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To assess the real‐world efficacy and safety of recombinant factor IX albumin fusion protein (rIX‐FP) in patients with hemophilia B (HB) in France.

Data on dosing frequency, weekly consumption, and bleeds before‐and‐after switching to rIX‐FP, were collected from December 2021 to February 2024. Annualized (spontaneous) bleeding rates [A(s)BRs] were calculated only in patients on prophylaxis with a follow‐up ≥ 6 months.

This interim analysis focused on 77 patients ≥ 12 years; 62 (81%) had severe HB. After switching to rIX‐FP, the infusion interval was 14 (7–14) days. Weekly consumption was 43 (35.5–53) IU/kg. ABRs and AsBRs were 0.5 (0–1.9) and 0 (0–0.7) (n = 63) at 18.2 (12.3–21.9) months of follow‐up. Prophylactic efficacy of rIX‐FP was considered ‘Excellent’/‘Good’ in 65/68 (95%) patients. Among the 43 patients previously treated with rFIXFc, 21 increased the infusion interval from 7 (7–11) days with rFIXFc to 14 (7–14) days with rIX‐FP; 33/43 (77%) reduced weekly factor IX (FIX) consumption from 59.95 (46.35–77.93) to 42.5 (35.88–50.25) IU/kg. Patients maintained good protection against bleeds.

This analysis confirmed that switching to rIX‐FP allows for reducing injection frequency and FIX consumption while maintaining good bleed protection.

