Haemophilia.

Haemophilia A and B are congenital X-linked bleeding disorders resulting from deficiencies in clotting factors VIII (haemophilia A) and IX (haemophilia B). Patients with severe deficiency, defined as having less than 1% of normal plasma factor activivity, often have spontaneous bleeding within the first few years of life. Those with moderate and mild deficiencies typically present with post-traumatic or post-surgical bleeding later in life.

Adeno-associated virus-based gene therapy for hemophilia-addressing the gaps.

Adeno-associated virus-based gene therapy for hemophilia has emerged as a revolutionary treatment option, offering potential correction of clotting factor deficiency through a single intravenous infusion of functional genes directed to hepatocytes. With 3 gene therapies recently approved, this approach shows promise in transforming the lives of individuals with hemophilia. However, the complexity of gene therapy and the lack of standardization of methods in different components of this therapy can lead to unique challenges for clinical implementation.

"A Study of Intracoronary Thrombolytic Agents In High Thrombus Burden Lesions During Primary PCI".

Objectives: High thrombus burden during Primary Percutaneous Coronary Intervention begets poor outcomes; there are several lacunas in the management of those patients.- The purpose of this study is to analyse the long-term outcomes of patients undergoing primary percutaneous coronary intervention with high thrombus burden, treated with intracoronary thrombolysis as an adjunctive therapy.

Methods: In this prospective observational study, 108 consecutive primary percutaneous coronary intervention patients with high thrombus burden were stratified into two groups basing on whether they received intracoronary thrombolytic agent before stent implantation.

Hyaluronic-Acid-Functionalized Tofacitinib Loaded Transethosomes for Targeted Drug Delivery in Rheumatoid Arthritis.

The Janus kinase inhibitor tofacitinib (TOF) is an FDA-approved drug for rheumatoid arthritis (RA) treatment, but its long-term oral use leads to significant systemic side effects. The present research aimed to conquer these challenges by formulating hyaluronic-acid-coated transethosomes (HA-TOF-TE), a novel system for targeted, topical delivery of TOF to reduce systemic toxicity and improve therapeutic efficacy. Transethosomes were synthesized via the cold sonication technique with HA functionalization enabling CD44 receptor-mediated targeting of inflamed synovial tissue.

Factor VIII Antibodies Demonstrate Type I or Type II Kinetics in Acquired Haemophilia A.

Background: Acquired haemophilia A (AHA) is an acquired bleeding disorder resulting from autoantibodies against Factor VIII (FVIII). Previous studies have reported differences in FVIII inhibitor kinetics (type I or type II) in AHA compared to severe haemophilia A.

Aim: To characterise inhibitor kinetics in AHA and evaluate the proportions displaying type I, II or indeterminate kinetics.

Contrasting Approaches in the Implementation of GRADE Methodology in Guidelines for Haemophilia and Von Willebrand Disease.

Introduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.

Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.

Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE.

Long-term safety and efficacy of fitusiran prophylaxis, and perioperative management, in people with hemophilia A or B.

Fitusiran is an investigational small interfering RNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia. Here, we present the results of a completed phase 2 open-label extension study, which evaluated the long-term safety and efficacy of fitusiran in participants with moderate or severe hemophilia A or B, with or without inhibitors. Male participants who had completed the phase 1 study (ClinicalTrials.

International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal.

Introduction: Evidence-based clinical practice guidelines drive optimal patient care and facilitate access to high-quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non-randomized and well-designed observational studies and real-world data, is challenging. The methodology used for assessing available evidence should consider this critical fact.

UKHCDO gene therapy taskforce: Guidance for implementation of haemophilia gene therapy into routine clinical practice for adults.

Introduction: 2022 was a landmark year with two adeno-associated viral vectors (AAVs) receiving conditional marketing authorization from EMA for the treatment of persons with severe haemophilia A and severe to moderately severe haemophilia B and a third in 2024. Gene therapy is a transformative, irreversible treatment with long-lasting effects, necessitating development of new clinical pathways to ensure optimal outcomes.

Aim: To develop a consensus framework and service specification for delivery of AAV gene therapy for haemophilia in adults within the UK using the hub-and-spoke model proposed by the European Association of Haemophilia and Allied Disorders and the European Haemophilia Consortium.

Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicentre, open-label, randomised, phase 3a trial.

Background: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff.

Assessment of Otolith Function with Subjective Visual Vertical Test in Sensorineural Hearing Loss: An Analytical Cross - Sectional Study.

The inner ear is responsible for balance and auditory function. Sensorineural hearing loss (SNHL) affects auditory function across various age groups. Vestibular apparatus, particularly the otolith organ can also be affected in cases of SNHL because of the close proximity of the otolith organs with the cochlea inside the bony labyrinth.

Moving towards Normalization of haemostasis and health equity: Evolving treatment goals for haemophilia A.

Background: Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile.

Treatment Goals: The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care.

Long-term outcomes with emicizumab in hemophilia A without inhibitors: results from the HAVEN 3 and 4 studies.

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.

FRONTIER1: a partially randomized phase 2 study assessing the safety, pharmacokinetics, and pharmacodynamics of Mim8, a factor VIIIa mimetic.

Background: Mim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality.

Objectives: The partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors.

Using theory of change to co-create a programme theory for a telerehabilitation intervention for pain management in people with haemophilia.

Background: Improved approaches for chronic pain management are a clinical and research priority for people with haemophilia (PWH). Involving people with lived experience in the design of a complex rehabilitation intervention strengthens the credibility and plausibility of the intervention, particularly in relation to rare disorders. Here we describe using a 'Theory of Change' (ToC) dialogue-based stakeholder process to create a programme theory for a telerehabilitation intervention.