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Presentation Details
| Major Orthopedic Surgeries Conducted Under Fitusiran Prophylaxis in People With Hemophilia A and B, With and Without Inhibitors Larissa Bornikova1, Laurent Frenzel2, Kaan Kavakli3, László Nemes4, Stephanie P'ng5, Jing Sun6, Chur-Woo You7, Ezio Zanon8, Vanessa Salinas9, Laurel A.Menapace10, Salim Kichou11, Abhimanyu Yarramaneni10, Yuqian Shen10, Alok Srivastava12. 1Cancer Center, Massachusetts General Hospital, Boston, MA, USA.2Groupe Hospitalier Necker Enfants Malades, Paris, France.3Ege University Faculty of Medicine, Izmir, Turkey.4Central Hospital of Northern Pest – Military Hospital, Budapest, Hungary.5Fiona Stanley Hospital, Murdoch, Australia.6Nanfang Hospital, Guangzhou, China.7Eulji University Hospital, Daejeon, South Korea.8Azienda Ospedale Università di Padova, Padua, Italy.9Center for Inherited Blood, Disorders, Orange, CA, USA.10Sanofi, Cambridge, MA, USA.11Sanofi Genzyme, Paris, France.12St.John's Medical College Hospital, Bengaluru, India |
Abstract
Introduction Data regarding the perioperative management utilizing novel non-factor hemophilia therapies is limited. Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia (PwH) A/B, with and without inhibitors. Breakthrough bleed management guidelines (BMG) with reduced dose and frequency of clotting factor concentrates (CFC)/bypassing agents (BPA) were recommended for perioperative management (Table 1). Here we describe hemostatic outcomes and provide case reviews of orthopedic surgeries performed in PwHA/B aged ≥12 years receiving fitusiran prophylaxis, regardless of inhibitor status. Methods All major orthopedic surgeries in the fitusiran clinical program until 14 June 2023 were evaluated, including participants on antithrombin-based dose regimen (AT-DR) and fixed 80 mg once-monthly dose. Procedures conducted during fitusiran prophylaxis with AT levels <60% were included. Major orthopedic surgeries were defined as operations on a joint or bone and associated soft tissue. Procedure management was at investigator/surgeon’s discretion. Perioperative hemostatic control was assessed using the ISTH 4-point response scale (excellent/good/moderate/poor) on the day of surgery. Informed consent and ethics committee approval were obtained. Results Nineteen major orthopedic surgeries were performed in 16 participants (Table 2). Seven surgeries were conducted with the AT-DR and 12 surgeries were conducted with the fixed 80 mg dose. Hemostatic control was rated as excellent/good in 13/15 (87%) and moderate in 2/15 (13%; knee arthroplasty and total knee replacement, both treated with BPAs) orthopedic surgeries with hemostatic assessment available on the surgery day. Reduced doses of CFC/BPAs, at ~50% of conventional quantities, were used in 15/19 (79%) orthopedic surgeries, per BMG. One surgery (metal plate and screw fixation in tibia) was managed successfully with fitusiran prophylaxis without any CFC/BPA. On the surgery day, AT level was 9.1% and hemostatic control was good; no complications were reported in the perioperative period. AT concentrate (ATIII) was utilized per investigator discretion, beginning on the day of surgery, in two participants who underwent orthopedic surgery, with excellent hemostatic control on the day of the surgery in one participant (internal fixation for femoral/patella fractures) and moderate in the other (right knee arthroplasty). No antifibrinolytic use was reported during major orthopedic surgeries. One postoperative lower limb deep vein thrombosis occurred in one participant who underwent knee arthroplasty in the setting of pre-existing thrombotic risk factors, including morbid obesity restricting mobility and excessive FVIII dosing exceeding BMG (26 injections over 15 days, with doses of up to 25.38 IU/kg per day) and ISTH recommendations; the participant discontinued the study 14 days after surgery due to this event. No postoperative safety findings or complications were reported when BMG were followed. Conclusion Major orthopedic surgeries can be safely and effectively performed in PwHA/B, with and without inhibitors, receiving fitusiran prophylaxis using reduced CFC/BPA doses as per BMG, highlighting the benefit and efficacy of reduced CFC/BPA consumption with fitusiran prophylaxis. Reversal of the effects of fitusiran with ATIII administration is not necessary. Postoperative thrombosis was reported in one participant with pre-existing increased thrombotic risk when dosing exceeded BMG, highlighting the importance of BMG adherence.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.