Haemophilia, a hereditary bleeding disorder due to a deficiency of clotting factors, causes a predisposition to bleed either spontaneously or secondary to minimal trauma. The bleeds lead to progressive joint damage by late adolescence or early adulthood in the absence of prophylaxis or replacement therapies. In lower-middle-income countries (LMICs) like India, access to prophylaxis for haemophilia being limited, many children develop severe joint disease by young adulthood [1], which significantly impacts their quality of life and productivity. Joint surgeries have offered hope for people living with haemophilia (PwH) with established joint disease, but numerous hurdles exist including a lack of laboratory diagnostics and monitoring facilities, shortage of haematologists and advanced orthopaedic teams, limited insurance coverage and inadequate access to clotting factor concentrates (CFCs) [2]. Comprehensive care centres, when they exist, can address some of these challenges, but the availability of CFCs remains crucial for effective orthopaedic surgeries. Our aim was to assess the impact of the World Federation of Hemophilia Humanitarian Aid Program (WFH HAP) donation of CFCs in orthopaedic surgical interventions at a single comprehensive haemophilia care centre in an LMIC. The study reviewed the clinical data of PwH who underwent major orthopaedic surgeries between November 2017 and June 2023 at a comprehensive care centre in India that previously lacked access to CFCs until the initiation of WFH HAP and analyzed the utilization of CFCs for the orthopaedic surgeries along with immediate surgical outcomes, and the CFC dosing guided by lab monitoring. PwH with inhibitor-positive status were excluded. Additionally, the impact on CFC utilization when performing two surgical interventions in one surgical setting was audited. Statistical analysis was performed with measures of central tendencies, coefficient of variation and student t test using IBM SPSS software version 26. The baseline factor levels, utilisation of CFCs prior to, during and post-operative periods were analysed. Of the 111 PwH registered to Amrita Institute of Medical Sciences, Kochi, Kerala in India from 2017, 87% (n = 97) were Haemophilia A and 14 were Haemophilia B. Surgical intervention was required in 37 PwH (Haemophilia A: 30, Haemophilia B: 7). The study included 21 PwH who underwent major orthopaedic surgeries–19 Haemophilia A (90.5%) and two Haemophilia B (9.5%). Seventeen PwH (80.9%) underwent elective joint replacement surgeries and four PwH (19%) had emergency internal fixation. Seven PwH underwent elective unilateral total knee replacement, two had unilateral total hip replacement and one had unilateral elbow replacement. Seven PwH underwent bilateral total knee replacement on the same day for efficient CFC utilization. The median age of PwH who underwent elective surgery was 40 (range 20–58) years and for emergency surgery was 27.5 (range 18–75) years. Three PwH (14%) with non-severe haemophilia also had surgeries (two emergency and one elective for age-related osteoarthritis). Extended half-life (EHL) CFC was used in 10 PwH (47.6%) and standard half-life (SHL) CFC was used in 2 PwH (9.5%), while the others received a combination of both as per availability. The CFC doses were calculated as per the low-dose practice pattern as utilized in a significant resource-constrained region [2]. None of the PwH in the cohort were on CFC prophylaxis prior to the surgery. Excluding the prosthesis, the mean expenditure for perioperative investigations including the pre- and post-surgery inhibitor screen and mean hospital stay for 14 days was 630 USD (range: 380–700 USD) and 960 USD (range: 735–1050 USD) for elective unilateral total knee arthroplasty and bilateral knee replacement, respectively. For logistic reasons, all PwH undergoing arthroplasty were in-patient for a mean period of 14 days (range 10–16 days). All PwH were evaluated by the team at the comprehensive care centre which includes a clinical haematologist, physiatrist, orthopaedic surgeon and clinical pharmacist along with a haemophilia nurse and coagulation lab team. All PwH taken up for elective joint replacement initially underwent functional assessment of joints by the physiatrist before being referred to an orthopaedic surgeon. Baseline factor levels along with inhibitor screening were performed in the week prior to the surgery for confirmation of the clinical condition. The clinical pharmacist applied for the WFH aid after the requirement of arthroplasty was finalized. The PwH were admitted on the evening prior to the surgery. The haemophilia nurse and clinical pharmacist coordinated with the coagulation lab and primed them regarding the need for repeated laboratory tests for the upcoming surgery on the following day. The lab ran the quality control before the factor assessment well in advance to reduce turn-around time. A stock of 600 units/kg of Factor VIII and 1000 units/kg of Factor IX was ensured before taking up PwHA and PwHB, respectively, for elective unilateral joint replacement. For PwHA who underwent bilateral joint replacement of knee, 1000 units/kg were ensured. The CFC products received for haemostasis through WFH HAP were Advate, Kovaltry, Eloctate, and Afstyla for PwHA and Alprolix, and Alphanine and Mononine for PwHB. PwH received CFC via bolus intravenous infusion 2 h pre-surgery, targeting 100% factor activity. Recovery was confirmed by sampling 15 min post-infusion, with in-person lab transport to prevent preanalytical errors. Those with <80% factor activity received additional CFC before surgery, followed by procedures under general anaesthesia. PwH undergoing dual joint replacements received additional 25 units/kg FVIII as top-up after the first arthroplasty, preceding the second surgery without waiting for interim factor assay results. Post-operatively, all PwH received CFC aiming for an additional 50% activity 8–10 h after the initial dose. Subsequent doses were scheduled 12 h apart for Haemophilia A and 24 h apart for Haemophilia B. Target factor activity for the first 3 days post-surgery was 50%–100%, tapering to 40%–80% from Day 4 to Day 6, 30%–60% from Day 7 to Day 9 and further tapering to 10%–20% from Day 10. Low-dose prophylaxis commenced post-Day 15, twice a week for Haemophilia A and once a week for Haemophilia B for 3 months, targeting peak 20% activity to aid physiotherapy. One PwHA experienced a knee bleed 3 weeks after bilateral knee arthroplasty following discharge during a Physiotherapy session and the prophylactic doses were increased to three times a week after the bleed was controlled. Factor assays, conducted around five times peri-operatively, included pre-operative peak, immediate post-operative trough, and Day 2 morning trough in Haemophilia A and random values in Haemophilia B. Additional tests on Day 4 and 6/7 re-assessed empirical CFC replacement adequacy. CFC utilization remained below empirically recommended WFH guidelines for resource-constrained settings, with no post-operative bleeds or inhibitor development [3]. Table 1 demonstrates the demographics, type of surgery, CFCs used and immediate outcomes of orthopaedic surgeries done using WFH HAP. WFH recommends maintaining pre-operative Factor VIII or IX levels at 120%, with post-operative trough levels of 60%–80% for the initial 72 h, 50% until the 14th day and ideally 40% with 20 units/kg doses before physiotherapy for up to 6 weeks [5, 3, 6, 7]. Resource constraints pose challenges in implementing these international guidelines for PwH undergoing surgery. In 1994, the first low-dose protocol that targeted post-operative trough levels of 20%–40% for FVIII and 15%–30% for FIX for 10 days for PwH undergoing invasive procedures was reported from India. The beneficiaries included 37 PwH (32 PwHA and 5 PwHB) and encompassed orthopaedic, general surgical, neurosurgical and cardiothoracic interventions while ensuring good haemostasis [8]. A subsequent series in 1998 included 16 cases, demonstrating comparable success in various surgeries for severe and moderate PWH [9]. Further validation came from India, managing 18 severe PwH undergoing 20 major surgical procedures using the low-dose CFC protocol [10]. PwH received tailored low-dose protocol treatment with CFC doses adjusted based on individual pharmacokinetics, CFC availability and post-surgery duration. Despite strict adherence, increased CFC boluses were required on Days 1 and 2, especially in bilateral knee replacements, suggesting heightened consumption due to tissue injury. Frequency of CFC administration significantly reduced after Day 4, notably for EHL product recipients from WFH HAP, allowing 24-h intervals by Day 6 and 36-h intervals by Day 9. EHL CFC usage facilitated early discharge, positively impacting overall treatment costs incurred by the PwH. The findings of this retrospective analysis demonstrate the transformative impact of WFH HAP in a comprehensive care centre for PwH in an LMIC. With access to CFCs, effective corrective arthroplasties and orthopaedic surgeries were made possible, providing hope and improved quality of life for PwH with established joint disease. Furthermore, preparing PwH for dual arthroplasties when feasible on the same day with an appropriate supply of EHL CFC will significantly reduce the CFC utilization and also ensure maximal utilization of available WFH HAP. This study demonstrates the feasibility of major surgical interventions and comparable outcomes for PwH with judicious use of factor products in both emergency and elective settings in an LMIC. This could only be achieved with timely aid from WFH HAP and possibly can be replicated in other resource-limited countries. We thank Ashwathy Beenakumary, Chitresh Yadav, Syamaprasad T. V. and Anjusha C. Institutional Ethics Committee clearance obtained. Informed consent to utilise the scientific data for research has been taken from all PwH prior to admission for surgery. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author, Dr Rema Ganapathi The data contain medical information and therefore are not publicly available due to both privacy and ethical restrictions.