Olga Benítez Hidalgo

Extended half-life (EHL) recombinant factor IX (rFIX) concentrates have improved prophylaxis in patients with haemophilia B by reducing infusion frequency and improving adherence. Albutrepenonacog alfa (rFIX-FP, Idelvion®) is an albumin fusion protein with a terminal half-life three to five times longer than standard FIX products. While Bayesian population pharmacokinetic (popPK) platforms such as WAPPS-Hemo are increasingly used for individualized dosing, discrepancies may arise compared with simpler models used in routine practice. We conducted a multicentre, prospective study including 18 patients with severe haemophilia B on rFIX-FP prophylaxis between March 2024 and January 2025. FIX activity was measured by one-stage clotting assay, and PK parameters were estimated using both WAPPS-Hemo and a classical one-compartment model. Simulations with the one-compartment model were performed to evaluate dosing regimens required to achieve trough concentrations (Cmin) of 3 and 5 IU/dL at dosing intervals of 10, 14, and 21 days. The one-compartment model yielded clearance (0.93 mL/h/kg) and half-life (88 h) values that closely matched those reported in pivotal trials (t½ 90–104 h; Cl 0.75–0.9 mL/h/kg), whereas WAPPS systematically overestimated half-life (139 h) and underestimated clearance (0.15 mL/h/kg). Simulations confirmed linear pharmacokinetics: increasing the Cmin from 3 to 5 IU/dL required approximately 1.67-fold higher doses across all intervals. Extending the dosing interval reduced infusion frequency (36.5 → 26.0 → 17.4 infusions/year) but required disproportionately higher daily doses (+59% and +352%). In conclusion, the one-compartment model provided PK estimates more consistent with reference values than WAPPS. Simplified PK modelling may serve as a pragmatic tool to optimize individualized prophylaxis in real-world haemophilia B management.

Background: Hemophilia adversely affects several health domains and impairs the daily life of both patients and caregivers. Objectives: To assess the impact of hemophilia A without inhibitors on humanistic outcomes in adult and young patients and their caregivers in a real-life setting. Methods: This was a 12-month multicenter prospective observational study conducted in 18 Spanish hospitals. Patients who were diagnosed with hemophilia A (PWHs), without inhibitors, and who were 12 years of age or older, and their caregivers were included in the study. Results: A total of 85 PWHs (mean age: 33 years) and 12 caregivers participated in the study; 51 PWHs completed it, representing a 40% lost-to-follow-up rate. Twenty-five percent of PWHs showed maladjustment at study completion, with ‘leisure time’ and ‘work/studies’ being the most affected domains. Quality of life was particularly impaired in the sport, physical health and future areas. ‘Lying/sitting/kneeling/standing’ and ‘leisure activities and sports’ were the most impaired functions. Productivity was mainly affected by presenteeism in adult PWHs; 40 painful joint bleeding episodes were reported. Active strategies were mostly used for coping with chronic pain, and anxiety and/or depression were present in more than 10% of PWHs. Anxiety and depression were more frequently reported by caregivers. Conclusions: The study results suggest sustained impairments in adaptation to their disease, quality of life, and functionality in PWHs without inhibitors, especially related to leisure and sports activities, and a nontrivial proportion of them presented clinical levels of depression and anxiety. Overall impairment was more marked in adults than in children. In addition, due to the limited number of caregivers, their results must be considered exploratory.

Introduction: The value of gene therapies for haemophilia needs to be assessed holistically.Aim: To determine the value of etranacogene dezaparvovec (ED) compared to current extended half‐life (EHL) recombinant factors (rFIX), using multi‐criteria decision analysis (MCDA).Method: MCDA EVIDEM methodology adapted to orphan drugs was used, with nine quantitative criteria and four contextual criteria. The MCDA framework was rated by 28 multidisciplinary experts. Descriptive statistics were performed for quantitative and qualitative criteria.Results: Haemophilia B (HB) was considered a severe disease (mean ± SD: 4.3 ± 0.7) with some unmet needs (mean ± SD 3.3 ± 0.9). Experts found ED more effective (mean ± SD 2.0 ± 2.3) and provide better quality of life (QoL) (mean ± SD: 1.8 ± 1.5) than the comparative HB treatments but with safety uncertainties (mean ± SD ‐1.2 ± 1.8). ED could lead to medical cost and non‐medical cost savings over time (mean ± SD: 1.6 ± 2.0 and 2.0 ± 1.5, respectively). The quality of the evidence was high (mean ± SD: 3.9 ± 0.9). ED was considered aligned with the priorities of the National Health System (NHS) and the specific interests of patients. ED's value contribution was 0.45 (+1 = highest value).Conclusions: ED brings added value in the treatment of moderately severe and severe HB (sHB) compared to current EHL rFIX, addressing the severity of the disease and increasing efficacy and patients’ QoL especially related to the single dose and low bleeding rate. Concerns about long‐term safety need to be addressed.

