIX knockout mice carried the majority of FIX extracellularly and plasma FIX levels did not correlate with bleeding. Mice genetically engineered with a FIX with poor collagen binding had a higher bleeding rate despite high plasma FIX levels. These data suggest that tissue distribution of FIX affects bleeding outcomes. Suggestions that the volume of distribution for each EHL FIX may explain tissue distribution and bleeding still begs the question as to the mechanism that regulates the local concentration of active FIX at sites of bleeding. FIX levels in the plasma versus the extravascular space have never been rigorously studied in humans and, as such, a causal relationship is still to be determined. FIX is found in the extravascular space (whether it contributes to clinical efficacy or not) and cannot be measured by pharmacokinetic assessments; therefore, trough levels may not directly correlate with the amount of FIX present in the tissues. While pathophysiologically interesting, there is currently insufficient evidence to support the hypothesis that increased FIX in the extravascular space improves haemostatic efficacy in patients with haemophilia B, especially since activated FIX is required at the site of bleeding. Despite these potential differences in extravascular distribution, all EHL FIX products have shown excellent efficacy in clinical trials.6-8 Differences in extravascular distribution observed across FIX products may also be due to variances in measurement parameters. In particular, inconsistency in pharmacokinetic (PK) models utilized across clinical trials makes indirect comparisons unreliable, and the introduction of multi-compartmental models and longer sampling times for the pharmacokinetics of EHL FIX have made the routine pharmacokinetic studies used in clinical trials unsatisfactory.9 Additionally, different aPTT reagents have been shown to have varied performance across different FIX molecules.9 Comparisons across studies must fully consider the comparability of the population and PK models utilized before drawing robust conclusions. Circulating factor levels are used to determine dosing regimens, and higher circulating FIX levels are generally associated with improved clinical outcomes. Although espousing a minimum plasma FIX level that protects patients from all bleeding would be

Miguel A Escobar,1 Christopher E Walsh,2 David L Cooper,3 Guy Young41Department of Internal Medicine, University of Texas Health Science Center at Houston—McGovern Medical School, Houston, TX, USA; 2Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3Clinical Development and Medical Affairs - Biopharm, Novo Nordisk Inc, Plainsboro, NJ, USA; 4Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USAThe safety and efficacy of N9-GP (nonacog beta pegol; Novo Nordisk A/S, Bagsværd, Denmark), a recombinant glycoPEGylated factor IX(FIX) with extended half-life (EHL),1 was investigated in the multinational, Phase 3, paradigm 2 trial (NCT01333111), previously reported by Collins et al in Blood.2 The trial was conducted in accordance with the Declaration of Helsinki and written informed consent was provided by all participants. Prior to trial initiation, the protocol, the protocol amendments, the consent form, and the patient information sheet were reviewed and approved according to local regulations by appropriate health authorities and by independent ethics committees/institutional review boards (see Table S1). Patients 13–70 years of age with previously treated hemophilia B (≤2% baseline FIX) were allocated to either once-weekly prophylaxis or on-demand (OD) treatment. TheODtreatment was a US Food andDrugAdministration requirement prior to enrolling patients on prophylaxis in the USA.

Introduction: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. Aim: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. Methods: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. Results: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. Conclusion: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) initiative was launched in an effort to address specific gaps in the understanding of the psychosocial impact of mild-moderate-severe hemophilia B. The original Hemophilia Experiences, Results and Opportunities (HERO) qualitative study evaluated the needs of people with hemophilia A or B in multiple countries; however, a majority of participants had the more common moderate-severe hemophilia A. The B-HERO-S study was designed in collaboration with the hemophilia community to evaluate the needs of adults with hemophilia B and caregivers of children with hemophilia B, including affected women and caregivers of girls with hemophilia. The report presented here describes participant demographics and comorbidities, as well as treatment regimens and access to treatment. Bleeding symptoms were reported by 27% of mothers of children with hemophilia B who participated. Women were more likely than men to self-report arthritis and depression/anxiety as comorbidities associated with hemophilia B. More adults and children with hemophilia B were on routine treatment than on on-demand treatment, and a high percentage of adults with moderate hemophilia B received routine treatment (86%). Many adults with hemophilia B (78%) and caregivers (69%) expressed concern about access to factor in the next 5 years, and of adults with hemophilia B, women more commonly experienced issues with access to factor in the past than did men (72% vs 44%). The findings of the B-HERO-S study reveal potential unmet needs of some patients with mild-moderate hemophilia B, and the results may be leveraged to inform patient outreach by hemophilia treatment centers and education initiatives.

