Will Lester

Introduction: Valoctocogene roxaparvovec is an adeno‐associated virus vector serotype 5 (AAV5)‐mediated gene therapy for severe haemophilia A (HA). Aim: Report the final safety and efficacy results of the phase 1/2 trial of valoctocogene roxaparvovec. Methods: An open‐label phase 1/2 trial (NCT02576795) enrolled adult males with severe HA (factor VIII [FVIII] ≤1 IU/dL) without FVIII inhibitors, anti‐AAV5 antibodies, or liver dysfunction to receive 6 × 10 ¹³ or 4 × 10 ¹³ vg/kg valoctocogene roxaparvovec. Efficacy endpoints included FVIII activity (chromogenic), annualized bleeding rate (ABR) of treated bleeds, annualized FVIII infusion rate, and quality of life. Safety was assessed by adverse events (AEs). Year seven 6 × 10 ¹³ vg/kg cohort results were reported previously. Results: Five of six 4 × 10 ¹³ vg/kg cohort participants completed the 7‐year study. Mean FVIII activity peaked within year 1 for the 4 × 10 ¹³ cohort (week 52 FVIII, 21.1 IU/dL) and decreased to 4.2 IU/dL at the end of year 7. Across all follow‐up, mean ABR declined 87% from baseline to 1.6 bleeds/year and mean annualized FVIII use declined 93% to 10.3 infusions/year. Overall, 3/5 of the 4 × 10 ¹³ participants remain off prophylaxis. Haemo‐QOL‐A Total Score was mostly stable from baseline. The last treatment‐related AE (TRAE) of alanine aminotransferase elevation occurred in year 1. No serious TRAEs occurred after year 1. No participants had thromboembolic events or developed FVIII inhibitors. Conclusion: Over 7 years, valoctocogene roxaparvovec increased FVIII activity from baseline and improved haemostasis compared with FVIII prophylaxis for most participants. The 6 × 10 ¹³ vg/kg dose was more efficacious than 4 × 10 ¹³ vg/kg. No concerning long‐term safety signals were identified.

This chapter provides a comprehensive overview of direct oral anticoagulants (DOACs), focusing on their mechanisms of action, clinical utility, and practical considerations in anticoagulation management. DOACs have revolutionised anticoagulation by selectively targeting thrombin and activated factor X (FXa), offering improved safety, predictable pharmacokinetics, and reduced need for monitoring. The chapter covers their indications, contraindications, dosing, perioperative management, reversal, and use in special populations, including those with renal or hepatic impairment, cancer-associated thrombosis, and extreme body weights. It provides clinicians with practical guidance for the effective application of DOACs in various clinical settings.

Background: Efanesoctocog alfa (EFA) is an ultra‐long half‐life FVIII product. However, measuring the level of EFA using standard one stage (OSA) and Chromogenic assays (CA) is affected by both underestimation and overestimation when using some commonly used APTT reagents for OSA and overestimation when using CA assays. Objectives: ECAT and NEQAS BC distributed samples containing EFA to centres for measurement of EFA using assays available locally. The aim was to provide method specific data and recommendations for additional OSA or CA assays. Methods: In Autumn 2024, four samples with levels of EFA between 5 and 100 IU/dL (based on potency label) were buffered and lyophilized for distribution to 300 hospital and university laboratories. Results: Two‐hundred participants returned 174 OSA and 148 CA results for samples EFA 24:01‐24:04. Twelve different APTT reagents, six were used by ( n ≥ 10) and 10 different chromogenic assays were employed, of which four were used by ( n ≥ 10). Conclusion: The NEQAS BC and ECAT exercise confirmed the field study: over‐estimation for Actin FS OSA and all CA assays at all EFA levels plus an under‐estimation for SynthasIL OSA at EFA levels of: 20, 50 and 100 IU/dL. Centres using Actin FSL on a Siemens/Sysmex or Stago analyser plus centres using Synthafax on a Werfen analysers had median recoveries within ±25% compared to the assigned potency for samples at EFA levels of: 20; 50 and 100 IU/dL. Centres using CK Prest and Pathromtin had median recoveries within ±25% compared to the assigned potency for samples at an EFA levels of 100 IU/dL.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultrarare thrombotic microangiopathy mediated through inherited deficiency in a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13). To date, >200 ADAMTS13 genetic variants have been associated with cTTP. We report longitudinal follow-up from the UK TTP registry in 104 confirmed cTTP cases (91 consented for follow-up) in a large multiethnic national cohort of patients with cTTP, including a large Black African cTTP cohort. A total of 71 ADAMTS13 variants were identified, with N-terminal variants associated with earlier age at presentation. During the follow-up period (median, 63 months; range, 1-179), 80.2% of patients received regular (plasma derived) prophylaxis, which reduced end organ damage, including stroke/transient ischemic attack (19.0%-1.5%) and renal impairment during follow-up. Postpresentation acute TTP episodes were reduced with prophylaxis (0.68 vs 0.06 acute episodes per follow-up year). Despite regular prophylaxis, symptom control remained apparent on plasma-derived therapy (including headache 42.6%, depression/anxiety 13.2%, fatigue 16.2%, and abdominal pain 13.2%). Most patients with cTTP in the United Kingdom have now switched to recombinant ADAMTS13 (n = 43 [58.9%]), owing to inadequate symptom control (53.5%), plasma reactions (30.2%), or subclinical disease activity (16.3%). This work shows the breadth of ADAMTS13 genetic variants in cTTP and demonstrates efficacy of regular prophylaxis in (1) reducing acute TTP episodes and (2) preventing end organ damage, but despite advances, cTTP related symptoms and the use of blood products remained problematic.

Introduction: Immune thrombocytopenia (ITP) is characterised by a low platelet count and increased risk of bleeding. Recent research has also proposed that having ITP increases thrombosis risk. Moreover, certain ITP treatments have been associated with an increased risk of thrombosis. This Delphi study aims to assess haematologist opinion regarding aspects of optimise thrombotic risk management in primary ITP in the UK. Methods: The methodology employed a modified Delphi process with two rounds of evaluation from a panel of experts. A literature review on the topic of primary ITP generated input to a steering group of three experts from the UK attended a virtual meeting in May 2024. During this meeting, and guided by an independent facilitator, the group identified five main domains. From these, 42 statements were agreed and developed into an online survey for testing with a wider panel of peers. Results: Overall, 33 statements achieved consensus agreement, and one statement did not achieve consensus. Eight scenario statements were included to identify preferable treatment options among healthcare professionals. Conclusion: Based on the agreement levels achieved, the steering group formulated a set of recommendations to optimise the management of thrombotic risk in patients with primary ITP in the UK. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.

Summary: Vaccine‐induced immune thrombocytopenia and thrombosis (VITT) is one of several anti‐platelet factor 4 (anti‐PF4)‐associated immune thrombocytopenia and thrombosis (PITT) syndromes. As well as following adenoviral vector vaccines, VITT has recently been described following acute adenovirus infection. We describe a patient with PITT following acute cytomegalovirus infection. The antibody clonotype and PF4 epitopes were distinct from those identified in VITT, and they were detectable as a paraprotein. PITT should be considered in all patients with thrombocytopenia and thrombosis, even without preceding vaccination or heparin, but who otherwise meet the VITT criteria defined by the British Society of Haematology Expert Panel.