Key Clinical Message: The increased life expectancy in patients with hemophilia (PwH) over the last years has raised the incidence of comorbidities, including thromboembolic events. Thromboembolic events are rare in PwH and most of them occur in the presence of exogenous risk factors. There is still scarce scientific evidence on the optimal antithrombotic treatment and management approach in this population. In the hemophilic population thromboembolic events are rare. Most of them are often multifactorial and occur in the presence of both exogenous (orthopedic surgery, intensive replacement therapy, use of central venous catheters…) and endogenous (cardiovascular diseases) risk factors. We describe the case of a 43‐year‐old patient with severe hemophilia B (sHB) receiving prophylaxis with eftrenonacog alfa (rFIXFc) and antithrombotic treatment due to portal vein thrombosis. The patient was treated with extended half‐ life factor IX (EHL‐FIX) prophylaxis maintaining higher trough levels to avoid new bleeding episodes associated to the underlying disease and the use of antithrombotic therapy with low molecular weight heparin. EHL‐FIX concentrates allow prolonged intervals between intravenous infusions and higher hemostatic protection thanks to increased factor trough levels. This current case report provides clinical evidence in antithrombotic management in a patient with severe hemophilia B.

BACKGROUND Evidence of net safety and benefit of anticoagulation for stroke prevention in patients with end-stage kidney disease (ESKD) on hemodialysis and with atrial fibrillation (AF) is lacking because patients with advanced CKD and those with end-stage kidney disease (ESKD) have been excluded from randomized clinical trials of stroke prevention in AF. In Europe, apixaban is not approved for the indication of prevention of stroke and systemic embolism in adult patients with ESKD on hemodialysis and AF. AIM To assess the effectiveness and safety according to Apixaban or VKA treatment. The effectiveness outcome was defined by ischemic stroke, all-cause death and myocardial infarction. The safety outcome was defined by a first event of major bleeding, clinically relevant nonmajor bleeding, or all-cause death. METHODS Unicenter, observational and retrospective study. Data was collected between January 2018 and July 2022. We included adult patients with ESKD on hemodialysis and AF and a CHA2DS2-VASc score ≥2 treated with low dose of Apixaban (2.5 mg twice daily) or VKA from the beginning of treatment. Patients in the VKA group received Acenocoumarol. Demographic, laboratory data and clinical presentation of AF were collected. Patients had a minimum follow-up (FU) of 6 months. Apixaban plasma drug concentrations were measured during the FU (week 1 and month 3). Blood samples were draw just before the next dose (Ctrough) and at 2-3 hours (Cpeak) after of drug intake using the Technoclone anti-Xa assay from Technoclone (Vienna-Austria). Bleeding events were classified according to ISTH criteria. RESULTS A total of 302 patients with NVAF and ESKD on hemodialysis were included. Among all patients, 192 (63.5%) were treated with Apixaban and 110 VKA. Mean FU was 14.8 and 12.5 months (DOAC vs VKA; p:0.53). Demographic characteristics are summarised in table 1. In Apixaban group, 100% of patients received reduce-dose, according to the care protocol established in our center and showed predictable pharmacokinetic, Ctrough (94.5- 180 μg/L) and Cmax (150-419 μg/L). In VKA group, Time in therapeutic range (international normalized ratio, 2.0-3.0) for Acenocumarol treated patients was 42% (interquartile range, 19%-60%). Stroke or systemic embolism occurred in three patients in the Apixaban group (1.04 %/year) and seven patients in the VKA group (7.2 %/year) [DOAC vs LMWH; p<0.05]. The apixaban group experienced fewer overall bleeding events than the VKA group (17.3% vs 39.7%; P = .01); this significant difference persisted in adjusted analysis (OR = 0.13; 95% CI = 0.04-0.42; P = .001). Major bleeding events were less frequent in the apixaban group compared with patients on VKA (4.7% vs 25%; P = .01). There were no significant differences regarding in all-cause mortality, 18.8% versus 21.5% respectively. CONCLUSIONS Compared to VKA, our findings suggest that low dose of apixaban is a safe and effective alternative in patients with AF and ESKD on hemodialysisis and low dose of apixaban showed predictable pharmacokinetic.