Here we review the recent literature on Hemophilia gene transfer/therapy. Gene therapy is one of several new technologies being developed as a treatment for bleeding disorders. We will discuss current and pending clinical efforts and attempt to relate how the field is trending. In doing so, we will focus on the use of recombinant Adeno-associated viral (rAAV) vector-mediated gene transfer since all currently active trials are using this vector. Recent exciting results embody nearly 20 years of preclinical and translational research. After several early clinical attempts, therapeutic factor levels that can now be achieved reflect several modifications of the original vectors. Patterns of results are slowly starting to emerge as different AAV vectors are being tested. As with any new technology, there are drawbacks, and the potential for immune/inflammatory and oncogenic risks have emerged and will be discussed.

The burden of disease in haemophilia patients has wide ranging implications for the family and to society. There is evidence that having a current inhibitor increases the risk of morbidity and mortality. Morbidity is increased by the inability to treat adequately and its consequent disabilities, which then equates to a poor quality of life compared with non-inhibitor patients. The societal cost of care, or 'burden of inhibitors', increases with the ongoing presence of an inhibitor. Therefore, it is clear that successful eradication of inhibitors by immune tolerance induction (ITI) is the single most important milestone one can achieve in an inhibitor patient. The type of factor VIII (FVIII) product used in ITI regimens varies worldwide. Despite ongoing debate, there is in vitro and retrospective clinical evidence to support the use of plasma-derived VWF-containing FVIII concentrates in ITI regimens in order to achieve early and high inhibitor eradication success rates.

Introduction: Health-related quality-of-life (HRQoL) is impaired in patients with severe congenital hemophilia due to pain and functional impairment associated with hemophilic arthropathy. The impact of mild or moderate hemophilia on HRQoL and on women with hemophilia in particular is less well characterized. Use of standardized instruments for assessment of pain/depression/anxiety also remains uncommon in patients with hemophilia.

Background: The paradigm (TM) 2 and 4 phase 3 clinical trials investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in previously treated haemophilia B patients. Aim: These post hoc analyses investigated the bleeding patterns in target joints. Methods: Patients randomized to 40 or 10 IU kg(-1) once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease-specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis (ISTH) definition of target joints was used. Results: A total of 67% and 8% of patients in the 40 and 10 IU kg(-1) arm, respectively, did not experience target joint bleeds during the paradigm (TM) 2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm (TM) 2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg(-1) arms respectively. All target joint bleeds in the 40 IU kg(-1) once weekly prophylaxis arm were controlled with a single injection of 40 IU kg(-1) nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg(-1) arms, respectively, were no longer considered target joints at the end of the paradigm (TM) 2 trial. At the end of the paradigm (TM) 4 extension trial, all target joints in the 40 IU kg(-1) arm were no longer considered target joints. Conclusion: Routine prophylaxis with 40 IU kg(-1) once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients.

The previously published mortality studies are limited in hemophilia populations but suggest that there is no increased risk of mortality in factor VIII inhibitor patients. This retrospective study analyzed surveillance data collected on 7,386 males with severe hemophilia A over a 13-year period to assess the association between a current inhibitor and death. During the study period, 432 participants died, among whom 48 were patients with an inhibitor. Clinical characteristics most strongly associated with death were increased number of reported bleeds, signs of liver disease, infection with either HIV or HCV, and the presence of inhibitor. Patients who underwent successful tolerization were not considered inhibitor patients in our analysis. In a multivariable analysis, the odds of death were 70% higher among patients with a current inhibitor compared to those without an inhibitor (P < 0.01). Deaths among patients with inhibitors were much more likely to be attributed to bleeding complications than those among patients without an inhibitor (42 vs. 12%, P < 0.0001). We conclude that males with severe hemophilia A and a current inhibitor are at increased risk of death.