Standard FIX prophylaxis for PWHB require frequent injections, which has led to the development of extended half-life products like rIX-FP (albutrepenonacog alfa) that has shown good efficacy in clinical studies. This ambispective study aims to report a real-world experience with rIX-FP in a Spanish centre with PWHB who switched from SHL-FIX or began prophylaxis with rIX-FP. Five PWHB were included in this study, Four PTP switched to rIX-FP with prophylaxis every 7 days whilst one PUP started with an every-14-days regimen. 3 PTPs extended their dosing intervals to every 14 days or every 21 days. In all PTPs, median annualized spontaneous and joint bleeding rates were maintained at 0.00 and median (range) of ABR was 0.92 (0.00-2.77) after switch to rIX-FP. Mean trough level with previous product was 3.68% (SD = 2.06), while it was 7.08% (SD = 3) with all rIX-FP dosing intervals. After switching to rIX-FP, all PTP reduced their annual infusion rate between 50 and 84% and their annual FIX consumption by 61% (59-67%). This is the first reported real-world experience with albutrepenonacog alfa in a small cohort in Spain and demonstrates good bleeding control together with a reduction of the infusion rate, factor consumption and higher through factor level than previous treatment.

Introduction: Rare bleeding disorders (RBD) constitute 5% of total hereditary bleeding disorders, although the number could be higher, due to the presence of undiagnosed asymptomatic patients. The objective of this study was to analyze the prevalence and characteristics of patients with severe RBDs in our area.Material and methods: We analyzed the patients with RBD followed at a tertiary-level hospital between January 2014 and December 2021.Results: A total of 101 patients were analyzed, with a median age at diagnosis of 27.67 years (range 0-89), of which 52.47% were male. The most frequent RBD in our population was FVII deficiency. Regarding the diagnostic reason, the most frequent cause was a preoperative test and only 14.8% reported bleeding symptoms at the time of diagnosis. A genetic study was carried out in 63.36% of patients and the most frequent mutation type found was finding a missense mutation.Conclusions: The distribution of RBDs in our centre is similar to the one reported in the literature. The majority of RBDs were diagnosed from a preoperative test and this allowed preventive treatment prior to invasive procedures to avoid bleeding complications. 83% of patients did not have a pathological bleeding phenotype according to ISTH-BAT

Prophylaxis with emicizumab, a bispecific monoclonal antibody that mimics FVIII function, has shown encouraging results in clinical trials in terms of efficacy and safety. However, current experien...

Objective: Activated prothrombin complex concentrate (aPCC) is a bypassing agent indicated to treat bleeds in patients with acquired hemophilia A (AHA). Nevertheless, its efficacy and safety in the real‐world setting have not often been addressed.Methods: We report the experience of Spanish reference centers for coagulation disorders and from acquired hemophilia Spanish Registry (AHASR) from August 2012 to February 2021. Follow‐up period of 30 days after aPCC withdrawal.Results: Thirty patients with a median age of 70 years old, suffering from 51 bleeds treated with aPCC were finally evaluated. As first‐line treatment, aPCC stopped bleeding in 13 of 14 (92.9%) cases. aPCC as the second line after recombinant factor VIIa failure, stopped bleeding in all cases. In 17 patients, aPCC was used far from initial bleed control as prophylaxis of rebleeding with 94% effectiveness. No thromboembolic episodes were communicated. One patient developed hypofibrinogenemia, which did not prevent aPCC from halting bleeding. No other serious adverse events possibly or probably associated with aPCC were reported.Conclusions: This data support aPCC as hemostatic treatment in AHA with high effectiveness and excellent safety profile in acute bleeds and as extended use to prevent rebleedings, even in aging people with high cardiovascular risk.

Extended half‐life FIX (EHL‐FIX) concentrates have been developed with the purpose of reducing the frequency of infusions in patients with severe or moderate hemophilia B. We describe the case of a 63‐year‐old patient with severe hemophilia B (sHB) treated with FIX‐Fc fusion protein (rFIXFc) who underwent neurosurgery.